Drug-Induced Movement Disorders

Drug-Induced Movement Disorders edited by

Kapil D. Sethi Medical College of Georgia Augusta, Georgia, U.S.A.

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NEUROLOGICAL DISEASE AND THERAPY Advisory Board

Louis R. Caplan, M.D.

William C. Koller, M.D.

Professor of Neurology Harvard University School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

Mount Sinai School of Medicine New York, New York

John C. Morris, M.D.

Bruce Ransom, M.D., Ph.D.

Friedman Professor of Neurology Co-Director, Alzheimer's Disease Research Center Washington University School of Medicine St. Louis, Missouri

Warren Magnuson Professor Chair, Department of Neurology University of Washington School of Medicine Seattle, Washington

Kapil D. Sethi, M.D.

Mark Tuszynski, M.D., Ph.D.

Professor of Neurology Director, Movement Disorders Program Medical College of Georgia Augusta, Georgia

Associate Professor of Neurosciences Director, Center for Neural Repair University of California-San Diego La Jolla, California

1. Handbook of Parkinson's Disease, edited by William C. Koller 2. Medical Therapy of Acute Stroke, edited by Mark Fisher 3. Familial Alzheimer's Disease: Molecular Genetics and Clinical Perspectives, edited by Gary 0. Miner, Ralph W. Richter, John P. Blass, Jimmie L. Valentine, and Linda A. Winters-Miner 4. Alzheimer's Disease: Treatment and Long-Term Management, edited by Jeffrey L. Cummings and Bruce L. Miller 5. Therapy of Parkinson's Disease, edited by William C. Koller and George Paulson 6. Handbook of Sleep Disorders, edited by Michael J. Thopy 7. Epilepsy and Sudden Death, edited by Claire M. Lathers and Paul L. Schraeder 8. Handbook of Multiple Sclerosis, edited by Stuart D. Cook 9. Memory Disorders: Research and Clinical Practice, edited by Takehiko Yanagihara and Ronald C. Petersen 10. The Medical Treatment of Epilepsy, edited by Stanley R. Resor, Jr., and Henn Kutt 11. Cognitive Disorders: Pathophysiology and Treatment, edited by Leon J. Thal, Walter H. Moos, and Elkan R. Gamzu 12. Handbook of Amyotrophic Lateral Sclerosis, edited by Richard Alan Smith 13. Handbook of Parkinson's Disease: Second Edition, Revised and Expanded, edited by William C. Koller

14. Handbook of Pediatric Epilepsy, edited by Jerome V. Murphy and Fereydoun Dehkharghani 15. Handbook of Tourette's Syndrome and Related Tic and Behavioral Disorders, edited by Roger Kutlan 16. Handbook of Cerebellar Diseases, edited by Richard Lechtenberg 17. Handbook of Cerebrovascular Diseases, edited by Harold P. Adams, Jr. 18. Parkinsonian Syndromes, edited by Matthew 8. Stern and William C. Koller 19. Handbook of Head and Spine Trauma, edited by Jonathan Greenberg 20. Brain Tumors: A Comprehensive Text, edited by Robed A. Morantz and John W. Walsh 21. Monoamine Oxidase Inhibitors in Neurological Diseases, edited by Abraham Lieberman, C. Warren Olanow, Moussa 6 . H. Youdim, and Keith Tipton 22. Handbook of Dementing Illnesses, edited by John C. Morris 23. Handbook of Myasthenia Gravis and Myasthenic Syndromes, edited by Robed P. Lisak 24. Handbook of Neurorehabilitation,edited by David C. Good and James R. Couch, Jr. 25. Therapy with Botulinum Toxin, edited by Joseph Jankovic and Mark Hallett 26. Principles of Neurotoxicology,edited by Louis W. Chang 27. Handbook of Neurovirology, edited by Robed R. McKendall and William G. Stroop 28. Handbook of Neuro-Urology,edited by David N. Rushton 29. Handbook of Neuroepidemiology, edited by Philip B. Gorelick and Milton Alter 30. Handbook of Tremor Disorders, edited by Leslie J. Findley and William C. Koller 31. Neuro-Ophthalmological Disorders: Diagnostic Work-Up and Management, edited by Ronald J. Tusa and Steven A. Newman 32. Handbook of Olfaction and Gustation, edited by Richard L. Doty 33. Handbook of Neurological Speech and Language Disorders, edited by Howard S. Kirshner 34. Therapy of Parkinson's Disease: Second Edition, Revised and Expanded, edited by William C. Koller and George Paulson 35. Evaluation and Management of Gait Disorders, edited by Barney S. Spivack 36. Handbook of Neurotoxicology, edited by Louis W. Chang and Robed S. Dyer 37. Neurological Complicationsof Cancer, edited by Ronald G. Wiley 38. Handbook of Autonomic Nervous System Dysfunction, edited by Amos D. Korczyn 39. Handbook of Dystonia, edited by Joseph King Ching Tsui and Donald B. Calne 40. Etiology of Parkinson's Disease, edited by Jonas H. Ellenberg, William C. Koller, and J. William Langston

41. Practical Neurology of the Elderly, edited by Jacob 1. Sage and Margery H. Mark 42. Handbook of Muscle Disease, edited by Russell J. M. Lane 43. Handbook of Multiple Sclerosis: Second Edition, Revised and Expanded, edited by Stuart D. Cook 44. Central Nervous System Infectious Diseases and Therapy, edited by Karen L. Roos 45. Subarachnoid Hemorrhage: Clinical Management, edited by Takehiko Yanagihara, David G. Piepgras, and John L. D. Atkinson 46. Neurology Practice Guidelines, edited by Richard Lechtenberg and Henry S. Schutta 47. Spinal Cord Diseases: Diagnosis and Treatment, edited by Gordon L. Engler, Jonathan Cole, and W. Louis Merton 48. Management of Acute Stroke, edited by Ashfaq Shuaib and Larry B. Goldstein 49. Sleep Disorders and Neurological Disease, edited by Antonio Culebras 50. Handbook of Ataxia Disorders, edited by Thomas Klockgether 51. The Autonomic Nervous System in Health and Disease, David S. Goldstein 52. Axonal Regeneration in the Central Nervous System, edited by Nicholas A. lngoglia and Marion Murray 53. Handbook of Multiple Sclerosis: Third Edition, edited by Stuart 0. Cook 54. Long-Term Effects of Stroke, edited by Julien Bogousslavsky 55. Handbook of the Autonomic Nervous System in Health and Disease, edited by C. Liana Bolis, Julio Licinio, and Stefan0 Govoni 56. Dopamine Receptors and Transporters: Function, Imaging, and Clinical Implication, Second Edition, edited by Anita Sidhu, Marc Laruelle, and Philippe Vernier 57. Handbook of Olfaction and Gustation: Second Edition, Revised and Expanded, edited by Richard L. Doty 58. Handbook of Stereotactic and Functional Neurosurgery, edited by Michael Schulder 59. Handbook of Parkinson’s Disease: Third Edition, edited by Rajesh Pahwa, Kelly E. Lyons, and William C. Koller 60. Clinical Neurovirology, edited by Avindra Nath and Joseph R. Berger 61. Neuromuscular Junction Disorders: Diagnosis and Treatment, by Matthew N. Meriggioli, James F. Howard, Jr., and C. Michel Harper 62. Drug-Induced Movement Disorders, edited by Kapil D. Sethi

Additional Volumes in Preparation

Series Introduction

Drugs are an important cause of adverse reactions, and movement disorders are commonly induced by medications. This book divides movement disorders induced by drugs into four distinct categories: movement disorders due to dopamine-blocking drugs, mood-altering drugs, sympathomimetic drugs, and anticonvulsants and other drugs. Drug-induced movement disorders may be acute (e.g., acute dystonic reaction) or chronic (e.g., tardive syndromes), and it is important to recognize the various movement disorders caused by drugs. For the most part these drug-induced conditions are reversible with early recognition and discontinuation of the offending drug. This book is an excellent reference in providing the latest knowledge on drug-induced movement disorders. Neurologists, psychiatrists, and physicians using neuroactive drugs will find this book helpful in their clinical practice. William C. Koller

iii

Preface

A drug is a single chemical that forms the active ingredient of a medicine. Medicines may also contain other substances designed to deliver a drug in a stable, convenient form for the patient. Despite these differences in definition, the terms ‘‘drug’’ or ‘‘medicine’’ are usually used interchangeably in the medical world. While many drugs serve to benefit mankind, other drugs are addictive, harmful, or dangerous and have limited medical use. Most drugs are double-edged swords with potential to do both good and harm. The harm may be as trivial as a mild hangover from diazepam or life threatening as in cases of sudden death following an injection of penicillin. Somewhere in the middle are movement disorders induced by drugs. Drug-induced movement disorders are encountered by physicians in every discipline of medicine, but especially by psychiatrists and neurologists. The introduction of neuroleptics in the 1950s provides an early example of drugs that were soon associated with abnormal movements, both acutely and in a delayed (tardive) fashion. Subsequently, hyperkinetic movement disorders became a major clinical problem in advanced levodopa-treated Parkinson’s disease patients. In addition to these examples, many other classes of drugs commonly used by neurologists and psychiatrists have been associated with the drug-induced movement disorders. Despite a more sophisticated science of drug design v

vi

Preface

today, newer drugs are frequently associated with inducing movement disorders in susceptible patients. This book provides authoritative reviews on the subject of iatrogenic movement disorders. Experts in psychiatry and neurology have been enlisted to review movement disorders due to dopamine-blocking agents since these drugs remain in extensive use. Selective serotonin reuptake inhibitors (SSRIs), discussed in Chapter 11, are one of the most commonly prescribed drugs associated with abnormal movements. Movement disorders due to both older and newer antiepileptics are also discussed. Chapter 6 reviews therapeutic options for drug-induced movement disorders including botulinum toxin therapy and replacing conventional neuroleptics with newer, atypical agents. Chapter 9 discusses several new antipsychotics introduced recently and more are on the horizon. There is increasing understanding of the complex basal ganglia circuitry and Chapter 13 is devoted to this topic to better understand the pathophysiology of movement disorders. As new drugs are developed the spectrum of drug-induced movement disorders will undoubtedly widen. We hope that this volume will provide a platform for building further knowledge in the evaluation and treatment of patients with drug-induced movements. Kapil D. Sethi

Contents

Preface Contributors

Part One

v ix

Movement Disorders Due to Dopamine Blocking Agents

1. Movement Disorders, Phenomenology, and Differential Diagnosis Kapil D. Sethi

1

2. Movement Disorders in Unmedicated Schizophrenia David M. Barbenel and Thomas R. E. Barnes

15

3. The Epidemiology of Tardive Dyskinesia Siow-Ann Chong and Perminder S. Sachdev

37

4. Drug-Induced Parkinsonism K. Ray Chaudhuri and Joanna Nott

61 vii

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Contents

5. Clinical Features and Management of Classic Tardive Dyskinesia, Tardive Myoclonus, Tardive Tremor, and Tardive Tourettism Maria L. De Leon and Joseph Jankovic

77

6. Acute and Tardive Dystonia Mohit Bhatt, Kapil D. Sethi, and Kailash Bhatia

111

7. Acute and Tardive Drug-Induced Akathisia Perminder S. Sachdev

129

8. Neuroleptic Malignant Syndrome Joseph H. Friedman and Hubert H. Fernandez

165

9. New Approaches to the Treatment of Dopamine Blocking Agent-Induced Movement Disorders Sanjay Gupta Part Two

Movement Disorders Due to Drugs Used in Mood Disorders

10. Lithium-Induced Movement Disorders Stewart A. Factor 11. Movement Disorders Induced by Selective Serotonin Reuptake Inhibitors and Other Antidepressants Kersi J. Bharucha and Kapil D. Sethi Part Three

193

209

233

Movement Disorders Due to Sympathomimetic Drugs Including Levodopa

12. Involuntary Movements Caused by Levodopa Peter A. LeWitt and Dragos Mihaila 13. Pathophysiology of Levodopa and Dopamine Blocking Agent-Induced Movement Disorders Aninda B. Acharya, Cheryl A. Faber, Rajesh Pahwa, and Kapil D. Sethi 14. Stimulant-Induced Movement Disorders Juan Sanchez-Ramos

259

279

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Contents

Part Four

ix

Movement Disorders Due to Anticonvulsants and Miscellaneous Drugs

15. Antiepileptic Drug-Induced Movement Disorders Mark W. Kellett and David W. Chadwick

309

16. Other Drug-Induced Movement Disorders Gary Hotton and Chris Clough

357

Index

373

Contributors

Aninda B. Acharya, M.D. Department of Neurology, St. Louis University School of Medicine, St. Louis, Missouri, U.S.A. David M. Barbenel Department of Neuroscience and Psychological Medicine, Imperial College School of Medicine, London, England Thomas R. E. Barnes, M.D., F.R.C.Psych., D.Sc. Department of Neuroscience and Psychological Medicine, Imperial College School of Medicine, London, England. Kersi J. Bharucha, M.D. Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, U.S.A. Kailash Bhatia, M.D., F.R.C.P. Department of Movement Neuroscience, Institute of Neurology, London, England Mohit Bhatt, M.D., M.D., D.M. Department of Movement Disorders, Jaslok Hospital and Research Centre, Mumbai, India xi

xii

Contributors

David W. Chadwick, D.M., F.R.C.P. Department of Neurological Sciences, Liverpool University, Liverpool, England. K. Ray Chaudhuri, M.D., F.R.C.P. Department of Neurology, King’s College Hospital and University Hospital, Lewisham, London, England Siow-Ann Chong, M.B.B.S., M.Med.Psych., F.A.M.S. Department of Psychological Medicine, Woodbridge Hospital and Institute of Mental Health, Singapore Chris Clough King’s College Hospital, London, England Maria L. De Leon, M.D. Department of Neurology, De Leon Neurological Clinic, Nacogdoches, Texas, U.S.A. Cheryl A. Faber, M.D. Department of Neurology, Neurology Associates, St. Louis, Missouri, U.S.A. Stewart A. Factor, D.O. Department of Neurology, Albany Medical Center, Albany, New York, U.S.A. Hubert H. Fernandez, M.D. U.S.A.

University of Florida, Gainesville, Florida,

Joseph H. Friedman, M.D. Department of Neuroscience, Brown University School of Medicine, Providence, Rhode Island, U.S.A. Sanjay Gupta Olean General Hospital, Olean, and University of Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, U.S.A. Gary Hotton King’s College Hospital, London, England Joseph Jankovic, M.D. Department of Neurology, Baylor College of Medicine, Houston, Texas, U.S.A. Mark W. Kellett, M.R.C.P.

Hope Hospital, Salford, England

Peter A. LeWitt, M.D. Department of Neurology, Wayne State University School of Medicine, Southfield, Michigan, U.S.A. Dragos Mihaila, M.D. Henry Ford Hospital, Detroit, Michigan, U.S.A.

Contributors

xiii

Joanna Nott Guy’s King’s and St. Thomas’s School of Medicine and King’s College, London, England Rajesh Pahwa, M.D. Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, U.S.A. Perminder S. Sachdev, M.D., Ph.D., F.R.A.N.Z.C.P. Department of Psychiatry, University of New South Wales, Sydney, and The Prince of Wales Hospital, Randwick, New South Wales, Australia Juan Sanchez-Ramos, M.D., Ph.D. Department of Neurology, University of South Florida College of Medicine, Tampa, Florida, U.S.A. Kapil D. Sethi, M.D., F.R.C.P. Department of Neurology, Medical College of Georgia, Augusta, Georgia, U.S.A.

1 Movement Disorders, Phenomenology, and Differential Diagnosis Kapil D. Sethi Medical College of Georgia Augusta, Georgia, U.S.A.

INTRODUCTION Movement disorders may manifest either by slowness and poverty of movement (hypokinesias), or by excessive, abnormal involuntary movements, i.e., hyperkinesias [1,2]. The hypokinetic group may also be termed parkinsonism, and Parkinson’s disease is the best example of a hypokinetic movement disorder. Hyperkinetic movement disorders include tremors, dystonia, ballism, chorea, athetosis, tics, myoclonus, and stereotypies. Table 1 lists the different movement disorders. Most movement disorders lack a distinctive biomarker; therefore the diagnosis and the differential diagnosis of movement disorders is primarily clinical, made on the basis of a detailed history and a careful neurological examination. The examination of patients with movement disorders requires observations that are usually not included in the standard neurological examination. The first step in the diagnosis is to define the phenomenology and to classify the movement disorder into one of the known categories. Abnormal movement must be considered a clinical sign for which there are many causes. Movement disorders may be ‘‘primary’’ (idiopathic) or ‘‘secondary’’ (symptomatic) disorders. When one 1

2

Sethi

TABLE 1 List of Movement Disorders A. Hypokinesias 1. Parkinson’s disease 2. Symptomatic parkinsonism 3. Atypical parkinsonism B. Hyperkinesias (in alphabetical order) 1. Akathisia 9. Myoclonus 2. Ataxia 10. Moving toes/fingers 3. Athetosis 11. Paroxysmal dyskinesias 4. Ballism 12. Restless legs syndrome (Ekbom’s syndrome) 5. Chorea 13. Stereotypies 6. Dystonia 14. Stiff muscles 7. Hemifacial spasm 15. Tics 8. Hyperekplexia 16. Tremor

considers the presence of a drug-induced movement disorder (DIMD), the history is of critical importance, because the DIMD can resemble any of the known idiopathic movement disorders. Often the presence of multiple different movement disorders in the same individual indicates DIMD. BALLISM Ballism, meaning ‘‘to throw’’ in Greek, refers to violent, irregular flinging movements of the limbs, due primarily to contractions of the proximal muscles. Although irregular, these movements are not as unpredictable as the movements of chorea. ‘‘Hemiballism’’ refers to movements involving upper and lower extremities on the same side with or without involvement of the face. ‘‘Monoballism’’ refers to ballism confined to one extremity. Paraballism is a term given to ballism affecting the lower extremities, and bilateral ballism refers to ballism affecting both sides of the body [3]. The most common form of ballism seen in clinical practice is hemiballism. Causes of ballism are listed in Table 2, and Table 3 lists the causes of biballism. CHOREA Chorea (Table 4) consists of irregular, nonrepetitive, brief, jerky, flowing movements that move randomly from one part of the body to another. The movements are brisk and abrupt in some cases (e.g., Sydenham’s chorea). In other disorders they are slower and more flowing (e.g., Huntington’s disease) [4]. The term ‘‘choreoathetosis’’ has been used in this situation, where chorea may be combined with features of dystonia and athetosis.

Movement Disorders, Phenomenology, and Differential Diagnosis

3

TABLE 2 Causes of Ballism A. Hemiballism 1. Vascular causes a. Infarction affecting the subthalamic nucleus or its connections b. Transient vascular insufficiency involving anterior circulation or the posterior circulation c. Arteriovenous malformation d. Venous angioma e. Subdural hematoma 2. Brain tumors a. Primary, i.e., cystic gliomas and other cysts b. Metastatic brain tumors 3. Infectious and postinfectious diseases a. Tuberculous meningitis with or without tuberculoma b. Sydenham’s chorea c. AIDS with cerebral toxoplasmosis d. Cysticercosis 4. Autoimmune disorders a. Systemic lupus erythematosus 5. Iatrogenic a. Oral contraceptives b. Surgical complication of stereotactic thalamotomy and pallidotomy c. Transiently in deep brain stimulation of subthalamic area in Parkinson’s disease 6. Metabolic causes a. Hyperglycemia 7. Degenerative diseases a. Multiple systems atrophy b. Tuberous sclerosis 8. Miscellaneous a. Multiple sclerosis b. Head trauma

It is generally accepted that ballism and chorea reflect a continuum of the same disorder [3]. These may coexist in the same patient, or ballism may evolve into chorea or dystonia. There is an overlap between chorea and ballism with regard to etiology, pathogenesis, and treatment. DYSTONIA Dystonia (Table 5) is a syndrome characterized by sustained patterned muscle contractions that frequently cause twisting and repetitive movements and/or ab-

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TABLE 3 Causes of Bilateral Ballism Bilateral striatal hemorrhagic infarctions Multiple sclerosis Phenytoin intoxication Oral contraceptives Intravascular dissemination of cancer Systemic lupus erythematosus Ventriculoperitoneal shunting Nonketotic hyperglycemia L-dopa-induced dyskinesia in Parkinson’s disease

normal postures [5,6]. Dystonic movements are often slow and twisting but may be quite rapid. Prolonged dystonic movements may result in abnormal posturing that can become fixed as the disorder advances. Dystonia may also result in rhythmical movements that worsen on the patient’s attempts to resist involuntary dystonic movements. This dystonic tremor usually improves when the patient is asked to relax and not fight the abnormal movements. This variability in the dystonic movements is responsible for frequent misdiagnosis. Another curious phenomenon that is seen in dystonia is the presence of ‘‘sensory tricks’’ (geste antagonistque). These are learned tricks performed by the patient in an attempt to diminish the severity of abnormal movements. Examples of sensory tricks include touching the chin in cases of cervical dystonia and gently pulling the upper eyelid in blepharospasm. These sensory tricks may be observed in idiopathic as well as secondary dystonias such as tardive dystonia. These patients may be labeled ‘‘psychogenic.’’ Dystonia of one region, i.e., craniocervical, may be accompanied by postural and action tremor of the upper limbs that is very similar to essential tremor. Early on, dystonia, especially idiopathic dystonia, may only be present on certain activities. This is called ‘‘action dystonia.’’ If the dystonia starts as a fixed posture, one should suspect secondary dystonia. The most frequent type of dystonia is adult-onset focal dystonia. The craniocervical region is the most affected in adult-onset focal dystonia. Spasmodic dysphonia is a focal dystonia involving the larynx. It may result in a choking voice (adductor dysphonia) or a whispering voice (abductor dysphonia). Other focal dystonias include focal limb dystonia, including dystonic writer’s cramp. TICS Tics are abrupt, complex, stereotypic, and coordinated movements. A characteristic feature is the feeling by the patient of an inner urge to execute the movement.

Movement Disorders, Phenomenology, and Differential Diagnosis

5

TABLE 4 Etiological Classification of Chorea 1. Developmental choreas a. Physiological chorea of infancy 2. Cerebral palsy—anoxic, kernicterus 3. Hereditary choreas a. Huntington’s disease b. Benign hereditary chorea c. Neuroacanthocytosis d. Spinocerbellar ataxias e. Ataxia telangiectasia f. Tuberous sclerosis g. Hallervorden-Spatz syndrome h. Dentato-rubral-pallido-luysian atrophy (DRPLA), familial calcification of basal ganglia 4. Metabolic disorders a. Wilson’s disease b. Mitichondrial disease, e.g., Leigh’s disease c. Porphyria d. Aminoacidopathies (propionic academia) 5. Drug-induced chorea a. Dopamine–blocking agents b. Antiparkinsonian drugs c. Anticonvulsants d. Amphetamines, cocaine e. Tricyclics f. Oral contraceptives g. Anticholinergics h. Lithium i. Digoxin 6. Systemic metabolic disorders a. Hyperthyroidism b. Hypoparthyroidism c. Chorea gravidarum d. Hyper–and hyponatremia e. Hypomagnesemia, hypocalcemia f. Hypoglycemia g. Hyperglycemia h. Acquired hepatocerebral degeneration i. Polycythemia rubra vera 7. Infectious and postinfectious diseases a. Sydenham’s chorea b. Tuberculous meningitis c. AIDS (Continues)

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TABLE 4 Continued 8. Immunological a. Systemic lupus erythematosus (SLE) and the primary antiphospholipid syndrome 9. Vascular (often hemichorea) a. Infarction b. Hemorrhage c. AVM 10. Tumors 11. Trauma—including subdural and epidural hematoma

This urge builds up with attempts at stopping the movement and is relieved upon the execution of the movement. Children may be unable to express the urge clearly. Voluntary suppression is not restricted to tics, and several other types of abnormal movements may be suppressed for varying periods of time. Tics often fluctuate over time. The tics are often brief and jerky (clonic), however slower, more prolonged movements (tonic or dystonic) may occur. A simple tic may be stable over time. Some patients may demonstrate a wide array of simple and complex motor or vocal tics as well as a number of associated behavioral symptoms including hyperactivity, attention deficit disorder, and obsessive-compulsive disorder. This is termed Tourette’s syndrome. Tics are often familial and idiopathic, but secondary causes of tics include encephalitis and the administration of dopamine-blocking agents (DBA) [7]. MYOCLONUS Myoclonus refers to sudden, brief, shocklike involuntary movements caused by muscular contraction (positive myoclonus) or inhibitions (negative myoclonus, asterixis). Myoclonus can be classified according to the distribution, i.e., focal, multifocal, or generalized. It can also be classified according to the source of electrical discharge or according to etiology [8]. Myoclonic jerks vary in severity and can range from mild muscular contractions that are too weak to cause visible movement to gross jerks that affect the whole body. Myoclonus may be symmetrical or asymmetrical. The jerks usually appear to be synchronous to the naked eye, but asynchronous jerking is also seen. A characteristic feature of myoclonus is its stimulus and action sensitivity. Sudden and unexpected noise, bright lights, or muscle stretch can trigger a myoclonic jerk. The jerks may be present at rest or triggered or aggravated by attempts to perform fine movements, especially goal-directed movements (action or inten-

Movement Disorders, Phenomenology, and Differential Diagnosis

7

TABLE 5 Etiological Classification of Dystonia I. Primary dystonia A. Sporadic—usually adult–onset focal dystonia B. Inherited 1. Autosomal dominant a. Classic (Oppenheim’s) dystonia (DYT 1) b. Dopa-responsive dystonia (DRD) c. Dystonia-myoclonus (alcohol-responsive) 2. Autosomal recessive a. Tyrosine hydroxylase deficiency b. Aromatic amino acid decarboxylase deficiency II. Heredogenerative diseases A. X-linked recessive 1. Lubag (X-linked dystonia-parkinsonism) B. Autosomal dominant 1. Rapid-onset dystonia-parkinsonism 2. Huntington’s disease 3. Spinocerebellar degenerations 4. Dentato-rubral-pallidoluysian atrophy 5. Hereditary spastic paraplegia with dystonia C. Autosomal recessive 1. Wilson’s disease 2. Neurodegeneration with brain iron accumulation type 1 (HallervordenSpatz syndrome) pank 2 associated neurodegeneration 3. Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome) 4. Aceruloplasminemia 5. Ataxia telangiectasia III. Associated with metabolic disorders A. Amino acid disorders 1. Glutaric acidemia B. Lipid disorders 1. Metachromatic leukodystrophy 2. Niemann-Pick type C 3. Hexosaminidase A and B deficiency C. Other metabolic disorders 1. Neuroacanthocytosis 2. Rett syndrome D. Mitochondrial 1. Leigh’s disease (Continues)

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TABLE 5 Continued IV. Due to a known specific cause A. Perinatal cerebral injury and kernicterus: athetoid cerebral palsy, delayedonset dystonia B. Infection: viral encephalitis, encephalitis lethargica, subacute sclerosing, panencephalitis, Jakob-Creutzfeldt disease, HIV infection C. Drugs: levodopa and dopamine agonists, dopamine receptor-blocking drugs (tardive dystonia), anticonvulsants, ergots D. Toxins: MN, CO E. Metabolic: hypoparathyroidism F. Paraneoplastic brainstem encephalitis G. Stroke H. Multiple sclerosis I. Head trauma and brain surgery (thalamotomy) J. Peripheral trauma (with causalgia) K. Electrical injury V. Psychogenic

tion myoclonus). Myoclonus may be rhythmic, in which case it is usually due to a focal lesion of the brainstem or the spinal cord. More typically, it is arrhythmic. Nocturnal myoclonus, originally described by Symonds, is characterized by movements of long duration. These movements are not myoclonic jerks and should be called periodic movements in sleep (PLMS, see restless legs syndrome). Focal myoclonus involves a small group of muscles. It may be rhythmic or arrythmic. In cortical myoclonus, the jerks are usually more distal than proximal and more flexor than extensor. Cortical myoclonus is often stimulus-sensitive. Epilepsia partialis continua (EPC) refers to repetitive focal cortical myoclonus with some rhythmicity. EPC can last for months, and the movements tend to persist during sleep. Most other involuntary movements, with the exception of palatal myoclonus, hemifacial spasm, and PLMS, disappear during sleep. Cortical myoclonus is frequently multifocal rather than focal. Palatal myoclonus refers to a rhythmic 2- to 3-Hz myoclonus affecting the muscles of the palate and pharynx. In some patients, the movements may resemble tremor; however, in most, they have a jerky component and are appropriately termed myoclonus. Palatal myoclonus is usually continuous and independent of rest, action, sleep, or distraction. There may be an associated rhythmic clicking noise that is more likely to occur in cases of essential palatal myoclonus as compared to symptomatic palatal myoclonus. Palatal myoclonus may occcur unilaterally or bilaterally and results in 1.5to 3-Hz movements that may also involve other muscles, including those of the

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eye, tongue, neck, and diaphragm. When these movements affect the extremities, they resemble a slow tremor with a rate less than 4 Hz (myorhythmia). The extremity myorhythmia is not necessarily synchronous with the palatal movements. STEREOTYPIES Stereotypy is defined as a simple or complex repetitive movement that is continual. The stereotypies are often seen in patients with schizophrenia and mental retardation, including autism [9]. Motor tics have often been considered to be stereotypic, but these abnormal movements almost always occur intermittently and not continuously, i.e., they occur paroxysmally out of a background of normal motor behavior. Moreover, each tic is not necessarily a repetition of the previous tic movement. Thus, tics are usually not repetitive from one burst to the next. Stereotypy is the hallmark of abnormal movements in patients with classical tardive dyskinesia that results from DBA. TREMOR Tremor can be defined as roughly sinusoidal and approximately rhythmic oscillation of a body part around a joint. Tremor is usually subdivided on the basis of the motor behavior in which it occurs [10]. A rest tremor is seen when the body part is in complete repose. Tremor of the forearms while standing is also a form of rest tremor. Maintaining a posture such as extending the arms reveals a postural tremor, while moving the body part brings out a kinetic tremor. A type of tremor that occurs maximally at the end of a goal-directed movement is called terminal kinetic or an intention tremor. This frequently occurs in cerebellar disease. Occasionally, a tremor is seen only with certain specific actions or limb positions. ‘‘Primary writing tremor’’ is the most common example of a task-specific tremor. Orthostatic tremor is a position-specific tremor that occurs in the proximal lower limbs and trunk upon standing. It is characterized by a very high frequency. Table 6 summarizes different types of tremors, and Table 7 lists the causes. PAROXYSMAL DYSKINESIAS Paroxysmal dyskinesias are a heterogenous group of disorders that have in common the occurrence of sudden abnormal involuntary movements out of a background of normal motor behavior [11]. The abnormal movements may be choreic, ballistic, dystonic, or a combination of these. Frequently the attacks are unwitnessed by the physician, and he or she has to rely on the description given by the untrained onlooker. Misdiagnoses are common in this setting, and it is fairly common for these patients to be labeled psychogenic. Because of the absence of

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TABLE 6 Classification of Tremor by Clinical Features 1. Rest tremor: Occurs when the muscles are not activated voluntarily, and the body part is supported against gravity 2. Postural tremor: Present while voluntarily maintaining a position against gravity 3. Kinetic tremor: Present during any form of voluntary movement; may be present throughout the movement or worse as the body part approaches the target (terminal kinetic tremor: intention tremor) 4. Task-specific tremor: Kinetic tremor that appears during performance of specific and skilled movements such as writing, speaking, or smiling

videotape documentation in most of these patients, it is not useful to use precise terms such as paroxysmal chorea or paroxysmal dystonia, and the term paroxysmal dyskinesia is preferred. Table 8 summarizes the clinical features of paroxysmal dyskinesias. RESTLESS LEGS SYNDROME Restless legs syndrome (RLS) is characterized by uncomfortable feelings in the legs (less often in the arms), including creeping or crawling, aching, ‘‘pulling,’’ heaviness, tension, burning, or coldness. Patients often find it hard to describe these abnormal feelings. These complaints are usually experienced when sitting and especially while lying down at night. Patients often have to get up and walk in order to relieve these abnormal sensations. RLS is commonly associated with insomnia and periodic limb movements of sleep (previously called ‘‘nocturnal myoclonus’’) [12,13]. These periodic, slow, sustained (1–2 sec) movements result in synchronous to asynchronous dorsiflexion of the big toes and feet to triple flexion of one or both legs. More rapid myoclonic movements of the feet and legs may be present in these patients while awake. RLS may be idiopathic (in some cases inherited) or secondary to uremia, pregnancy, and peripheral neuropathy. The differentiation between RLS and akathisia may be difficult. The patients with akathisia often pace in place that is not a feature of RLS. Moreover, the symptoms of RLS are often worst at night. HEMIFACIAL SPASM Hemifacial spasm results in irregular tonic and clonic contractions involving the muscles on one side of the face innervated by the seventh cranial nerve. Eyelid twitching usually is followed by lower facial muscle involvement. In rare cases

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TABLE 7 Differential Diagnosis of Tremors I. Rest tremors A. Parkinson’s disease 1. Drug-induced parkinsonism 2. Other parkinsonian syndromes (multi-infarct parkinsonism, multiple system atrophy, dementia with Lewy bodies) II. Postural and action tremors A. Physiological tremor (hard to see with naked eye) B. Exaggerated physiological tremor 1. Stress, fatigue, anxiety, hypoglycemia, thyrotoxicosis, pheochromocytoma 2. Drugs: bronchodilators, amphetamines, lithium, tricyclics, SSRIs, caffeine, valproic acid, alcohol withdrawal, steroids and cyclosporine; rarely, statins C. Essential tremor (familial or sporadic) D. Other causes 1. Parkinson’s disease (rest tremor more obvious) 2. Peripheral neuropathy, inherited and acquired 3. Cerebellar tremor—most often terminal kinetic (intention tremor) III. Kinetic tremor A. Cerebellar disorders, especially affecting the outflow; disorders include multiple sclerosis, head trauma, strokes, tumor, and inherited disorders B. Wilson’s disease (may cause complex tremors, classic being wing-beating tremor) C. Holmes tremor (midbrain or “rubral” tremor, myorhythmia)—kinetic ⬎ postural ⬎ rest D. Psychogenic tremor (often present at rest and persists in action and has a kinetic component, often distractable) IV. Miscellaneous rhythmic movement disorders A. Rhythmic movements in dystonia (dystonic tremor) B. Rhythmic myoclonus (segmental myoclonus—e.g., palatal or branchial myoclonus, spinal myoclonus, extremity myorhythmia in association with palatal myoclonus)

of bilateral involvement, the spasms are asynchronous on the two sides, in contrast to blepharospasm. Also, a cardinal feature of hemifacial spasm is the presence of synkinesia between the orbicularis oculi and lower facial muscles that may be demonstrated clinically and electrophysiologically. Hemifacial spasm is the bestrecognized ‘‘peripheral movement disorder,’’ others being giant fasciculations (usually moving the fingers), myokymia, and painful legs, moving toes syndrome.

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TABLE 8 Clinical Features of Paroxysmal Kinesigenic Dyskinesia (PKD), Paroxysmal Nonkinesigenic Dyskinesia (PNKD), Paroxysmal Exertional Dyskinesia (PED), and Paroxysmal Hypnogenic Dyskinesia (PHD) Feature Inheritance

PKD

PNKD

PED

Autosomal dominant or sporadic 4:1

Autosomal dominant or sporadic 1 : 5:1

Autosomal dominant

Age at onset Attacks Duration

⬍1 yr–40 yrs

⬍1 yr–30 yrs

2 yrs–20 yrs

⬍5 min

2 min–4 hr

5–30 min

Frequency Trigger

100/day to 1/mo Sudden movement, startle, hyperventilation Stress

3/day–2/yr Nil

1/day–2/mo Prolonged ex vibration, pas movement, co Stress

Male:female

Precipitant Treatment

Anticonvulsants, acetazolamide

Alcohol, stress, caffeine, fatigue Clonazepam, oxazepam

2:5

Levodopa

PHD Autosomal dominant or sporadic Short 20–50 sec, long 5–30 mins 10–40 yrs Short 20–50 sec, long 5–30 mins 5/night-2–3 yr NREM sleep

Stress menses Anticonvulsants acetazolamide

STIFF MUSCLES Stiff-person syndrome refers to a condition in which the skeletal muscles are continuously contracting isometrically, resembling ‘‘chronic tetanus’’ [14]. This is in contrast to dystonic movements that produce abnormal twisting movements and postures. The contractions of stiff-person syndrome are usually forceful and painful and most frequently involve the trunk musculature, especially the extensors. The limbs may also be involved. Electromyography shows continuous motor unit activity resembling voluntary contraction. This disorder has now been recognized to be an autoimmune disease, with circulating antibodies against the glutamic acid decarboxylase (GAD) [14]. Diabetes is often present. This condition may be a paraneoplastic complication in patients with breast and lung cancer. Other disorders leading to stiff muscles include myotonia and the syndrome of continuous muscle fiber activity (Isacc’s syndrome). PAINFUL LEGS, MOVING TOES The painful legs, moving toes syndrome refers to a disorder in which the toes of one foot are in continual flexion-extension with some lateral motion, associated with pain in the ipsilateral leg [15]. The constant movement has a sinusoidal

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quality. The movements are continual and occur even during sleep, though they are reduced. The normal sleep pattern is altered, and patients complain that the pain persists during sleep. The leg pain is much more of a problem than the constant movements. Most patients have lesions in the peripheral nervous system, including lesions in the lumbar roots or in the peripheral nerves. An analogous disorder, ‘‘painful arm, moving fingers,’’ has also been described [16]. REFERENCES 1. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco, NY: Futura, 1989. 2. Lang AE. Movement disorder symptomatology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD, Eds. Neurology in Clinical Practice. Boston: ButterworthHeinemann, 1996:299–320. 3. Buruma OJS, Lakke JPWF. Ballism. In: Vinken PJ, Bruyn GW, Klawans HL, Eds. Handbook of Clinical Neurology. Extrapyramidal Disorders. Vol. Volume 49. Amsterdam: Elsevier Science, 1986:369–380. 4. Jankovic J. International classification of diseases. Tenth revision: Neurological adaptation (ICD-10 NA) extrapyramidal and movement disorders. Move Disord 1995; 10:533–540a. 5. Fahn S. Clinical variants of idiopathic torsion dystonia. J Neurol Neurosurg Psychiatry Special Suppl 1989:96–100. 6. Fahn S, Bressman S, Marsden CD. Classification of dystonia. Adv Neurol 1998; 78: 1–10. 7. Bharucha KJ, Sethi KD. Tardive Tourettism after exposure to neuroleptic therapy. Move Disord 1995; 10(6):791–793. 8. Fahn S, Marsden CD, Van Woert MH. Definition and classification of myoclonus. Adv Neurol 1986; 43:1–5. 9. Jankovic J. Stereotypies. In: Marsden CD, Fahn S, Eds. Movement Disorders—3. Butterworth-Heinemann, 1994:503–517. 10. Deuschl G, Bain P, Brin M. Ad Hoc Scientific Committee. Consensus statement of the Movement Disorder Society on tremor. Move Disord 1998; 13(suppl 3):2–23. 11. Sethi KD. Paroxysmal dyskinesias. Neurologist 2000; 3:177–185. 12. Coleman RM, Pollak CP, Weitzman ED. Periodic movements in sleep (nocturnal myoclonus: Relation to sleep disorders. Ann Neurol 1980; 8:416–421. 13. Hening W, Walters A, Kavey N, Gidro-Frank S, Cote LJ, Fahn S. Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: Treatment with opioids. Neurology 1986; 36:1363–1366. 14. Blum P, Jankovic J. Stiff-person syndrome: An autoimmune disease. Move Disord 1991; 6:12–20. 15. Montagna P, Cirignotta F, Sacquegna T, Martinelli P, Ambrosetto G, Lugaresi E. ‘‘Painful legs and moving toes’’ associated with polyneuropathy. J Neurol Neurosurg Psychiatry 1983; 46:399–403. 16. Verhagen WIM, Horstink MWIM, Notermans SLH. Painful arm and moving fingers. J Neurol Neurosurg Psychiatry 1985; 48:384–389.

2 Movement Disorders in Unmedicated Schizophrenia David M. Barbenel and Thomas R. E. Barnes Imperial College School of Medicine London, England

INTRODUCTION The introduction of antipsychotic medication in the 1950s transformed the practice of psychiatry. The routine use of such agents in clinical practice heralded an improvement in prognosis and opportunities for treatment outside asylums for many patients with psychotic illness. However, it was soon apparent that, in addition to having beneficial sedative and antipsychotic effects, these agents were associated with movement disorders. Several extrapyramidal motor syndromes were identified, specifically acute dystonia, parkinsonism, akathisia, and tardive dyskinesia. As clinical awareness of tardive dyskinesia grew, so too did medico-legal concerns about the condition, particularly in the United States. These factors stimulated widespread research activity into tardive dyskinesia, which peaked in the late 1970s and early 1980s. However, at the same time, the assumed role of antipsychotic drugs in the development of the condition was being challenged. The controversy centered on whether the abnormal involuntary movements seen in tardive dyskinesia were identical to those that had been observed in patients who suffered from schizophrenia prior to the introduction of antipsychotic medi15

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cation. The epidemiological validity of the concept of tardive dyskinesia as a condition that could be produced or provoked by antipsychotic drugs could not really be denied. Nevertheless, it was asserted that the movements of tardive dyskinesia were similar to, if not indistinguishable from, motor disturbances described in psychotic patients in the preneuroleptic era, and therefore represented intrinsic motor features of the schizophrenic illness [1,2]. Such a view was countered by other authors [3,4], who judged that the latter motor phenomena were different in character from those of tardive dyskinesia. They suggested that the historical reports that referred to motor disturbance in people with schizophrenia before the advent of antipsychotic drugs required careful interpretation. Their argument was that the terminology used to describe these spontaneous movements had been inconsistent, reflecting the various notions of the origin of the motor phenomena being observed [4,5]. Further, the patient population may have included individuals with intracranial infections such as encephalitis lethargica and syphilis, and those suffering from spontaneous movement disorders such as Huntington’s disease or Wilson’s disease—conditions that may have psychiatric manifestations as well [4,6,7]. This debate reawakened the idea of schizophrenia as a psychomotor disorder, and spurred studies in drug-naı¨ve patients with schizophrenia. Subsequently, systematic studies have applied standardized tools to matched groups of medicated and unmedicated patients suffering from schizophrenia. These studies have helped to establish the presence of abnormal involuntary movements of the type seen in tardive dyskinesia in patients whose psychotic illness is untreated. In this chapter, we discuss accounts of movement disorder observed in patients prior to the ‘‘neuroleptic era’’ and review the published studies examining the relative prevalence of movement disorder in the healthy population and those suffering from schizophrenia, both unmedicated and those treated with antipsychotic agents. The methodological difficulties in such investigations are highlighted and tentative conclusions are drawn about the relative contributions of the aging process, drug exposure, and the illness itself to the development of movement disorder. MOVEMENT DISORDER IN THE PRE-NEUROLEPTIC ERA As described above, the introduction of antipsychotic agents into widespread clinical practice raised concerns about the risks of iatrogenic movement disorders, which may have diverted attention from the contribution of the schizophrenic illness itself to the development of abnormal involuntary movements. This situation was challenged by the findings of a study by Owens et al. [8] in the United Kingdom. Significant motor disorder was identified in a small number of patients who had never been exposed to neuroleptic medication, despite having spent many years in a psychiatric hospital. However, this proved to be a unique study,

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as the use of antipsychotic medication in the treatment of schizophrenia had become so universal that such a patient sample was an extreme rarity. At that time, the relative paucity of methodologically sound studies investigating movement disorders in drug-naive patients meant that clinical records and reports written before the 1950s remained the primary sources of information about the range of motor phenomena exhibited by patients with unmedicated schizophrenia. However, anyone attempting to distill relevant information on movement disorder from historical sources faces several problems. A key difficulty relates to the interpretation of the terms used. Diagnostic criteria, etiological theories, and the classification of motor phenomena have all changed dramatically since the texts were written. The descriptions often incorporate a variety of apparently related phenomena, which from a contemporary viewpoint may appear quite disparate. Individual authors possibly used different terminology when referring to the same phenomena, or may have applied subtle variations of meaning to the same term, a particular issue when translations of original texts are studied.

THE ‘‘CONFLICT OF PARADIGMS’’ Phenomenological descriptions are inevitably colored by the particular theoretical viewpoint of the writer. A persistent dilemma was whether a ‘‘neurological’’ or ‘‘psychological’’ causation could best be ascribed to the complex variety of motor phenomena observed in patients with schizophrenia. This issue is succinctly expressed in Jaspers’ statement [9]: ‘‘Somewhere between the neurological phenomena, seen as disturbances of the motor-apparatus, and the psychological phenomena, seen as sequelae of psychic abnormality with the motor-apparatus intact, lie the psychotic motor-phenomena, which we register without being able to comprehend them satisfactorily one way or the other.’’ This ‘‘conflict of paradigms’’ was resolved in various ways by different authors. For example, Bleuler [10] did not regard movement disorders as fundamental symptoms of schizophrenia, emphasizing that ‘‘the patients are quite nimble; the psychomotor aspect of speech reveals nothing abnormal . . . even delicate and refined movements such as violin-playing do not appear to be disturbed.’’ While he did acknowledge unequivocally that patients with schizophrenia exhibited motor abnormalities, these were viewed as secondary to other disturbance of thought and emotion, and therefore classified as ‘‘accessory’’ symptoms. The impact of this ‘‘conflict of paradigms’’ on the observation and theoretical understanding of movement disorder in schizophrenia has been discussed in detail by Rogers [5]. For the purpose of this account, however, its significance is that the intended meaning of a particular description is often available only through reference to its context. There is a danger that selective quotation from historical texts can be used to provide spurious support for a particular contempo-

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rary viewpoint, especially if ambiguities in the use of terms in original texts and the essentially subjective nature of interpretation of source material are not acknowledged. In this chapter, some bias in the selection of material may have been unavoidable, but we have sought to reduce its impact by providing an adequate degree of contextual detail. An attempt has been made to categorize abnormal phenomena along currently recognized lines. However, such categorization is inherently problematic and rather arbitrary in nature. It should be understood merely as a convenient method of grouping together descriptive accounts of phenomena that appear to share some clinical features, rather than taken to imply any etiological or neuropathological specificity.

HISTORICAL ACCOUNTS OF SPONTANEOUS MOVEMENT DISORDER In the first half of the last century, a broad range of abnormal motor phenomena was observed in patients diagnosed as suffering from dementia praecox or schizophrenia. These included oral and perioral movements, nystagmus, tremors, incoordination, choreiform movements, and more localized motor abnormalities, as well as epileptiform phenomena (see Table 1). In addition, a range of motor disturbance was subsumed under the term ‘‘catatonia,’’ which held for different authors a variety of meanings and theoretical implications.

ORAL AND PERIORAL MOVEMENTS Several authors noted abnormal facial and perioral movements. The descriptions seem to imply a differentiation of the movements into two main groups according to whether they were either similar to the range of normal facial expression, or appeared spasmodic and involuntary. Kraepelin’s descriptions provide an indication of the character of these phenomena: ‘‘Some of them resemble movements of expression, wrinkling of the forehead, distortion of the corners of the mouth, irregular movements of the tongue and lips, twisting of the eyes, opening them wide, and shutting them tight, in short those movements which we bring together under the name of ‘making faces’ or grimacing’’ [11]. Distinct from these ‘‘grimaces’’ and ‘‘grotesque gestures which have long been regarded as characteristics of madness’’ [9] were phenomena which appeared more clearly involuntary in nature. Kraepelin’s descriptions of ‘‘mannerisms accompanying speech’’ suggest spasmodic activity, affecting several muscle groups, unrelated to the normal range of facial expression. These included ‘‘wrinkling of the eyes, senseless shaking and nodding of the head and drawing of the muscles of expression . . . loud hawking and grunting . . . with smacking movements of the lips, the face . . . distorted by spasmodic grinning.’’

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TABLE 1 Motor Phenomena Described in Psychiatric Patients in the Preneuroleptic Era Phenomenon Oral and perioral movements that resembled normal facial expression Involuntary oral and perioral movements

Choreiform movements

Incoordination Focal motor abnormalities Tremor

Focal epileptiform phenomena

Generalized epileptiform phenomena

Description

Author

Wrinkling of the forehead, distortion of the corners of the mouth, irregular movements of the tongue and lips, twisting of the eyes, opening them wide, and shutting them tight In the lip muscles, fine lightninglike or rhythmical twitchings, which in no way bear the stamp of voluntary movements Fibrillary contractions, particularly noticeable in the facial muscles and “sheet-lightning” has long been known as a sign of a chronically developing illness Fibrillary movements in the muscles of his face, neck and upper extremity Wriggling the body, hotching the shoulders as if … infested with fleas, twisting their heads to one side Peculiar sprawling irregular choreiform out-spreading movements Peculiar writhing movements of the body, roll around, stretch their backs, distort their fingers in bizarre fashion, fling their limbs about Athetotic restlessness of the fingers The feet are often set down quite irregularly, both in regard to time and space Spasms and intensifications of idiomuscular contractions Chiefly true parkinsonisms Regular, fine tremor which, on the whole, is independent of the psychic state … a coarse, irregular tremor is … a signal of the conscious or unconscious emotional agitation Cramps … are often typically epileptiform … tonic, then clonic phases of short duration, rarely lasting more than a minute Myoclonic jerkings The patients collapse like apoplectics. Speech becomes thick or fails completely. … Sometimes the symptoms have a clearly hemiplegic character. … Consciousness is for the most part clouded, … such attacks usually last a couple of hours

Kraepelin

Kraepelin Bleuler

Reiter FarranRidge Kraepelin Jaspers

Reiter Bleuler Bleuler Bleuler Reiter Bleuler

Bleuler

Reiter Bleuler

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More localized involuntary movements of the facial musculature were also recorded by Kraepelin: ‘‘We observe, specially in the lip muscles, fine lightninglike or rhythmical twitchings, which in no way bear the stamp of voluntary movements. The same is the case of the tremor in the muscles of the mouth which appears sometimes in speaking and which may completely resemble that of paralytics’’ [11]. Farran-Ridge, Bleuler, and Reiter [6,10,12] also described fibrillary movements of the muscles of facial expression. In addition, the latter described what appears to be blepharospasm: ‘‘rapid fluttering of the upper eyelids, an increase in the rate of blinking, which is spasmodic.’’ It is difficult to ascertain whether the assortment of terms applied by experienced clinicians to these motor phenomena represents subtle variations in the nature of the phenomena themselves, or rather a divergence of interpretations of identical movements, arising from the observers’ theoretical prejudices. CHOREIFORM MOVEMENTS Chorea refers to involuntary, nonrepetitive random and rapid jerky movements that have no specific rhythm pattern [13]. On the basis of the descriptions provided, there appears to be no very clear distinction between some of the movements outlined above and those considered as choreic or choreiform. Several writers made explicit similarities between the movements exhibited by patients with schizophrenia and those with chorea or other neurological disorders. Kraepelin [12] described ‘‘peculiar sprawling irregular choreiform out-spreading movements, which I think I can best characterise by the term ‘athetoid ataxia.’’’ Eschewing neurological categories and the use of technical terms, Farran-Ridge, paints a vivid picture of patients ‘‘wriggling the body, hotching the shoulders as if…infested with fleas, twisting their heads to one side, distorting their faces and [making] clicking noises with their tongues’’ [6]. There was a spectrum of opinion about whether the similarities between schizophrenic movement disorder and chorea were in some way essential, merely superficial in nature, or artefactual, the result of biased observation. While Kraepelin’s ‘‘athetoid ataxia’’ seems to imply a true (that is, etiological or pathogenetic) resemblance to a neurological disorder, Jaspers’ comments were simply descriptive: ‘‘Externally, many of these movements remind us of athetotic, choreic or involuntary movements as we find them in patients with lesions of the cerebellum and cerebellar tracts. Patients make peculiar writhing movements of the body, roll around, stretch their backs, distort their fingers in bizarre fashion, fling their limbs about.’’ Bleuler [10], on the other hand, stated categorically that these features were unrelated to ‘‘true’’ chorea as it was seen in neurological illness. He viewed them instead as distortions of normal expressive movements, arising from other disturbance of thought or emotion: ‘‘Every conceivable stilted gesture occurs . . .

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grimaces of all kinds, peculiar ways of shrugging the shoulder, extraordinary movements of tongue and lips, finger play, sudden involuntary gestures—all these peculiarities are the reason why some authors have spoken of choreic or tetanic movements in catatonia, quite mistakenly though…choreal, athetotic and tetanic phenomena are entirely different from the motor symptoms which accompany schizophrenia.’’ He went on to claim that: ‘‘In my entire, intensive and extensive experience I have never seen ‘choreal’ disturbances which belong to schizophrenia. The reason why Wernicke’s school assumes the presence of such disturbances, can only be that their concept of choreal movements extends far beyond anything which is actually seen in the various forms of chorea’’ [14]. It is hard to reconcile these opposing views. Both the nature of the observed movements and their origin were disputed. Kraepelin viewed the movements which ‘‘remind us of choreic movements’’ as ‘‘quite independent of ideas and feelings,’’ whereas Bleuler stated the contrary: ‘‘The confinements of the movements to specific groups of muscles can be much better explained on a psychic than on an anatomic basis, aside from the fact that in some cases the psychic origin of the symptoms can be demonstrated.’’ One may question why experienced observers, who would presumably have been familiar with a range of neurological complaints producing chorea, should have reached such extreme positions. From these accounts, it seems probable that the term ‘‘chorea’’ carried different resonance for Bleuler and Kraepelin, which extended far beyond the superficial appearance of the movements, with implications for both interpretation of the behavior of individual patients and the conceptual understanding of the schizophrenic illness itself. CATATONIA Catatonia is a term whose application has remained somewhat confused over the years, and even today there is ‘‘no clear and universally accepted definition’’ [15]. Since Kahlbaum’s original monograph on catatonia was published in 1874 [16], the term has been variously applied to a behavioral syndrome, a diagnostic entity in its own right, used as a synonym for schizophrenia, and applied to a subtype of schizophrenia with motor disturbance as a prominent feature. In current usage, the term applies to both this subtype of schizophrenia and a behavioral syndrome with prominent motor disturbance, arising as a result of psychiatric illness, brain injury, lesion or infection, metabolic disorder, or exposure to drugs and toxins. Kahlbaum [16] considered that catatonia was the result of a brain disease precipitated by childbirth or trauma, or occurring as a result of alcoholism or other cerebral pathology, which in some cases, described as lethal catatonia, was rapidly progressive and fatal. The core feature of catatonia for Kahlbaum was a ‘‘locomotor neural process’’ or catalepsy, an increase in muscle tone, which led

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to waxy flexibility of the limbs, the assumption of fixed postures, and ‘‘a motionless state, speechless and with rigid mask-like facies.’’ Other motor features included spasmodic pursing of the lips (Schnautzkrampf), outbursts of unnatural laughter, strange gesticulations and movements of the arms, and, frequently, strong resistance to imposed movement. Outbursts of motor excitement during which patients would run, jump, gyrate, scream, or behave in an aggressive manner punctuated the ‘‘melancholic state’’ and were referred to as ‘‘delirium actum’’ or ‘‘catatonos raptus.’’ Under the term catatonia, a broad range of relatively complex motor features were described, involving muscle groups at various sites, and in some cases also ‘‘characterised by similarity to purposeful acts’’ [9]. These features included stupor, negativism, stereotypies, catalepsy, automatism, mannerisms, excitement, and echopraxia [17]. Given the evolving nature of the definition of catatonia and the variety of phenomena subsumed, it is not possible in this chapter to cover the topic exhaustively, as has McKenna [18]. Joseph [15] also provide a helpful overview of the subject, both in historical context and current clinical practice. TREMOR AND OTHER FOCAL MOTOR ABNORMALITIES Tremor was observed in patients during acute, remitted, late, and terminal stages of the schizophrenic illness. Reiter [12] described the tremor of late stages of the illness as ‘‘chiefly true parkinsonisms,’’ but also described other patterns of tremor, which occurred as agonal phenomena in patients with dementia praecox in the terminal stages of acute, fulminant pyrexial illness. Bleuler [10] indicated a relationship between the pattern of the tremor observed and its etiology: ‘‘The tremor, which may be traced even in the completely ‘cured’ cases, may perhaps also be indicative of poisoning of the motor apparatus. In such cases, it is usually a rather regular, fine tremor which, on the whole, is independent of the psychic state . . . a coarse, irregular tremor is (as in all nervous individuals) a signal of the conscious or unconscious emotional agitation. . . . The tremors, which in acute conditions often are quite similar to the coarse shivering of the feverish, and which in the chronic arise quite independently of agitations, excitements or strains, can also be interpreted as organic.’’ Although, as already noted, Bleuler regarded motor disturbances as accessory symptoms of schizophrenia, it is clear from his writings that focal motor abnormalities affecting individual muscles were both common and readily observed. ‘‘Spasms and intensifications of idio-muscular contractions…are rarely absent and in many cases so obvious that upon a light percussion of the muscle in pectoralis major, the muscle bundles under the pleximeter stand out in long bulges.’’ While Bleuler had been quite clear in defining choreiform motor disorder as secondary to mental disturbance, in the case of focal abnormalities the issue

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was less clear. ‘‘On the whole, the cramps may be due to either psychic or physical influences . . . they are often typically epileptiform (tonic, then clonic phases of short duration, rarely lasting more than a minute)’’ [10]. However, he also stated that such focal signs were ‘‘generally independent of the psyche,’’ and proposed various etiologies, including ‘‘a sign of intoxication’’ associated with tissue dehydration and severe nutritional disturbance, or ‘‘an abnormal mechanical and probably also electrical irritability of the nerves,’’ which was common in male patients. One may speculate on the etiology of the condition, and similarities between these abnormalities and both the ‘‘myoclonies’’ observed by Reiter [12] and the fibrillary movements of the facial muscles described earlier in this chapter. INCOORDINATION Bleuler [10] observed that the patients’ gaits were often strikingly disturbed as a result of both abnormal muscular tone and failure to smoothly integrate components of movements. ‘‘The co-ordination of arm and leg movements is often disturbed; some patients keep their arms stiff while walking. Particularly important however, is the fact that the feet are often set down quite irregularly, both in regard to time and space.’’ Whether or not the latter is essentially the same phenomenon denoted by Kraepelin’s ‘‘peculiar sprawling irregular choreiform out-spreading movements’’ remains a matter for conjecture. EPILEPTIFORM MOVEMENTS Kahlbaum [16] was aware that a relatively high proportion of patients with catatonia also suffered from epilepsy. Bleuler [10] vividly described the nature of epileptic seizures as they affected patients with schizophrenia: ‘‘Suddenly or gradually, with or without prodromes, the patients collapse like apoplectics. Speech becomes thick or fails completely; swallowing or ocular fixation and other functions may be distinctly disturbed; saliva may flow from the mouth; all movements of the body become uncertain, etc.; incontinence of faeces and urine is less frequent. Sometimes the symptoms have a clearly hemiplegic character, one half of the body slackening during the attack and seeming weaker afterwards. If the attack is accompanied by contractions, they may be unilateral or more marked on one side than the other. Consciousness is for the most part clouded, but may also remain normal or be completely abolished; the same holds for subsequent memory. Such attacks usually last a couple of hours; occasionally they may pass more quickly or extend over some days.’’ These attacks were features of both acute and chronic stages of the schizophrenic illness. On the basis of the original literature, it is impossible to gauge whether patients who experienced seizures were in other ways clinically distinct from the general population of patients with schizophrenia. One might infer from the

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relatively high incidence of epilepsy that the clinical population diagnosed as suffering from schizophrenia, catatonia, or dementia praecox by the early writers was quite distinct from the current clinical population. Given the range of physical disorders which could have mimicked schizophrenia in the ‘‘preneuroleptic era,’’ even greater doubt is thrown on the extent to which other aspects of these historical accounts of motor disorder can be applied to current groups of patients with schizophrenia.

ORGANIC DISORDERS Clearly, caution must be exercised in interpreting these phenomenological descriptions and extrapolating from them to current models of pathology. The patients discussed were, in essence, unselected samples drawn from large, heterogeneous clinical populations, contaminated by a variety of other neurological complaints. Psychiatric diagnoses were not operationally defined, and there may have been biases to reporting certain phenomena. Further, the original authors may have experienced problems in clinical differential diagnosis, even when no such difficulty was reported. Careful review of the literature suggests that boundaries between diagnoses of schizophrenia and other disorders such as epilepsy may have been more porous prior to the introduction of operational definitions than at present. For example, would the presence of epileptic seizures have been judged as stemming from the schizophrenic illness or as a manifestation of another organic disease process? The account of epileptic seizures that we have quoted seems to suggest that such seizures were viewed as a part of the schizophrenic disease process itself rather than a manifestation of an organic brain disorder, which also generated psychotic symptoms. A second example is Reiter’s [12] descriptions of motor disorders in schizophrenia associated with fever, which seem from a contemporary point of view to relate clearly to toxic states rather than to intrinsic features of any psychiatric disorder. Both Bleuler and Kraepelin described other, more subtle features of the schizophrenic illness that would currently be regarded as atypical of schizophrenia. These included autonomic abnormalities and cardiovascular and pupilliary changes, which were apparently unrelated to emotional state. As already mentioned, similarities between the movement disorder in dementia praecox and neurological disorders were clearly identified by a number of authors. Contemporary reports suggested that even when clinicians strongly suspected neurological or other physical illness, distinguishing schizophrenia from these disorders and the array of other physical illnesses with similar clinical features may have been a formidable, at times even impossible task, given the lack of laboratory aids to diagnosis.

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NEUROSYPHILIS It is likely that some of these patients suffered from neurosyphilis, either as a cause of psychosis or as a complication of preexisting dementia praecox. Although available reports do not allow any definitive conclusions to be drawn about links between this infection and abnormal movements, neurosyphilis was undoubtedly relatively common among patients with schizophrenia. As evidence, the Argyll pupillary sign was found to be positive in 14% of a survey of cases of dementia praecox reported in the Traite´ International de Psychologie Pathologique of 1911 [19]. In the same paper, other clinical features attributed to dementia praecox also appear consistent with syphilitic infection, including late-emerging ataxia and le tremblant de la langue (tremor of the tongue). Kraepelin commented that the ‘‘tremor of the muscles of the mouth’’ observed in dementia praecox ‘‘may completely resemble that of paralytics.’’ Bleuler also remarked on the similarity between muscular fasciculations observed in schizophrenia and those of paresis. These clinical similarities and the lack of laboratory aids to differential diagnosis support the contention that distinguishing dementia praecox and general paralysis of the insane may have been extremely difficult.

ENCEPHALITIS LETHARGICA Interpretation of the historical accounts is made even more complex by the advent of encephalitis lethargica. Von Economo first described this condition in 1917. Over the next 10 years, widespread epidemics were observed, although the pathogenic organism was never identified. Contemporary accounts describe a condition whose motor manifestations may have been indistinguishable from schizophrenia [6,20,21]. Jaspers’ descriptions [9] of encephalitic patients bear a strong resemblance to his descriptions of catatonic states, with patients ‘‘lying on the back with head bent forward; the head not touching the pillow. Lengthy retention of passively received postures whether uncomfortable or not; fixation of the final posture after action or the freezing of a movement in the middle of an action; when the spoon is taken to the mouth, the hand stops halfway, or the arms are kept rigid during walking.’’ These similarities led Farran-Ridge [6] to propose that movement disorders in schizophrenia and encephalitis lethargica shared a pathological basis with other diseases known to involve the basal ganglia. He suggested that the disease process in both illnesses tended ‘‘to fall on the same part of the brain,’’ namely, the basal ganglia, and that abnormal movements in dementia praecox arose from abnormal stimuli in the basal ganglia which ‘‘find expression or are exteriorized via the various psycho-motor paths.’’ Although the similarities between catatonic schizophrenia and epidemic encephalitis were ‘‘obvious and fascinating’’ [22], patients’ subjective experience

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of motor disturbance and observation of mental state could sometimes distinguish the two conditions. In contrast to those with catatonia, patients with encephalitis were able to ‘‘see their disturbance objectively; though spontaneous movement is extremely difficult for them, they can carry out the same movements by request from someone else. Hence patients may try out psychological devices on themselves; they work themselves up, make themselves furious, or enthusiastic to keep the movements up. Once their attention is distracted the tonus increases and movement becomes more difficult.…The patients remain aware and thinking is orderly. They are orientated and not psychotic; there is no negativism, resistance or contrariness.’’ Jaspers also emphasized that external stimuli could produce temporary relief of akinesia in patients with encephalitis but not schizophrenia: ‘‘in the encephalitic the whole thing is resolved by outside influences—daylight, music, command, laughter, optical stimulus etc., and then the rigidity reasserts itself’’ [9]. Despite these clinical differences, in practice, distinguishing dementia praecox from epidemic encephalitis may have been extremely difficult, if not in some cases impossible for even the most experienced observers. Farran-Ridge [6] expresses the dilemma succinctly: ‘‘among all the psychoses whose symptoms may be thus simulated by epidemic encephalitis, dementia praecox occupies the foremost place; in fact the semiological resemblance between the two diseases is in some cases so striking as to give rise to real difficulty in the differential diagnosis.’’

STUDIES OF DYSKINESIA Advances in medical technology and the development of operational definitions of psychiatric disorder allowed exclusion of physical disorder in many cases, and permitted easier interpretation of clinical reports. Soon after the introduction of antipsychotic medication into clinical practice, it became apparent that these drugs were associated with clearly abnormal patterns of movement. For example, signs resembling Parkinson’s disease, such as motor retardation and a wooden facial expression, were noted by Delay et al. in 1952 [23], and the syndrome was more formally identified a couple of years later by Steck [24]. Similarly, a syndrome of restlessness was observed during an early clinical trial of promethazine [25]. A few years later, it was Steck [24] again who described in detail the restless or rhythmic movements of the legs and feet exhibited by patients receiving antipsychotic drugs, and coined the term ‘‘neuroleptic induced akathisia.’’ Orofacial dyskinesia, as an early side effect of chlorpromazine, was first recorded by Schonecker [26], but the recognized syndrome of tardive dyskinesia as a late-onset disorder was described and named by Uhrbrand and Faurbye [27] a few years later. The need to formally investigate these abnormal drug-induced movements,

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particularly tardive dyskinesia, was the principal driving force for the development of rating scales for movement disorder. The introduction of validated, objective rating scales for assessing druginduced movement disorder in patients with psychosis [28] surmounted some of the difficulties which arose from the inconsistent use of terms, which had been applied to the multiplicity of abnormal movements described in patients with dementia praecox in the preneuroleptic era, and which still lacked universally accepted definitions. These assessment tools permitted prevalence studies in both hospital and community populations, and allowed comparisons between centers to be made. Some of the scales, most particularly the Rogers motor disorder scale [5], were designed to be nonprejudicial, in that they would allow rating of the full range of movement disorder in patients with schizophrenia, avoiding assumptions about a psychiatric or neurological etiology. PREVALENCE OF SPONTANEOUS DYSKINESIA For a period, research interest in motor disorder in schizophrenia was focused on investigating the etiological role of antipsychotic drugs, with neglect of abnormal motor phenomena as intrinsic to the disorder itself. However, in the 1980s a reawakening of interest in motor features of schizophrenia, and its conceptualization as a psychomotor disorder [5,29], led to studies designed to define in contemporary samples the extent to which dyskinesia and other motor phenomena were intrinsic to the illness process. These studies examined the nature and prevalence of movement disorder in samples of patients who were drug-naive. One major spur to such research was the question whether tardive dyskinesia could be attributed solely to the effects of antipsychotic medication, or whether the schizophrenic disease process contributed to its development. An influential study by Owens et al. [8], cited earlier in this chapter was conducted at Shenley Hospital. A cohort of 411 inpatients with chronic schizophrenia, 47 of whom had no history of treatment with antipsychotic medication, was examined on two occasions, 12 to 18 months apart. The never-treated patients were somewhat older (mean age 67 years) than those receiving antipsychotic drugs (mean age 57 years). The prevalence of abnormal involuntary movements in the two groups was compared according to different severity criteria, based on rating using the Abnormal Involuntary Movements Scale (AIMS) [30] and the Rockland (or Simpson Dyskinesia) Scale [31]. Overall, no statistical differences in the prevalence of abnormal involuntary movements were reported between those with and without a history of drug treatment. Initial interpretations of the findings of this study were that spontaneous involuntary movements were a feature of severe, chronic schizophrenia, and that their expression was unmodified by antipsychotic treatment. However, further analysis taking account of age effects demonstrated a clear effect for treatment

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on both prevalence and severity. There was a significant relationship between the presence of abnormal movements, particularly orofacial dyskinesia, and whether or not there was past antipsychotic exposure. Treated patients also exhibited more severe abnormality [32]. Nevertheless, the prevalence of abnormal movements using a criterion of at least one rating of 2 or more on an AIMS item yielded a prevalence of 45% for the never-treated patients. These findings were, however, not uniformly confirmed by subsequent studies of abnormal involuntary movements in drug-free individuals with schizophrenia. Several studies failed to detect abnormal movements in such patients [33–36], or found them to be rare. For example, Chatterjee et al. [37] identified spontaneous dyskinesia in just one of a sample of 89 neuroleptic-naive, first-episode patients. Woerner et al. [38] carried out an extensive survey of abnormal involuntary movements in 2250 subjects recruited from psychiatric and geriatric settings. The prevalence figures for samples of patients never exposed to antipsychotic drugs varied from 0 to 2%. The majority of studies, however, have reported higher prevalence figures [39–42]. For example, Fenn et al. [40] found that 14% of a small sample of neuroleptic-naive patients with schizophrenia fulfilled research diagnostic criteria for probable tardive dyskinesia, while a further 23% exhibited mild dyskinesia. The same group of researchers [41] also assessed abnormal involuntary movements in 62 never-medicated patients with schizophrenia, 42 patients who had received antipsychotic medication for at least a year, and 21 control subjects without psychiatric illness. None of the healthy controls met the criteria for tardive dyskinesia. Although mean total AIMS scores did not differ between the two patient groups, significantly more of the untreated patients (26%) fulfilled criteria for tardive dyskinesia than the drug-treated patients (19%). In Chestnut Lodge, New York State, Fenton et al. [42] carried out a retrospective case note study of psychiatric patients who had never received treatment with antipsychotic medication. They found dyskinetic movements to be more common in 94 patients with schizophrenia (15% of whom had documented evidence of orofacial dyskinesia), compared to 179 patients with other psychiatric diagnoses. The age of the patient samples studied could be one explanation for these inconsistent findings, as spontaneous dyskinesia tends to show a positive correlation with age [43]. Kerr and McClelland [44] noted that in the Nigerian study conducted by McCreadie et al. [35], the mean age of the never-medicated patients with schizophrenia was 42 years, while in a subsequent, similar study in India by the same investigators [39], the mean age was 65 years. None of the patients in the first study manifested dyskinesia, compared with 38% of the second, older sample. However, they argue that age is not sufficient explanation. For example, they cite the Chestnut Lodge study [42], which detected a relatively high proportion of untreated patients with evidence of dyskinesia although the mean age was only 29 years.

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In 1984, Casey and Hansen reviewed the prevalence of spontaneous dyskinesia reported in studies dating back to 1959, most of which had examined samples of institutionalized psychiatric patients [45]. They summarized data from 24 reports of 29 study samples, involving 13,575 patients from various clinical settings. Prevalence figures ranged from 0 to 53%, with a weighted mean of just over 4%. These authors also plotted the prevalence of both spontaneous dyskinesia and tardive dyskinesia in studies where drug-free and drug-treated ‘‘institutionalized’’ patients had been compared. They found that both spontaneous dyskinesia and tardive dyskinesia had increased proportionately over the period from 1966 to 1984. They took this as supportive evidence for the view that the increase in the reported prevalence in tardive dyskinesia over the years reflected increased awareness and vigilance rather than a genuine increase in prevalence. Overall, the relative prevalence of tardive dyskinesia was approximately 15% higher than that of spontaneous dyskinesia. FIRST-EPISODE STUDIES Two recent prospective, first-episode studies of schizophrenia report similar prevalence figures for a tardive dyskinesia-like syndrome in neuroleptic-naive patients. Gervin et al. [46] investigated spontaneous abnormal involuntary movements in 79 patients presenting with schizophrenia or schizophreniform psychosis, who were neuroleptic-naive or had received medication for less than 1 month. Six patients (7.6%) had spontaneous dyskinesia according to the AIMSbased Schooler and Kane [47] criteria. Puri et al. [48] examined 27 first-episode patients with schizophrenia who had never received antipsychotic medication. The proportion of these drug-naive patients fulfilling criteria for tardive dyskinesia on the AIMS ranged from 4% to 11% depending on the criterion threshold score used. Using a diagnostic threshold score of 2 or greater on one or more AIMS item, similar to the Scooler and Kane criteria used by Gervin et al., yielded a point prevalence of 7.4%. SPONTANEOUS OROFACIAL DYSKINESIA IN THE ELDERLY Aside from the first-episode studies, many of the patient samples investigated have included relatively elderly patients. For example, in the study by Owens et al. [8], the age range for antipsychotic-free patients with schizophrenia was from 29 to 90 years of age. Crane [49] was of the view that common factors in those receiving drug treatment and those who did not might be relevant to the development abnormal movements in older, long-stay inpatients. These variables included chronicity of illness and ‘‘institutionalization with attendant emotional and physical deprivation.’’

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The interpretation of movement disorder data in samples of elderly psychiatric patients needs to take account of the presence of spontaneous or idiopathic orofacial dyskinesia seen in the normal elderly, a condition that is generally considered to be indistinguishable from orofacial tardive dyskinesia. The reported range for the prevalence of spontaneous dyskinesia in the elderly varies from less than 1% to around 37% [45]. For example, Varga et al. [50] found that orofacial dyskinesia was present in 10% of a sample of elderly people never exposed to antipsychotic drugs, while a figure of 18% was reported in a similar survey by Bourgeois et al. [51]. Many of these studies involved samples of institutionalized patients. The prevalence in community surveys tends to be at the lower end of the range, around 1.5% [52,53]. The proportion of individuals exhibiting spontaneous orofacial movements increases with age. For example, in a sample of 661 patients, Klawans and Barr [54] found that the prevalence of ‘‘spontaneous lingual-facial-buccal dyskinesias’’ rose with age from less than 1% in patients aged 50–59 years to nearly 8% in patients between 70 and 79 years of age. The prevalence of such dyskinesia has been assessed in various samples of nonpsychiatric, drug-free elderly individuals, such as residents of old-age homes [55]. Greenblatt et al. [56] estimated that the condition was present in some 2% of the geriatric home population. Blowers et al. [57] examined 500 elderly residents in local authority homes using the AIMS. Of the 378 individuals who had apparently never received antipsychotic drugs, 50 (13%) were diagnosed as having ‘‘tardive dyskinesia’’ on a criterion of a score of 3 or more on the AIMS global assessment scale. The findings from these various surveys suggest that advancing age is associated with an increasing risk of developing spontaneous, abnormal, involuntary movements, related to various neurological and medical conditions, independent of antipsychotic drugs. One caveat to the findings of prevalence studies, particularly in the elderly population, is that of unrecognized previous exposure to drugs which carry risks of motor dysfunction, as a wide variety of agents have been implicated in cases of tardive dyskinesia (see Table 2). SPONTANEOUS DYSKINESIA AND PROGNOSIS Yarden and Discipio [58] formed the opinion, derived partly from comments by Kraepelin and Kleist and partly from their own observations, that people with schizophrenia characterized by abnormal involuntary movements, particularly choreiform movements, showed a deteriorating course unmodified by antipsychotic medication. They tested this notion in a small study of 18 drug-free, firstadmission patients with a clinical diagnosis of schizophrenia and evidence of choreiform or athetoid movements, and 36 matched controls not exhibiting such movements. Compared with the controls, the group with dyskinesia (as well as grimacing, tics, mannerisms, and stereotypies) had an earlier onset of an illness

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TABLE 2 Basic Differential Diagnosis of Spontaneous Abnormal Involuntary Movements in People with Schizophrenia Aetiology Movement disorder related to schizophrenic illness Unsuspected exposure to drugs capable of producing movement disorder Pharmacotherapy causing acute dystonia Pharmacotherapy causing tardive dyskinesia Basal ganglia and other disorders associated with schizophrenia-like psychosis Motor disorder related to coincidently occurring conditions

Examples See Table 3 Antiemetics (such as metoclopramide), antipsychotic drugs used as hypnotics, illicit drug use (such as amphetamines) Caffeine, phenytoin, lithium, estrogens, chloroquine L-dopa, tricyclic antidepressants, anticholinergics, antihistamines Huntington’s disease, Wilson’s disease, Sydenham’s chorea, Fahr’s syndrome, Hallevorden-Spatz disease, and systemic lupus erythematosus Hyperthyroidism, hypoparathyroidism, Tourette’s disorder and other disorders, Idiopathic dystonia, spontaneous dyskinesia of the elderly, and tic disorder

prodrome, in terms of personality change, and earlier onset of illness. Followup for a period of 2.5–3.5 years revealed that this group also showed a steadily progressive course and severe deterioration, characterized by severe thought disorder, purposeless activity, negativism, and neglect of personal hygiene. Overall, the mean duration of hospitalization was significantly greater for the dyskinetic group, the majority (61%) of whom remained in hospital over the entire observation period. The conclusion by the investigators that the appearance of spontaneous dyskinesia in the early stages of schizophrenia is a grave prognostic sign has not been systematically tested since. However, it echoes the statement by Griesinger, quoted by Owens [8], over a century ago, that the ‘‘persistent, automatic grimacing’’ and ‘‘chorea-like movements’’ in those with mental illness augured a poor prognosis. CONCLUSION Many of the writers in the preneuroleptic era strove not only to describe the abnormal patterns of movement which they observed in their patients (Table 3), but also to understand what these movements signified, or, as Jaspers put it, to

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TABLE 3 Simple Classification of Spontaneous Abnormal Involuntary Movements Associated with Schizophrenia Category of motor abnormality Decreased spontaneous movement

Abnormal response to witnessed or imposed movement

Increased spontaneous movement

Postural abnormalities

Abnormal patterned movement

Clinical features Poverty of movement Stupor: akinetic mutism with relative preservation of consciousness “Echo” phenomena: echopraxia, echolalia Excessive compliance: automatic obedience Resistance: negativism, obstruction Opposition Restlessness Excitement Tremor Increased tone Catalepsy Manneristic/stereotyped posturing, “psychological pillow,” grimacing Clumsiness Spasms Myoclonic movement Tics Athetoid movements Choreiform movements Parakinesia Perseveration Impulsive acts Stereotypies/mannerisms

Source: After Manschreck [58].

both ‘‘register and comprehend’’ [9]. The challenge that they faced, in disentangling which abnormal movements were the expression of mental state features and which were in some sense primary manifestations of the psychotic illness, remains a difficult distinction for clinicians today. Patients with schizophrenia treated with antipsychotic agents exhibit relatively delineated, recognized syndromes of abnormal involuntary movement, which are abnormal in their nature and characteristics and appear unrelated to the normal range of expressive gesture. These include orofacial dyskinesia, dystonia, and parkinsonism, including features such as tremor and bradykinesia. While motor problems of this kind are

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generally exacerbated by increased arousal and anxiety, they seem otherwise not to be driven directly by aberrant thought content, affect, or perception. This would seem to preclude further interpretation of these phenomena in terms of psychological causation. Therefore, if these motor syndromes are seen in drugnaive patients with schizophrenia, they are more likely to be viewed as inherent to the pathophysiology of the illness. For example, the distinct and coherent nature of orofacial dyskinesia observed in a proportion of untreated patients with schizophrenia has led to the conclusion that this is a motor component of the illness. However, other motor phenomena seen in patients with schizophrenia are highly idiosyncratic, and tend not to appear qualitatively different from normal movements in the way that dyskinesia, dystonia, and tremor do. Movements of this kind would include those characterized as stereotypies and posturing. These are more likely to be judged as secondary to psychological disturbance. These movements may not fall so very far outside the spectrum of recognized social patterns of expressive gesture. They also tend to be interpretable by an observer, or explained by the person experiencing them, as secondary to other disturbance of thought, emotion, perception, or volition. Clinicians and researchers will tend to consider the abnormal movements they observe in patients with schizophrenia within these two broad categories, with perhaps the implicit assumption that motor disorder of the first type arises from dysfunction of neurological circuits which primarily mediate motor function and that the more idiosyncratic patterns of abnormal movement may potentially be explicable in terms of ‘‘higher-level’’ abnormalities. Technological and methodological advances in neuroimaging now offer the prospect that further work may be able to address the validity of such assumptions and lead to the glimmerings of a greater understanding of the nature of movement disorder in schizophrenia.

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28. Barnes TRE, Kane JM. Assessment of movement disorder in psychosis. In: Barnes TRE, Nelson HE, Eds. The Assessment of Psychosis: A Practical Handbook: London, Chapman & Hall Medical, 1994:191–210. 29. Barnes TRE, Liddle PF. Tardive dyskinesia: Implications for schizophrenia? In: Schiff AA, Roth M, Freeman HL, Eds. Schizophrenia: New Pharmacological and Clinical Developments. Royal Society of Medicine Series, International Congress and Symposium Series. Vol. No. 94, 1985:81–87. 30. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education and Welfare Publ 76–338, US Government Printing Office. 1976: 534–537. 31. Simpson GM, Lee JH, Zoubouk B, Gardos G. A rating scale for tardive dyskinesia. Psychopharmacology 1979; 64:171–179. 32. Owens DGC. Involuntary disorders of movement in chronic schizophrenia—the role of the illness and its treatment. In: Casey DE, Chase TN, Christensen AV, Gerlach J, Eds. Dyskinesia—Research and Treatment (Psychopharmacology suppl 2). Berlin: Springer-Verlag, 1985:79–87. 33. Kane JM, Smith JM. Tardive dyskinesia: Prevalence and risk factors, 1959–1979. Arch Gen Psychiatry 1982; 39:473–481. 34. Chorfi M, Moussaoui D. Les schizophre`nes jamais traite´s n’ont pas de mouvements anormaux type dyskine´sie tardive. L’Ence´phale. 1985; XI:263–265. 35. McCreadie RG, Ohaeri JV. Movement disorder in never and minimally treated Nigerian schizophrenic patients. Br J Psychiatry 1994; 164:184–189. 36. Hernan Silva I, Jerez CS, Ruiz TA, Sequel LM, Court LJ, Labarca BR. Lack of involuntary abnormal movements in untreated schizophrenic patients. Actus LusoEspanolas de Neurologia, Psiquiatria y Ciencias Afines 1994; 22:200–202. 37. Chatterjee A, Chakos M, Koreen A, Geisler S, Sheitman B, Woerner M, Kane JM, Alvir J, Lieberman JA. Prevalence and clinical correlates of extrapyramidal signs and spontaneous dyskinesia in never-medicated schizophrenic patients. Am J Psychiatry 1995; 152:1724–1729. 38. Woerner MG, Kane JM, Lieberman JA, Alvir J, Bergman KA, Borenstein M, Schooler NR, Mukherjee B, Rotrosen J, Rubenstein M. The prevalence of tardive dyskinesia. J Clin Psychopharmacol 1991; 11:34–42. 39. Fenn DS, Moussaoui D, Hoffman WF, Kadri N, Bentounssi B, Tilane A, Khomeis M, Casey DE. Movements in never-medicated schizophrenics: A preliminary study. Psychopharmacology 1996; 123:206–210. 40. Hoffman W, Kadri N, Fenn D, Tilane A, Green C, Lakloumi M, Bousaid F, Bentounssi B, Moussaoui D, Casey D. Choreo-athetoid movements occur spontaneously in never-medicated patients with schizophrenia. Eur Neuropsychopharmacol 1996; 6(suppl 3):223. 41. McCreadie RG, Thara R, Kamath S, Padmavathy R, Latha S, Mathrubootham N, Menon MS. Abnormal movements in never-medicated Indian patients with schizophrenia. Br J Psychiatry 1996; 168:221–226. 42. Fenton WS, Wyatt RJ, McGlashan TH. Risk factors for spontaneous dyskinesia in schizophrenia. Arch Gen Psychiatry 1994; 51:643–650. 43. Barnes TRE, Rossor M, Trauer T. A comparison of purposeless movements in psychiatric patients treated with antipsychotic drugs, and normal individuals. J Neurol Neurosurg Psychiatry 1983; 46:540–546.

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44. Kerr A, McLelland H. Spontaneous dyskinesia. CPD Psychiatry 1998; 1:17–19. 45. Casey DE, Hansen TE. Spontaneous dyskinesias. In: Jeste DV, Wyatt RJ, Eds. Neuropsychiatric Movement Disorders. Washington. DC: American Psychiatric Association, 1984:67–95. 46. Gervin M, Browne S, Lane A, Clarke M, Waddington JL, Larkin C, O’Callaghan E. Spontaneous abnormal involuntary movements in first-episode schizophrenia and schizophreniform disorder: Baseline rate in a group of patients from an Irish catchment area. Am J Psychiatry 1998; 155:1202–1206. 47. Kane JM, Weinhold P, Kinon B, Wegner J, Leader M. Prevalence of abnormal involuntary movements (‘‘spontaneous dyskinesia’’) in the normal elderly. Psychopharmacology 1982; 77:105–108. 48. Puri BK, Barnes TRE, Chapman MJ, Hutton SB, Joyce EM. Spontaneous dyskinesia in first-episode schizophrenia. J Neurol Neurosurg Psychiatry 1999; 66:76–78. 49. Crane GE. Persistent dyskinesia. Br J Psychiatry 1973; 122:395–405. 50. Varga E, Sugerman AA, Varga V, Zomorodi A, Zomorodi W, Menken M. Prevalence of spontaneous oral dyskinesia in the elderly. Am J Psychiatry 1982; 139:329–331. 51. Bourgeois M, Boueilh P, Tignol J, Yesavage J. Spontaneous dyskinesia versus neuroleptic-induced dyskinesia in 270 elderly subjects. J Nerv Ment Dis 1980; 168: 177–178. 52. D’Allessandro R, Benassi G, Cristina E, Gallassi R, Manzaroli D. The prevalence of lingual-facial-buccal dyskinesias in the elderly. Neurology 1986; 36:1350–1351. 53. Klawans HL, Barr A. Prevalence of spontaneous lingual-facial-buccal dyskinesia in the elderly. Neurology 1982; 32:558–659. 54. Delwaide PJ, Desseilles M. Spontaneous buccolinguofacial dyskinesia in the elderly. Acta Neurol Scand 1977; S6:256–262. 55. Greenblatt DL, Dominick RN, Stotsky BA, DiMascio A. Phenothiazine-induced dyskinesia in nursing-home patients. J Am Geriatr Soc 1968; 16:27–34. 56. Blowers AJ, Borison RL, Blowers CM, Bicknell DJ. Abnormal involuntary movements in the elderly. Br J Psychiatry 1982; 139:363–364. 57. Yarden PE, Discipio WJ. Abnormal movements and prognosis in schizophrenia. Am J Psychiatry 1971; 128:317–323. 58. Manschreck TC. Motor abnormalities in schizophrenia. In: Nasrallah HA, Weinberger DR, Eds. Handbook of Schizophrenia, Vol. 1. Amsterdam: Elsevier, 1986:65–96.

3 The Epidemiology of Tardive Dyskinesia Siow-Ann Chong Woodbridge Hospital and Institute of Mental Health, Singapore

Perminder S. Sachdev University of New South Wales, Sydney, and The Prince of Wales Hospital Randwick, New South Wales, Australia

INTRODUCTION This chapter reviews the epidemiology of tardive dyskinesia (TD), examining its prevalence and incidence, and the putative risk factors. While there is an extensive literature on the epidemiology of TD, the findings are varied, even though consensus has emerged on many aspects. The diversity of the epidemiological findings calls for an explanation, and many possible reasons can be suggested. Importantly, the very definition of TD has been the subject of much debate. While the movements that are characteristic of TD are usually choreoathetoid, neuroleptic-induced tardive movements may also be dystonic, akathisic, ticlike, myoclonic, or tremorous in their manifestation. This has led to a debate between ‘‘lumpers’’ and ‘‘splitters,’’ i.e., those who include all these different movements within the rubric of TD, and those who make a distinction between TD and other tardive syndromes such as tardive dystonia, tardive akathisia, or tardive tics. Another issue is the time factor of the condition as implied by the term ‘‘tardive,’’ which 37

38

Chong and S. Sachdev

is derived from the French word tardif, meaning ‘‘late.’’ Until the widely accepted criteria proposed by Schooler and Kane [1] in 1982, which specified a time criterion for persistent TD (3 months) and chronic TD (6 months), there had been a lack of standardization which made comparisons among studies problematic. These criteria also specify that a definite research diagnosis of TD be made only if movements of moderate severity are present in one or more body parts, or of mild severity in two or more body parts. This excludes cases with mild movement in one body area, which Jeste and Wyatt [2] have proposed to be sufficient to diagnose TD. Other factors that may confound any epidemiological study include the following: temporal aspects of TD (fluctuating course of the condition); differences in assessment (nominal versus ordinal criteria, use of different rating instruments, single or multiple assessments); differences in treatment practices (type, dosage, and duration of neuroleptic treatment, concurrent medication, e.g., anticholinergic drugs, whether patients are currently on neuroleptics at time of assessment, etc.); and the heterogeneity of the patient population (age, gender, ethnicity, duration of illness, exposure to medications, diagnosis, the presence of pseudoparkinsonism masking the disorder). In a critical examination of the literature, all these factors need to be taken into consideration. While it is not possible in this chapter to examine all the studies, we take a considered approach in including salient studies, remaining cognizant of their limitations. PREVALENCE In two key review articles [3,4] that examined the prevalence rates of TD in the diverse studies, the authors used the retrospective ‘‘pooled data’’ method, in which frequency figures from selected primary studies are pooled and a mean is calculated. In a review of 56 studies spanning from 1959 to 1979, Kane and Smith [3] reported point prevalence rates ranging from 0.5% to 65%, with an average point prevalence of 20%. In a later review of 76 published studies, Yassa and Jeste [4] reported an overall prevalence of 24% among a total of 39,187 patients. The clinical significance of these figures is limited, as they were derived from studies that differed in assessment criteria, methodology, and population characteristics. The study by Woerner et al. [5] attempted to address some of the previous methodological issues. The overall prevalence of TD in neuroleptic-treated individuals in this study was 23.4%, of whom 3.8% had another neuromedical illness that might have had an etiological role, thus giving a conservative prevalence rate of 19.6%. The rate varied with the setting, being 13.3% at a voluntary hospital with a young population, 23% in a Veterans Administration hospital, and 36% in a state hospital. In the same study, when a group of patients with no evidence of TD was withdrawn from neuroleptic drugs and examined weekly for 3 weeks, 34% developed emergent dyskinesia.

The Epidemiology of Tardive Dyskinesia

39

Another large-scale study by Muscettola et al. [6] reported a prevalence rate of 19.1% among 1651 psychiatric patients. However, the samples of these two studies were different: the study by Woerner et al. [5] was on normal subjects as well as those with a range of psychiatric disorders, while the study by Muscettola et al. [6] was on mixed psychiatric disorders. While both studies used the operationalised criteria of Schooler and Kane, it also meant that those with mild dyskinetic movements were excluded.

SPONTANEOUS DYSKINESIA Hyperkinetic involuntary movement also occurs in some individuals without any known causes. Prevalence rate of 0.8%, 6.0%, and 7.8% for spontaneous dyskinesia have been reported in the sixth, seventh, and eighth decades of life, respectively, in otherwise healthy subjects [7]. Kane et al. [8] reported a rate of 4.0% in healthy elderly (mean age 73 years) subjects. Prevalence is higher in psychogeriatric patients, especially in those with dementia [9]. Most of the studies were performed in elderly populations, owing to the observation that spontaneous dyskinesias are more common in the elderly. However, one study [10] found that 12.6% of neuroleptic-naive young subjects (aged 3–7 years) had at least a rating of ‘‘mild’’ on the Abnormal Involuntary Movement Scale (AIMS), and 4.1% fulfilled the Schooler and Kane criteria for TD. The presence of spontaneous dyskinesias in psychiatric populations confounds the true prevalence rate of neuroleptic-induced TD. Studies have reported that the prevalence of these spontaneous movements is higher among neurolepticnaive patients with schizophrenia (Table 1) than that found among older nonpsychiatric patients [11–13] and patients with other psychiatric diagnoses [14,15]. Age is a risk factor as well. Reviewing 14 studies which reported prevalence rates of spontaneous dyskinesia among neuroleptic-naive schizophrenic patients, Fenton [15] found a positive correlation with age: 12% among schizophrenic patients with mean age of 30 years or younger, 25% among those between 31 to years, and 42% among those over 60 years. The pathophysiology of such spontaneous dyskinesia is unknown. The evidence, though not very robust, suggests that these spontaneous movements are found more significantly among neuroleptic-naive schizophrenic patients than among neuroleptic-naive patients with other diagnoses [15]. It has been suggested that this abnormality of movement is intrinsic to the pathophysiology of schizophrenia [16], and Waddington and Crow [9] have suggested that it may be a manifestation of brain damage. Whether the presence of spontaneous dyskinesia will worsen or accentuate neuroleptic-induced TD remains to be elucidated, as there is no study to date that has examined this relationship prospectively.

12%

14%

32.1 (8.9)

37.1 (12.2)

(Continues)

27%

29.6 (6.5)

DSM-III-R male paranoid inpatients

28% 28 (range 15–55) 67% ⱕ 30

Medical record review up to 3 mo following index admission AIMS, Schooler and Kane

Caligiuri et al., 1993 [134]

14% 28 (5.3)

AIMS, Schooler & Kane

Maryland Psychiatric Research Involuntary Movement Scale ⬎ 3 on global scale AIMS ⱖ 1 (minimal) in ⱖ 2 body areas

7.6%

27.7 (9.7)

AIMS ⱖ 2 on one or more item

Moroccan, DSM-IV, never treated Subjects with schizophrenia spectrum personality

7%

27.2 (8.4)

Casey et al., 1996 [132] Cassady et al., 1998 [133]

1%

25.8 (range 16–40)

Simpson Dyskinesia Rating Scale ⱖ 1 on global total AIMS ⱖ 2 on one or more item

First-episode RDC inpatients in acute phase Neuroleptic-naive firstepisode schizophrenia Irish, first-episode schizophrenia, DSM III-R DSM-III-R Morocco Preneuroleptic DSM-III or Feighner inpatients

0

24

Age in yrs, mean (SD) Prevalence

AIMS, not blind

Measurement/criteriaa

Moroccan, DSM-III

Population/diagnostic criteria

Chorfi & Moussaoui, 1989 [127] Chatterjee et al., 1995 [102] Puri et al., 1999 [128] Gervin et al., 1998 [129] Fenn et al., 1996 [130] Fenton et al., 1994 [131]

Authors

TABLE 1 Prevalence of Spontaneous Dyskinesia Among Schizophrenic Patients

40 Chong and S. Sachdev

Not reported

Examined

AIMS ⱖ 2 on global scale AIMS ⱖ 2 global AIMS ⱖ 2 on one or more item

Indian, DSM-IV Subjects from UK, catchment area Feighner and PSE chronic, hospitalized continuously ⱖ 1 yr

Source: Adapted from Fenton et al., 1997 [14].

AIMS, Abnormal Involuntary Movement Scale; RDC, Research Diagnostic Criteria.

a

Tardive dyskinesia group ⫽ 75 75

AIMS ⱖ 2 on one or more item

Chronic inpatients hospitalised ⬎ 2 yr Chronic inpatients hospitalised ⬎ 2 yr Feighner, chronic inpatients Rockland Scale ⱖ 2 total

66.7 (11.7) (range 29–90) 66.7 (11.7) (range 29–90) 70.3

AIMS, Schooler & Kane criteria

Nigerian, DSM-III

McCreadie & Ohaeri, 1994 [136] Owens et al., 1982 [137] Owens et al., 1982 [137] Owens & Johnstone, 1980 [138] McCreadie et al., 1996 [139] McCreadie et al., 1982 [140] Owens, 1985 [141]

Selected from larger sample with age at admission of roughly 41–45 45 (14)

45%

29%

29%

52%

77%

53%

0

29%

Age in yrs, mean (SD) Prevalence

Case record review

Measurement/criteriaa

Preneuroleptic RDC inpatients

Population/diagnostic criteria

Turner, 1989 [135]

Authors

TABLE 1 Continued

The Epidemiology of Tardive Dyskinesia 41

42

Chong and S. Sachdev

INCIDENCE Given the difficulties inherent in prevalence estimates, it has been much more rewarding to examine the incidence of TD; the salient studies are summarized in Table 2. The varying rates probably reflect differences in methodologies and samples, as discussed previously. Notwithstanding the difficulties, these studies suggest that the cumulative incidence of TD increases with increasing duration of neuroleptic treatment at the rate of about 3–5% per year for the first several years, reaching a plateau at about 20–25%, but new cases continue to occur many years after drug initiation. It is difficult to identify a point in time after which the risk decreases. The plateau is accounted for by cases that remit while new cases are being added. The two largest prospective studies, from Yale [17] and Hillside Hospital, New York [18], provided sizable patient populations that were followed up for 5 and 7 years, respectively. However, both studies examined patients who had been psychiatrically unwell and treated with neuroleptics for some time prior to onset of study, with the implication that any past history of TD could not be excluded. Of great clinical interest is the incidence of TD in drug-naive patients with a first-episode psychosis. Such studies have the advantages of a ‘‘cleaner’’ cohort without the likelihood of past history of TD. The prospective medication and clinical data also enable a more robust examination of the relationship of TD to other factors. In a prospective study [19] of 118 patients with first-episode

TABLE 2 Summary of Longitudinal Studies of Incidence of Tardive Dyskinesia in Schizophrenia Patients Authors Gibson, 1981 [142] Kane et al., 1984 [18] Yassa et al., 1984 [100] Chouinard et al., 1986 [143] Morgenstern & Glazer, 1993 [17] Jeste et al., 1995a [20] Chakos et al., 1996b [19] Caligiuri et al., 1997c [38] Woerner et al., 1998a [28] a

N

Years

Risk/year

5-year risk

343 554 108 131

3 7 2 5

5.6% 3.9% 3.9% 8.7%

24.4% 17.8% 17.8% 35.1%

398

5

8.7%

35.1%

266 118 378 261

3 4 3 3

20% 5.2% 7.6% 17.6%

⬎60% 19.5% 22.9% 53%

Elderly neuropsychiatric patients. First-onset schizophrenic patients followed up. c Severe tardive dyskinesia only. b

The Epidemiology of Tardive Dyskinesia

43

schizophrenia (mean age 25.2 years), the cumulative incidence of TD was 4.8% in the first year, 7.2% in year 2, and 15.6% after 4 years. The incidence is many times higher in elderly individuals, with reported cumulative annual incidence of TD of more than 25% [20,21]. Jeste et al. [22] reported that among older patients (mean age of 66.2 years), the risk of TD is high even after a short duration of typical neuroleptic treatment, with a mean cumulative incidence of TD of 3.4% and 5.9% after 1 and 3 months of treatment, respectively. The advent of atypical neuroleptics is likely to have an impact on the future incidence of TD. The preliminary data with the atypical neuroleptics indicate a lower risk for TD, with an expectant fall in the incidence of TD. However, most of the studies to date are of relatively short follow-up periods that do not allow any confident predictions for the development of TD [23]. We will return to this issue later in this chapter.

RISK FACTORS Age Advancing age is the most consistently established risk factor for TD, and there appears to be a linear correlation between age and both the prevalence and severity of TD [24]. High rates have almost invariably been reported in elderly patients on neuroleptics. Yassa et al. [25] followed 99 geriatric psychiatric inpatients for 5 years and found that 30% had developed TD at the end of this time. In another prospective study of 266 patients with a mean (SD) age of 65.5 (12.0) years, the cumulative incidence of TD was 26%, 52%, and 60% after 1, 2, and 3 years, respectively [20]. This contrasts sharply with a prospective study on 850 young adults (mean age of 29 years), in whom the cumulative incidence of TD was 5%, 19%, and 26% after 1, 4, and 6 years of treatment [26]. TD in the elderly is also more likely to affect the oro-buccal-facial-lingual musculature, develop early in the course of neuroleptic treatment, and be irreversible. The elderly also show a higher frequency of abnormal movements from other causes [27]. The underlying mechanism mediated by aging is unclear. Proposed hypotheses include interactions with drug-induced changes in the receptors in the striatum and age-related degenerative changes in the nigrostriatal system [11]. Older patients are also more likely to develop diabetes mellitus and cerebrovascular insults, which may in part account for the increased vulnerability for TD [28]. In a review of clinical and animal studies, Waddington et al. [29] concluded that age-related and disease-related structural brain changes might be associated with TD. Aging is also associated with less efficient metabolism and excretion of drugs, and these age-related pharmacokinetic changes may lead to exposure to higher neuroleptic blood levels [30].

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Chong and S. Sachdev

While TD has been reported in children and adolescents, it is considered to be uncommon [31], but adequate epidemiological studies are few. Rates of withdrawal-emergent dyskinesia of 8% [32] and 51% [33] have been reported in two studies of children on long-term neuroleptics. Gender A number of studies have indicated a higher risk for women to develop TD [34–37], but other studies have either failed to find an association [38] or have conversely reported a higher risk for men [39]. In the 75 studies reviewed by Yassa and Jeste [4], only 6 studies reported rates stratified by age groups which indicated excess risk for women aged 51 years or older, and TD was evenly distributed by gender in the lower age groups. This suggests a possible interaction with age, with women having a higher risk in the elderly age group. Estrogen has been suggested to have a protective antidopaminergic effect, and the decline in the levels of this hormone at menopause may account for the reported increased prevalence in older women [4]. Race In a review of studies from 15 different countries involving 33,000 neuroleptictreated patients, Kane et al. [40] found wide variation in TD rates among these countries. Yassa and Jeste [4] noted that, across studies undertaken in four continents reviewed by them, the lowest prevalence of TD was reported from Asia. In a Shanghai study, the point prevalence of TD among Chinese patients was 8.4% [41], while Chiu et al. [42] reported a rate of 9.3% among Chinese in Hong Kong. Suggested lower prevalence rates of TD among Chinese subjects from these studies, when compared to studies in Western subjects, have led some authors to suggest interethnic differences—possibly genetic—in the vulnerability to developing TD [43,44]. A contrary view was expressed by Pi et al. [45], who established differing prevalence rates of TD among Chinese patients in Beijing, China (8.2%), Hong Kong (19.4%), and Yanji, China (18.6%), and suggested that environmental factors such as differing prescribing patterns were more likely to account for any such differences. In support of this, the prevalence rate of TD among 537 Chinese patients with schizophrenia in Singapore was found to be 40.5% [46]. This rate, which is higher than those previously reported in other Chinese populations, is comparable to the highest rate in Western populations. However, environmental and cultural factors, and methodological problems, cannot be controlled in studies conducted in different settings in various countries. A better design is to study different groups within the same setting. The group of investigators at Yale [17,47] found that nonwhite patients (97% of who were African Americans) were about twice as likely to develop TD even after adjusting for dose and duration of exposure. In their sample of 266 patients, which included

The Epidemiology of Tardive Dyskinesia

45

215 Caucasians and 32 African Americans, Jeste and co-workers [20] reported an annual cumulative incidence rate of 26% in Caucasians and 48% in African Americans. The two groups did not differ significantly in daily neuroleptic dose or duration of treatment. Of the studies that examined the relationship with ethnicity, it appears that African Americans may have a heightened vulnerability for TD. However, it would be premature to come to any conclusion about the role of ethnicity in TD. The considerable methodological issues mentioned may give rise to conflicting results. There is also the problem of making an accurate assessment of ethnicity, especially in a multiracial society [48]. Even when a significant relationship is demonstrated, the association may be caused by genetic factors and/or environment factors such as diet, smoking, alcohol consumption, and medication types and dosages [49]. Neuroleptic Drugs While there has always been a suspicion that neuroleptic drug dose is important in the risk of TD, empirical evidence for this was lacking. Recent longitudinal studies have provided empirical support for higher dose increasing the risk [16,38]. It is possible that in previous studies this dose effect was masked by the high current doses the subjects were receiving, and became apparent when patients were treated with lower doses [50]. The dose effect may, moreover, be apparent in the first few years of exposure to drugs. Taking the dose and duration of use together, the total neuroleptic load is considered to be a risk factor. The data in relation to neuroleptic blood levels and the development of TD are inconsistent. While one study [51] suggested a positive correlation between neuroleptic plasma levels and TD, another study found no such relationship [52]. Whether drug type is important has remained controversial. There is no convincing evidence that, once drug dosage has been accounted for, any of the conventional neuroleptics presents a differentially smaller risk; nor is there empirical evidence that depot neuroleptics are more likely to cause TD [11]. Studies of this issue are limited by the use of polypharmacy and the common occurrence that many patients received different neuroleptics at different times. All the atypical neuroleptics have in common a high serotonin-to-dopamine receptor blockade ratio in the brain, and this high serotonergic blockade is thought to play a role in reducing acute extrapyramidal symptoms [53]. A corollary is that these atypical neuroleptics would have a lower liability to cause TD. The evidence for this is still preliminary. While there are anecdotal reports of TD with risperidone [54,55], olanzapine [56,57], and quetiapine [58], there is no convincing report of TD with clozapine monotherapy, and this may indeed be the safest drug [11,59]. Clozapine may be successful in improving TD and present a lower risk for TD [60], and has therefore been proposed as a treatment for TD

46

Chong and S. Sachdev

[61,62]. However, it is unclear whether it helps some patients with TD by merely permitting spontaneous remission, or whether, in fact, it represents active treatment. There are a limited number of drug trials which compared atypical neuroleptics with another atypical or a typical neuroleptic agent for the incidence of TD (Table 3). These studies have included patients with mixed diagnosis as well as past history of illness and exposure to typical neuroleptics. The periods of these studies were also short. Long-term prospective studies with drug-naive patients are needed before their lower risk can be generally accepted. The practice of drug holidays, which was once advocated to reduce the total neuroleptic load in an individual, is now believed to be either ineffective or in fact harmful by increasing the risk of TD [63]. Brief intermittent or targeted treatment may, however, offer an advantage, but it should be further investigated and balanced against any increased risk of schizophrenic relapse [64]. Other Drugs The role of anticholinergic drugs in the development of TD remains controversial. Anticholinergic drugs are known to exaggerate TD or make latent TD become manifest, but there is no convincing evidence they are risk factors for TD per se [11] however, in a population of 1745 patients, Muscettola et al. [6] reported that the combined use of neuroleptic and anticholinergic drugs was associated with a significantly increased rate of TD. Patients with extrapyramidal symptoms are more likely to receive anticholinergic medication, and it may be that the presence of these symptoms (which usually precede the onset of TD) is, in fact, a predictor of TD vulnerability. The concurrent administration of lithium in affective disorder could possibly reduce the risk of TD, as suggested by animal data [65]. However, subsequent animal studies [66] showed that lithium augmented the amphetamine effect on the development of dopamine receptor supersensitivity, and this is consistent with other clinical reports suggesting that lithium could reinduce or exacerbate the vulnerability for TD [67–69]. A review of 71 case studies [70] indicates that there seems to be a causal relationship between selective serotonin reuptake inhibitors (SSRIs) and extrapyramidal syndromes including TD. There is no prospective study that has systemically examined the incidence of treatment-emergent TD with these agents, although the impression is that it is an uncommon phenomenon [71]. Genetic Factors Genetic predisposition to TD has been suggested from family studies that show concordance for TD among first-degree relatives of patients with TD [72,73]. As the hypothesis for the pathophysiology posits a state of dopamine receptor

AIMS, Abnormal Involuntary Movements Scale.

a

Conley et al., 2001 [148]

Randomized double-blind study of quetiapine vs haloperidol Randomized double-blind study of olanzapine vs risperidone

Risperidone vs haloperidol

Jeste et al., 1999 [146] Copolov et al., 2000 [147]

Tran et al., 1997 [145]

Randomized, double-blind comparative study of clozapine vs haloperidol Double-blind maintenance phases of 3 acute studies of olanzapine vs haloperidol Randomized, double-blind study of olanzapine vs risperidone

Studies

Rosenheck et al., 1997 [60] Beasley et al., 1999 [144]

Authors

Schizophrenia and schizoaffective disorder

Chronic and subchronic schizophrenia

337

448

8 wk

6 wk

9 mo

28 wk

339

122

2.6 yr

174

Schizophrenia, schizoaffective and schizophreniform psychosis Schizophrenia, schizoaffective and schizophreniform psychosis

1 yr

Duration

423

N

Treatment-refractory Schizophrenia

Population

TABLE 3 Comparative Studies on Risk of TD Among Various Neuroleptics

Significant improvement in AIMS score in quetiapinetreated group No significant difference in Dyskinesia item total score of the Extrapyramidal Symptom Rating Scale

Pooled data analysis: 1 yr risk for tardive dyskinesia with olanzapine (0.52%) vs haloperidol (7.45%) Tardive dyskinesia as according to Schooler & Kane criteria: olanzapine (4.6%) vs risperidone (10.7%)

Significant reduction in AIMS in clozapine-treated group

Outcomea

The Epidemiology of Tardive Dyskinesia 47

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Chong and S. Sachdev

hypersensitivity from chronic neuroleptic treatment, an obvious candidate gene is the D2 receptor gene. Chen et al. [74] reported a significant association between the dopamine D2 receptor gene (DRD2) and TD; however, this was not replicated by other investigators [75,76]. Dopamine D3 receptor polymorphism has been implicated as a vulnerability factor in some reports [77,78] but not all [75]. The interindividual variation in vulnerability for TD also suggests a pharmacogenetic component. A particular line of investigations has focused on the genetic polymorphism of the cytochrome P450 isoenzyme, debrisoquine 4-hydroxylase (CYP2D6). The poor metabolizer (PM) phenotype, characterized by lack of CYP2D6 activity, is caused by a number of mutations [79] that may confer a greater vulnerability for concentration-dependent side effects including TD. Andreassen et al. [80] reported an increased (but not significant) susceptibility of PM to TD. Ohmori et al. [81] also found a positive association between TD and a particular PM (CYP2D*10) allele, but not with the CYP2D6*2 allele [82]. Heterozygous carriers for other mutations (CYP2D6*3, CYP2D*4, and CYP2D6*5) may also be more vulnerable to developing TD [83]. Diabetes Mellitus There is some evidence that diabetes increases the risk of both spontaneous dyskinetic movements (21%) and TD (79% in diabetics versus 53% in nondiabetics) [84]. Woerner et al. [85] reported a risk ratio of 2.3 for diabetics exposed to neuroleptics compared to similarly treated nondiabetics, with the risk greater in aged diabetics. Fasting blood glucose is higher among those with tardive dyskinesia [86]. Schultz et al. [87] reported that patients with impaired glucose tolerance had higher mean AIMS scores (although not reaching statistical significance) and an association between the magnitude of the fasting insulin level and abnormal movements. The pathophysiology of this association between hyperglycemia and TD is unknown. Glucose-induced dopamine sensitivity has been suggested in animal studies [88], and a possible genetic factor may also be involved, as suggested by a report which found greater incidence of diabetes in relatives of patients with TD [89]. Neuropsychiatric Disorder A number of investigators have commented on a higher relative incidence of TD in patients with affective disorder treated long-term with neuroleptics [18,90,91], but this finding is inconsistent, and may apply to early- and not late-onset TD [92]. Kane et al. [18] reported incidence figures of 26% for affective and schizoaffective disorders, and 18% for schizophrenia. A positive family history of affective disorder in schizophrenic patients has also been associated with increased risk of neuroleptic-induced TD [93]. Depression may, furthermore, produce a

The Epidemiology of Tardive Dyskinesia

49

state-dependent exacerbation of TD [94], while mania may lead to the reverse [95]. Whether schizophrenia increases or decreases the risk for TD is not known. The similarity between the spontaneous dyskinesias of schizophrenia and TD has been suggested as evidence for schizophrenia as a risk factor, but the opposite has also been suggested [96]. Within schizophrenia, those with the negative syndrome, or evidence of cognitive impairment and neurological deficits, are reported to be more at risk [97], and the presence of TD indicates a poorer prognosis for schizophrenia. The presence of brain damage (as evidenced by epilepsy, head trauma, dementia, etc.) has been suggested as a risk factor. High rates (34%) have also been reported in neuroleptic-treated individuals with mental retardation [98,99]. Yassa et al. [100], in a study of 300 patients treated with neuroleptics and who had organic mental disorders, found that brain damage was a risk factor, but the evidence was inconsistent [30]. TD is known to develop in Tourette’s disorder patients treated with neuroleptics, but the prevalence rate, though not well studied, is likely to be lower than that seen in schizophrenia, possibly because of the youth of the patients and the lower neuroleptic doses used [96]. Extrapyramidal Side Effects Several reports have suggested that early extrapyramidal side effects (EPS) are a risk factor for the later development of TD. Kane et al. [101], reported that patients with a history of severe EPS were 2.3 times more likely to develop TD than those without such a history. Two prospective studies of elderly patients [20,21] found that the presence of EPS early in treatment was a predictor of TD. Chatterjee et al. [102], in a prospective study of 89 neuroleptic-naive and firstepisode patients with schizophrenia, did not find any correlation with EPS and TD. However, the sample comprised young adults, and the period of follow-up (234 weeks) may have been insufficient for the risk to manifest itself. The Yale group [17] also found a relationship between TD and history of EPS, but the clinical history was obtained retrospectively and therefore may not have identified all cases of TD. The putative role of EPS is in keeping with the supersensitivity hypothesis of TD, suggesting a vulnerability to extrapyramidal symptoms in these patients. The basis of this sensitivity to ‘‘basal ganglia disease’’ is not well understood though. Electroconvulsive Therapy A history of electroconvulsive therapy (ECT) has been suggested as a predictor for TD vulnerability [100], although other studies showed no such association [11,103,104], and one study indicated a lowering of risk [105]. A history of ECT

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may be an epiphenomenon in that patients who had received ECT could be a subgroup with severe mood or ‘‘true’’ mood disorders, the presence of which be may a risk factor for TD [28]. Substance Use Two studies have reported a positive correlation between smoking and TD [106,107]. Menza et al. [108] found a positive association between higher neuroleptic doses and smoking but not between TD and smoking. Alcohol abuse has been reported to increase the risk of TD [109–114], with one study suggesting a three-fold increase in risk [113]. Alcohol has been suggested to increase the vulnerability for TD through its neurotoxic effect [113], or indirectly by being related to other factors such as poor compliance and hence intermittent exposure [115]. Iron Status One of the hypotheses for the pathogenesis of TD is that it is due to the neurotoxic effects from free radicals, which are the by-products of increased catecholamine metabolism caused by D2 receptor-blocking medications [116]. As iron is a catalyst of free-radical damage, it may have a role in free-radical-mediated neurotoxicity, especially in the basal ganglia, where both iron and dopamine levels are high [117]. Wirshing et al. [118] found a significant positive correlation between serum iron indices (ferritin, iron, and total iron-binding capacity) and AIMS scores in 30 patients with schizophrenia. One postmortem report showed extensive iron deposition in the basal ganglia and substantia nigra in a man with bipolar affective disorder and persistent TD [119]. Magnetic resonance imaging (MRI) enables the in-vivo assessment of brain iron status, and one MRI study suggested increased caudate iron levels in schizophrenic patients compared to patients without TD [120]. Elkashelf et al. [121], on the other hand, found no difference in basal ganglia iron between schizophrenic patients with and without TD. Technical problems and poor specificity of simple T2 measures may account for these inconsistencies [118]. Edentulism Oral dyskinetic movement may be secondary to edentulousness [122], but the possible underlying mechanism remains speculative. Two studies showed that neuroleptic-treated edentulous patients had more severe ratings of tardive dyskinesia [123,124]. Inferring from the observation that lesions of the globus pallidus alter trigeminal sensory-induced reflexive neck muscle activity in rats, Sandyk and Kay [124] suggested that edentulousness, by disrupting trigeminal proprioceptive input from the oral cavity to the basal ganglia, may increase the risk

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for TD. The edentulous state may be a marker of the ‘‘true biological age’’ of the patient, FUTURE DIRECTIONS There has been significant progress in the understanding of the epidemiology of TD and its risk factors. The increasing use of atypical neuroleptics has made it necessary that the epidemiology of TD be revisited, with the expectation that the newer drugs will lower the incidence of TD and provide new insights into its pathophysiology. The issue of interethnic differences needs to be elucidated with well-designed studies, preferably by the same investigators among different ethnic groups in the same setting. Longitudinal studies of patients who receive atypical neuroleptics as their primary treatment from the first episode of psychosis onward are necessary to assess the incidence of TD with these drugs and to distinguish drug-induced TD from spontaneous dyskinesia. Epidemiological studies help us understand the pathophysiology of the disorder. The dopamine receptor supersensitivity hypothesis of TD [125] that dominated debate in the 1970s and 1980s has a number of limitations. It does not explain the observation that supersensitivity in animals is almost invariable, whereas TD develops in only a fraction of patients, nor does it explain the spontaneous occurrence of dyskinesia in many schizophrenic and healthy subjects, and the increased risk with age and many other host factors. Another hypothesized mechanism posits that TD is the consequence of neuroleptic-induced neuronal loss, particularly in the striatum [116], from production of free radicals and excitotoxicity, both of which lead to apoptotic death of neurons. Neuroleptics lead to the accumulation of iron in the basal ganglia that may be neurotoxic through free-radical mechanisms [126]. It is also possible that both mechanisms operate concurrently to produce the varying features of TD. Further epidemiological work, complemented by genetic, brain imaging, and animal studies, will help address the important issue of the pathophysiology of TD and set the stage for a rational therapy. REFERENCES 1. Schooler NR, Kane JM. Research diagnosis for tardive dyskinesia (letter). Arch Gen Psychiatry 1982; 39:486–487. 2. Jeste DV, Wyatt RJ. Understanding and Treating Tardive Dyskinesia. Guilford. New York, 1982. 3. Kane JM, Smith J. Tardive dyskinesia: prevalence of risk factors, 1959–1979. Arch Gen Psychiatry 1982; 39:473–481. 4. Yassa R, Jeste DV. Gender differences in tardive dyskinesia: A critical review of the literature. Schizophr Bull 1992; 18:701–715.

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127. Chorfi M, Moussaoui D. Lack of dyskinesias in unmedicated schizophrenics. Psychopharmacology 1989; 97:423. 128. Puri BK, Barnes TR, Chapman MJ, Hutton SB, Joyce EM. Spontaneous dyskinesia in first episode schizophrenia. J Neurol Neurosurg Psychiatry 1999; 66:76–78. 129. Gervin M, Browne S, Lane A, Clarke M, Waddington JL, Larkin C, O’Callaghan E. Spontaneous abnormal involuntary movements in first episode schizophrenia and schizophreniform disorder: Baseline rate in a group of patients from an Irish catchment area. Am J Psychiatry 1998; 155:1202–1206. 130. Fenn DS, Moussaoui D, Hoffman WF, Kadri N, Bentounssi B, Tilane A, Khomeis M, Casey DE. Movements in never-medicated schizophrenics: A preliminary study. Psychopharmacology (Berl) 1996; 123:206–210. 131. Fenton WS, Wyatt RJ, McGlashan TH. Risk factors for spontaneous dyskinesia in schizophrenia. Arch Gen Psychiatry 1994; 51:643–650. 132. Casey D, Moussaoui D, Hoffman W, Kadri N, Fenn D, Tilane A, Green C, Lakloumi M, Bousaid F, Bentounssi B. Choreo-athetoid movements occur spontaneously in never-medicated patients with schizophrenia. Eur Neuropsychopharmacol 1996; 6(suppl 3):223. 133. Cassady SL, Adami H, Moran M, Kunkel R, Thaker GK. Spontaneous dyskinesia in subjects with schizophrenia spectrum personality. Am J Psychiatry 1998; 155: 70–75. 134. Caligiuri M, Lohr JB, Jeste DV. Parkinsonism in neuroleptic-naive schizophrenic patients. Am J Psychiatry 1993; 150:1343–1348. 135. Turner T. Rich and mad in Victorian England. Psychol Med 1989; 19:29–44. 136. McCreadie RG, Ohaeri JU. Movement disorder in never and minimally treated Nigerian schizophrenic patients. Br J Psychiatry 1994; 164:184–189. 137. Owens DG, Johnstone EC, Frith CD. Spontaneous involuntary disorders of movement: Their prevalence, severity, and distribution in chronic schizophrenics with and without treatment with neuroleptics. Arch Gen Psychiatry 1982; 39:452–461. 138. Owens DG, Johnstone EC. The disabilities of chronic schizophrenia: Their nature and the factors contributing to their development. Br J Psychiatry 1980; 136: 384–395. 139. McCreadie RG, Thara R, Kamath S, Padmavathy R, Latha S, Mathrubootham N, Menon MS. Abnormal movements in never-medicated Indian patients with schizophrenia. Br J Psychiatry 1996; 168:221–226. 140. McCreadie RG, Barron ET, Winslow GS. The Nithsdale Schizophrenia Survey, II: abnormal movements. Br J Psychiatry 1982; 140:587–590. 141. Owens DG. Involuntary disorders of movement in chronic schizophrenia: The role of the illness and its treatment. Psychopharmacology 1985; 2:79–87. 142. Gibson AC. Incidence of tardive dyskinesia in patients receiving depot neuroleptic injection. Acta Psychiatr Scand 1981; 297:111–116. 143. Chouinard G, Annable L, Mercier P, Ross-Chouinard A. A five-year follow-up study of tardive dyskinesia. Psychopharmacol Bull 1986; 22:259–263. 144. Beasley CM, Dellva MA, Tamura RN, Morgenstern H, Glazer WM, Ferguson K, Tollesfson GD. Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol. Br J Psychiatry 1999; 174:23–30.

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145. Tran PV, Hamilton SH, Kuntz AJ, Potvin JH, Andersen SW, Beasley C, Tollefson GD. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol 1997; 17: 407–418. 146. Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ, Caligiuri MP. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999; 47:716–719. 147. Copolov DL, Link CGG, Kowalcyk B. A multicentre, double-blind, randomised comparison of quetiapine (ICI 204,636, ‘Seroquel’) and haloperidol in schizophrenia. Psychol Med 2000; 30:95–105. 148. Conley RR, Mahmoud R. A randomised double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. Am J Psychiatry 2001; 158:765–774.

4 Drug-Induced Parkinsonism K. Ray Chaudhuri King’s College Hospital and University Hospital Lewisham, London, England

Joanna Nott Guy’s King’s and St. Thomas’s School of Medicine and King’s College London, England

INTRODUCTION Drug-induced parkinsonism (DIP) is most frequently recognized as an extrapyramidal motor complication of dopamine receptor-blocking neuroleptic agents which are used to treat various neuropsychiatric disorders [1,2]. However, a range of other drugs apart from neuroleptics have also been reported to cause parkinsonism, as illustrated in Table 1. At first glance, DIP appears phenotypically similar to idiopathic Parkinson’s disease (PD), since tremor, rigidity, and bradykinesia occur in both. However, DIP is usually described with bilateral symptoms, particularly at the onset, which is unusual in the idiopathic form. Evidence shows that DIP appears to develop in any patient given sufficient dose of dopamine receptor antagonist so as to block approximately 80% of central dopamine receptors [3] and that the majority of cases are completely reversible. Most of this review will focus on DIP caused by neuroleptics. 61

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EPIDEMIOLOGY AND RISK FACTORS FOR NEUROLEPTICINDUCED PARKINSONISM The dopaminergic theory of schizophrenia hypothesizes that psychoses are caused by overactivity of mesocortical and mesolimbic dopaminergic pathways. Hence, in the past, dopamine receptor antagonists have formed the mainstay of treatment for schizophrenia. Studies estimate the frequency of DIP after exposure of neuroleptics at between 15% and 60% depending on the type of neuroleptic, the dose, and possibly, underlying patient susceptibility [3,4]. Furthermore, depot preparation of neuroleptics have been reported to cause DIP in 89% of a cohort of schizophrenic patients over a 6-month follow-up period [5]. This may, however, be due to the fact that depot preparations tend to block a higher percentage of dopamine receptors. The elderly may be more susceptible, as studies of DIP in the elderly show that they are five times more likely to take an antiparkinsonian drug if they are on neuroleptics than a control group of non-neuroleptic users [70]. Recovery from DIP usually occurs within several months of withdrawal, although it may take up to 15 months and in a minority of patients DIP may persist and progress [6,7]. DIP is regarded as part of an acute extrapyramidal syndrome that develops after exposure to neuroleptics, as opposed to tardive dyskinesia that occurs during chronic neuroleptic treatment [8]. Although manageable by discontinuing the offending drug, acute extrapyramidal syndromes cause significant physical and mental disability and may cause patients to discontinue drugs required for mental health. The prevalence of DIP and other acute extrapyramidal reactions to neuroleptics seem to be steadily rising, possibly due to use of higher drug dosages. In vulnerable groups such as patients with AIDS, these reactions may occur in 100% of cases [71]. In a subset of patients, DIP can be severe and idiopathic PD may emerge after apparent recovery from DIP [3–7]. This raises the possibility that DIP may unmask idiopathic PD or even accelerate the emergence of the idiopathic type. A genetic basis for DIP has been postulated based on case reports indicating a familial predisposition to DIP and a bias toward the female sex [4,9,10]. Family history may also be relevant, as Gartmann and colleagues reported six patients with family history of PD who developed DIP on neuroleptics while others without family history of PD tolerated neuroleptics without side effects [10]. Other postulated risk factors for development of DIP are listed in Table 2. PATHOPHYSIOLOGY Receptor Blockade and Neurotransmitter Involvement DIP appears to develop in virtually 100% of patients given high doses of high-potency dopamine receptor-blocking agents sufficient to block about 80% of central dopamine receptors [15]. Drug-induced depolarization blockade of the A9 dopami-

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TABLE 1 Drugs Reported to Cause Parkinsonism Drug name Neuroleptics Phenothiazines, butyrophenones, thioxanthenes Vestibular sedatives Cinnarizine, flunarizine Ca channel antagonists Amlodipine, diltiazem Manidipine, verapamil Amiodarone Amphotericin B Bupropion Cephaloridine Clebopride Co-trimoxazole Cyclosporin Disulfiram Fluoxetine (⫹ other SSRIs) Lithium Manganese Meperidine Metclopramide, domperidone, metoprimazine, trithylperazine Methyldopa Methylphenidate Phenelzine Pentoxifylline Procaine Reserpine Tacrine Vaccines Valproic acid Veralipride

Use

References

Antipsychotic

Vestibular disorders

24,25

Cardiovascular

26 27 28 29 30 73 31 32 33 34 35 36 37 38 39 72

Antiarrythmic Antineoplastic Nicotine dependence Antimicrobial Neuroleptic Antimicrobial Immunosuppressant Alcoholism Antidepressant Antipsychotic Parenteral nutrition Analgesic Antiemetic Hypertension Attention deficit Antidepressant Peripheral vascular disease Local anaesthetic Antihypertensive Cognitive therapy Vaccination Epilepsy Menopause

40 41 42 74 43 41 44 45 46, 47, 75 72

nergic neurons within the substantia nigra is thought to result in DIP [16] and in rat models, neuroleptics appear to suppress formation of striatal and ventral tegmental dopaminergic neurons [17]. Both dopamine D1-like and D2-like receptors in the striatum have been implicated, but D2 receptor blockade appears to be important and it is the main site of action for most of the typical neuroleptics [8]. A confound-

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TABLE 2 Suggested Risk Factors for Development of DIP Postulated risk factorsa

References

High-dose, low-milligram, high-potency drug use Piperazine side chain in neuroleptics Age: Elderly Sex: Female:Male ⫽ 2 : 1 Heritable susceptibility (FH of PD) Preclinical parkinsonism Cerebral atrophy AIDS Coexistence with tardive dyskinesia

8 8 6, 70 2 9, 10 11 12 13, 71 14

FH ⫽ family history; AIDS ⫽ acquired immune deficiency syndrome.

a

ing aspect is the discrepancy in time between the molecular action of the drugs and the onset of DIP. While neuroleptics block the dopamine receptors within minutes to hours, DIP appears after a time lag of many days following drug exposure, suggesting that there is a complex relationship between exposure to neuroleptic drugs and the development of DIP [8]. Some workers suggest that the dose–response curve between drug dose and development of DIP is similar to a U-shaped curve and thus moderate doses are more harmful than very high or low doses [8]. Furthermore, the effects of these drugs on neurotransmitters and receptors apart from the dopaminergic system, such as acetylcholine, serotonin, histamine, norepinephrine, and GABA (gamma-aminobutyric acid) receptors, may also contribute to the development of DIP and other extrapyramidal side effects [8]. Comparative ratios between relative antagonism at different receptors may also be important. For instance, reports suggest that: 1. A high degree of acetylcholine/dopamine receptor antagonism produces a decreased frequency of acute extrapyramidal reactions. 2. A favorable ratio between serotonin (S2) and dopamine (D2) receptor antagonism will produce relatively less extrapyramidal effects including DIP [18]. Evidence in favor of hypothesis 1 is that low-milligram, high-potency compounds such as haloperidol and fluphenazine containing a piperazine side chain have little anticholinergic action and cause DIP more readily than compounds such as chlorpromazine or thioridazine (with piperidine or aliphatic side chams), which have relatively more anticholinergic action. Cholinergic hyperactivity in DIP is also suggested by the response of this syndrome to anticholinergic drugs. It has been suggested that cholinergic hyperactivity causes activation of inhibitory GABAergic pathways projecting to the thalamus within the stratum. This in turn

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would lead to emergence of bradykinesia and rigidity. It had been previously thought that risperidone showed a decreased propensity for extrapyramidal side effects, but it seems that despite its putative 5-HT2 occupancy, DIP still occurs at high frequencies [68] Drug dose has been implicated in the development of DIP, and most but not all studies indicate a positive correlation between blood levels and emergence of clinical signs of DIP [19,20] Susceptibility Due to ‘‘Preclinical’’ Parkinson’s Disease: Clinical and Positron Emission Tomography (PET) Studies In a proportion of cases with DIP, the condition may persist and some patients may develop idiopathic PD [1,3,6,7]. Rajput et al. suggested that there may be individual susceptibility to DIP, and these workers reported pathological evidence of nigral Lewy body disease in two patients who developed DIP on neuroleptic treatment with complete recovery on withdrawal of neuroleptics [3]. After death from unrelated causes, however, postmortem examination revealed slight to moderate loss of nigral dopaminergic cells and Lewy bodies, thus suggesting that ‘‘preclinical’’ PD may have predisposed both patients to DIP by exposure to neuroleptics. Three further patients, developing PD which after DIP was reversed following withdrawal of neuroleptic drugs, were reported by Goetz [1]. PD developed 12–30 months after reversal of DIP [1]. Other reports of PD (Table 3) developing in patients who had suffered from reversible DIP and reports of DIP developing in patients with a family history of PD suggest that there may be individual susceptibility to development of DIP, due to ‘‘preclinical’’ PD in these subjects. 18 F-dopa PET studies, which can detect subclinical nigral dysfunction, have been performed to study the nigrostriatal system in DIP patients so as to examine the hypothesis that ‘‘preclinical or latent’’ PD may predispose to DIP [21]. This is because 18F-dopa PET would examine striatal presynaptic dopaminergic integrity, which would be normal if DIP developed entirely secondary to postsynaptic striatal dopamine receptor blockade. In 4 of 13 DIP cases (31%) there was evidence of significant reduction of putamen 18F-dopa uptake within the PD range, and in 3 of the 4 cases (75%) there was continuing or worsening parkinsonism [21]. This study further supports the hypothesis that underlying nigrostriatal dopaminergic dysfunction may predispose to development of DIP in some subjects. A normal 18F-dopa PET scan, however, correlated well with recovery from DIP. CLINICAL FEATURES Neuroleptic-Induced DIP DIP appears to be indistinguishable from idiopathic PD and is characterized by development of rigidity, bradykinesia, and a typical parkinsonian rest tremor. The

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TABLE 3 Reports of Parkinson’s Disease Developing in Patients with a History of Reversible Drug-Induced Parkinsonism Author

No. of cases

Nature of study

Rajput et al. [3]

2

Goetz CG [1]

3

Pathological evidence of nigral cell loss and Lewy bodies IPD developing 12–30 months DIP was reversed 5 of 48 cases with DIP develop PD after mean 11 months (range 3–18 months) following recovery from DIP. Retrospective analysis of 72 DIP cases with 6 developing PD after an “asymptomatic period” DIP developing in a cohort of patients with family history of PD

Stephens & Williamson [6]

5/48

Marti Masso et al. [7]

6/72

Gartmann et al. [10]

6

condition develops after 2 weeks and almost always within a month of neuroleptic exposure and tends to coincide with clinical improvement of schizophrenia [8]. Bradykinesia, however, may be difficult to recognize because of depression or negative symptoms of schizophrenia. In some patients, tolerance to parkinsonian effects may develop and symptoms may disappear or improve after some months of continued treatment or may merge into development of tardive dyskinesia [14]. Tremor is relatively uncommon, although a distinct syndrome known as the rabbit syndrome may develop in some patients and is manifested as perioral lip tremor that may occur at any time during neuroleptic treatment [22,23]. This tremor has the typical characteristics of parkinsonian tremor and tends to respond to antiparkinsonian agents. In some cases, severe parkinsonism may be provoked by high doses of high-potency neuroleptics, resulting in a syndrome that resembles catatonia. This may progress to mutism or akinetic mutism that may be confused with schizophrenic symptoms. Non-neuroleptic DIP A whole range of drugs has been reported to cause DIP (Table 1). Most of these are based on sporadic or isolated case reports, although some associations may be more robust and will be considered separately.

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DIP Due to Vestibular Sedatives A common cause of DIP, apart from that induced by neuroleptics, is the use of the vestibular sedatives cinnarizine and its derivative flunarizine [24,25]. Cinnarizineinduced parkinsonism was first reported in 1985, and its ability to aggravate PD was reported in 1986 [24,48]. These drugs are used to treat peripheral vestibular disorders or vestibular nausea and possess marked antihistaminergic and calcium channel-blocking activity. A retrospective study spanning 15 years revealed 74 cases of DIP due to cinnarizine among 172 cases of DIP [24]. Cinnarizine-induced parkinsonism was more common in women, similar to neuroleptic-induced DIP, and complete recovery occurred in most subjects within 1–16 months after withdrawal of cinnarizine. However, 11 patients developed PD and in 4, PD developed 12–72 months after recovery from cinnarizine-induced parkinsonism. The most common manifestation of vestibular sedative-induced parkinsonism appears to be rigidity and a parkinsonian rest tremor or a bilateral distal postural tremor (see Table 4) [49]. Drug dose is important, and the risk appears to be low in those taking less than 150 mg of cinnarizine. The time course to onset of symptom is variable and may range from days to years. The symptoms are reversible in most cases after withdrawal of the vestibular sedative, although in some cases progressive parkinsonism may occur [24]. The mechanism is unclear and is possibly linked to the calcium-antagonist action of vestibular sedatives. Studies have indicated that cinnarizine can inhibit lipid peroxidation and block postsynaptic striatal dopamine receptors. Indeed, systemic injection of flunarizine in mice induces a transient loss of tyrosine hydroxylase immunoreactive nigrostriatal neurons without cell loss [50–52]. More recent studies show that cinnarizine is a potent uncoupler of the HⳭ-ATPase in catecholamine storage vesicles, thus possibly inhibiting dopamine uptake into storage vesicles in vivo [66]. Cinnarizine is also thought to have a toxic effect on monoamine and serotonin neurons, and in old mice treated with cinnarizine there is reduced numbers of dopamine D1 and D2 receptors in different brain

TABLE 4 Symptoms Reported in Cinnarizine-Induced Parkinsonism Rigidity and akinesia Bilateral rest tremor Unilateral tremor Tremor, rigidity, and akinesia Postural tremor at onset Perioral tremor Source: Ref. 24.

46% 37% 13% 5% 51% 23%

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regions [24]. It is likely, therefore, that a combination of presynaptic dopamine depletion, postsynaptic dopamine receptor blockade, and effects on nondopaminergic neurons may be responsible for cinnarizine-induced parkinsonism. DIP Due to Other Calcium Channel Antagonists These dihydropyridine and nondihydropyridine calcium channel antagonists are frequently used to control cardiovascular conditions such as angina, hypertension, and tachyarrythmias. Various movement disorders have been described with their use, and drugs such as amlodipine, manidipine, diltiazem, and verapamil have been reported to aggravate or unmask parkinsonism (Table 1). The effects are reversible, and rechallenge in one case caused reemergence of parkinsonism [53]. These agents inhibit L-type voltage-gated calcium channels, and it is known that the burst activity of dopaminergic nigral neurons is mediated through L-type voltage-gated calcium channels [54]. Another possible mechanism may be mediated via an L-type calcium channel-independent inhibition of anatoxin-a, a potent nicotinic agonist which facilitates dopamine release from striatal synaptosomes [55]. DIP Due to Valproic Acid A range of motor abnormalities including postural tremor and parkinsonism has been reported after chronic valproate use [46]. Parkinsonism related to valproate use is of insidious onset and typically mimics PD. In a study evaluating 36 patients in an epilepsy clinic taking therapeutic levels of valproate for at least 12 months, 32 patients had very mild to advanced forms of parkinsonism on formal assessment [46]. This parkinsonian syndrome is reversible, and discontinuation of valproate led to subjective and objective improvement in 96% of affected subjects after 3 months of follow-up. Unsteadiness and tremor were most reversible. Total Unified Parkinson’s Disease Rating Scale (UPDRS) assessments showed a mean value of 29.7 Ⳳ 21.7 on valproate, falling to 10.1 Ⳳ 12.6 at follow-up [46]. Several authors have reported cases with parkinsonism developing in association with valproate, and these are listed in Table 5 [56–59]. Our own observations in a cohort of epileptic patients on chronic valproate therapy (⬎1.2 g/day) suggest that a variety of tremors—resting, postural, and kinetic—could result from valproate use, along with a mild asymmetric akinetic rigid syndrome [75]. This syndrome may be compounded by hearing loss and cognitive slowing and appears to affect the elderly more frequently [75]. A minimum period of exposure to valproate for 12 months is thought to be necessary for parkinsonism to develop. The mechanism of valproate-induced parkinsonism is poorly understood and is likely to be complex and multifactorial. Valproate increases brain levels of GABA, suppresses repetitive firing of neurons, and also attenuates current through the T-calcium channel [60]. Valproate therapy may cause defective func-

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TABLE 5 Valproate-Induced Parkinsonism Authors

No. of cases

Comments

Armon et al. [46]

32/36 affected

Park-Matsumoto & Tazawa [56]

3 cases

Del Real Francia et al. [57] Froomes and Stewart [58] Alvarez-Gomez et al. [59] Agapito et al. [75]

2 cases

Reversible parkinsonism in 96% after 12 months exposure to valproate Parkinsonism after 7–41 months following 800 mg of valproate exposure Reversible parkinsonism several years after starting therapy Parkinsonism and hepatotoxicity after addition of carbamazepine Parkinsonism in childhood following valproate treatment Reversible parkinsonism complicated by deafness after long-term valproate therapy

1 case

4/14 cases

tioning of the mitochondrial enzyme NADH CoQ reductase (Complex 1) in vitro, and complex 1 activity has been shown to be impaired in PD [61,62]. Furthermore, current models of basal ganglia circuit in PD suggest that activation of GABAergic inputs from internal palladium to the thalamus may cause akinesia. Chronic valproate therapy thus may aggravate the GABAergic inhibitory impulses to the thalamus. Paradoxically, however, in the 1970s, valproate therapy was advocated in PD and levodopa-induced dyskinesias [63,64]. MANAGEMENT Management of Established DIP Syndromes Due to Neuroleptics Management of established DIP syndromes due to neuroleptics includes the following stages. 1. Prophylaxis: This can be achieved by using an antiparkinsonian agent at the start of neuroleptic treatment, although this strategy remains controversial. Some authorities argue that these dopaminergic agents can cause side effects such as dysautonomia, neuropsychiatric problems, and memory difficulties, which can complicate management issues. A reasonable approach may be to cover patients with a family history of PD, elderly patients, and females with dopaminergic agents

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such as amantadine or anticholinergics when starting neuroleptic treatment (particularly if a high-dose, high-potency compound is used), as these patients appear to have an increased risk of DIP. 2. Treatment emergent symptom management: This can be managed with anticholinergic and antihistaminic agents. Amantadine also seems to be effective in this respect [8]. In some patients with severe DIP, a small dose of levodopa may be helpful, and while there is some evidence to show that high doses of levadopa are not useful, the evidence remains unclear. 3. Extended prophylaxis: This is required if the neuroleptic agents are used for more than 3 months. Prophylaxis could be achieved through the use of anticholinergic agents, although this needs review, as some patients develop tolerance to DIP. In most cases, the condition is reversible once the offending agent is withdrawn. However, in some cases the condition may necessitate neuroleptic therapy, and in these cases reduced doses of the neuroleptic or changing to an atypical neuroleptic may be useful. Clozapine, an atypical neuroleptic, has a very low acute extrapyramidal syndrome profile and is a high-milligram, low-potency anticholinergic compound, although it may cause agranulocytosis in approximately 1% of cases [65,67]. Other atypical neuroleptics are listed in Table 6, although it is to be noted that most do have antagonistic effects at dopamine D2 receptor, and therefore, in large doses will produce DIP. The risk, however, appears to be low with clozapine, quetiapine, and olanzapine, and relatively high with risperidone. DIP Due to Other Agents Vestibular sedative and valproate-induced DIP usually recover once the syndrome is recognized and the offending agent withdrawn. In some cases of cinnarizineinduced parkinsonism, levodopa has been used with beneficial effect because of a mistaken diagnosis of PD.

TABLE 6 Atypical Neuroleptics and Antagonist Effects on Brain Receptorsa

Clozapine Olanzapine Risperidone Sertindole Quetiapine

D2

5-HT

NA

Histamine

Muscarinic

⫹ ⫹⫹ ⫹⫹ ⫹ ⫹

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹

⫹⫹⫹ ⫹ ⫹⫹ ⫹⫹ ⫹⫹

⫹⫹⫹ ⫹ ⫺ ⫺ ⫹⫹

⫹⫹ ⫹ ⫺ ⫺ ⫺

5-HT ⫽ 5-hydrotryptamine; NA ⫽ noradrenaline.

a

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CONCLUSIONS The most common cause of clinically obvious DIP is the use of high-potency, high-dose typical neuroleptics, which modulate the dopaminergic systems within the brain. Subtle signs of asymmetric parkinsonism, however, can also be seen frequently in patients taking seemingly ‘‘innocuous’’ drugs such as vestibular sedatives used commonly for symptoms such as ‘‘dizziness’’ and motion sickness. A great many other drugs have also been reported to cause parkinsonism (Table 1), although often, true causality cannot be established due to polypharmacy and ethical issues surrounding rechallenge. Recently it is being increasingly recognized that valproate therapy may also cause a syndrome of tremulous parkinsonism, particularly in the elderly. This relationship needs close examination, as valproate is a commonly used, extremely effective first-line antiepileptic drug with a good safety profile. The development of parkinsonism, presumed secondary to valproate and a diverse range of other drugs as listed in Table 1, suggests that mechanisms other than manipulation of dopaminergic pathways may occur. A strong contender in this area may be calcium channel antagonism, which is shared by many of these drugs. Fortunately, the vast majority of cases of DIP have a reversible syndrome, although in a proportion these drugs may well unmask idiopathic Parkinson’s disease or a syndrome of progressive parkinsonism. REFERENCES 1. Goetz CG. Drug-induced parkinsonism and idiopathic Parkinson’s disease. Arch Neurol 1983; 40:325–326. 2. Ayd F. A survey of drug induced parkinsonism in older schizophrenics. JAMA 1961; 175:1054–1060. 3. Farde L, Wiessel FA, Halldin C, Sedvall G. Central D2 dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988; 45:71–76. 3a. Rajput AH, Rozdilsky B, Hornykiewicz O, et al. Reversible drug-induced parkinsonism: Clinicopathological study of two cases. Arch Neurol 1982; 39:644–646. 4. Korczyn AD, Goldberg GJ. Extrapyramidal effects of neuroleptics. J Neurol Neurosurg Psychiatry 1976; 39:866–869. 5. Bristow MLF, Hirsch SR. Pitfalls and problems of long-term use of neuroleptic drugs in schizophrenia. Drug Safety 1993; 8:136–148. 6. Stephen PJ, Williamson J. Drug-induced parkinsonism in the elderly. Lancet 1984; 2:1082–1083. 7. Marti Masso JF, Carrera N, Urtasun M. Drugs inducing parkinsonism in our environment [abstr]. J Neurol Neurosurgery Psychiatry 1991; 54:1025. 8. Casey DE. Neuroleptic induced acute extrapyramidal syndromes and tardive dyskinesia. Psychiatric Clin N Am 1993; 16:589–610. 9. Myrianthopoulos NC, Waldrop FN, Vincent BL. A repeat study of hereditary predisposition in drug-induced parkinsonism. In: Barbeau A eds., Brunette JR, Eds.

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5 Clinical Features and Management of Classic Tardive Dyskinesia, Tardive Myoclonus, Tardive Tremor, and Tardive Tourettism Maria L. De Leon De Leon Neurological Clinic Nacogdoches, Texas, U.S.A.

Joseph Jankovic Baylor College of Medicine Houston, Texas, U.S.A.

INTRODUCTION The term tardive syndrome refers to a collection of disorders that include the following criteria: (1) the dominant clinical feature is a movement disorder manifested chiefly by paucity or slowness of movement (hypokinetic disorders), an abnormal, excessive involuntary movements (hyperkinetic disorders), or increased muscle tone (rigidity); (2) the movement disorder is temporarily related to an exposure to at least one dopamine receptor-blocking drug (DRBD), also known as neuroleptic, within 6 months of the onset of symptoms; and (3) the disorder persists for at least 1 month after cessation of the offending drug [1,2]. Tardive dyskinesia (TD) has been defined by the American Psychiatric Associa77

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tion Task Force as abnormal involuntary movements induced by neuroleptic (DRBD) drug treatment for a period of 3 months in a patient with no other identifiable etiology for movement disorders [3]. DSM-IV criteria, however, specify that the duration of exposure to DRBD may be only 1 month in individuals 60 years or older [4]. Most drug-induced movement disorders are caused by DRBD, also known as neuroleptics. The term neuroleptic literally means ‘‘that which takes the neuron.’’ Deniker later used the word to denote a class of ‘‘major tranquilizers’’ [5]. The use of the term has gradually broadened to include antiemetics, antipsychotics, and other drugs that block dopamine receptors. While the classic neuroleptics block D2 dopamine receptors, concentrated chiefly in the striatum (caudate and putamen), the new atypical neuroleptics seem to be more specific for dopamine receptors in the mesolimbic system, which may be one reason why they are less likely to induce TD [6–14]. TD is the most recognized complication of DRBD therapy. However, these drugs can produce a variety of movement disorders, including acute dystonia, a sustained twisting movement, often occurring immediately after drug exposure. Acute dystonic reaction usually resolves spontaneously, but dystonia can persist permanently as a complication of neuroleptics and is referred to as ‘‘tardive dystonia’’ [15,16]. Tardive stereotypy is the most common form of TD. Akathisia, a term used to denote a feeling of inner restlessness, is usually seen within 3 months of neuroleptic administration but may persist as tardive akathisia after the offending drug is discontinued [16]. While acute dystonia often develops soon after offending drug is introduced, akathisia and parkinsonism tend to have a more subacute presentation, usually within 3 months of drug exposure [17,18]. Some patients, after prolonged exposure (month or years), develop a wide range of drug-induced movement disorders collectively referred to as tardive syndrome or tardive dyskinesia. This includes tardive stereotypy, tardive dystonia, tardive myoclonus, tardive akathisia, tardive tics, and tardive tremor. Tardive syndrome tends to run a persistent course despite cessation of the offending drug therapy, and in some cases the drug-induced movements may become permanent and irreversible. Five years after the introduction of chlorpromazine (Thorazine) in the early 1950s, three elderly women were described as having developed lip-smacking movements after 2–8 weeks’ exposure to this drug [19]. TD, however, was not described in the U.S. literature until 1960 [20]. The notion that TD was a rare disorder persisted for almost a decade, and it was not until the early 1970’s that the association of TD with long-term neuroleptic therapy was accepted [7]. The first therapeutic trials for TD followed shortly thereafter [21]. Since the first reports of TD, there has been a tendency by many authors to group all neuroleptic-induced movement disorders as ‘‘tardive dyskinesia’’ or ‘‘tardive syndrome.’’ Therefore, in the first half of the chapter we will focus on the differentiation of the various forms of TD and how to distinguish the more

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common tardive syndromes phenomenologically. The management strategies for the various drug-induced movement disorders and prevention guidelines will be reviewed in the second half. The term dyskinesia denotes any abnormal involuntary movement, regardless of etiology. It is commonly used in the context of drug-induced repetitive, coordinated, seemingly purposeful movements, so-called stereotypies. Stereotypy is the most common presentation of classic TD; other movement disorders seen in patients with TS include chorea, tics, dystonia, myoclonus, tremor, and miscellaneous involuntary movements [22]. The most typical presentation of TD is orofacial stereotypy. However, orofacial stereotypy can also occur spontaneously, as seen in edentulous elderly individuals [23–26]. Involuntary buccolingual masticatory movements (e.g., smacking, chewing, ‘‘fly-catching,’’ and puckering tongue movements) are the most typical and most frequently recognized manifestations of TD. However, many patients with TD exhibit a combination of movements disorders. Most frequently, stereotypy of classic TD is combined with choreic movements of the hands, fingers, arms, and feet [27] or with dystonia. The diaphragm and chest muscles are frequently involved in ‘‘respiratory dyskinesias’’ [28], resulting in noisy and difficult breathing which leads rarely to respiratory compromise and even respiratory arrest [29–33]. The abdominal and pelvic muscles may also be involved, producing truncal or pelvic rocking movements known as ‘‘copulatory’’ dyskinesia. Occasionally, hyperkinetic (e.g., stereotypy, chorea, dystonia, tics) and hypokinetic (parkinsonism) movement disorders coexist [34–36]. EPIDEMIOLOGY Although epidemiological data support neuroleptic exposure as the most significant etiological factor in the development of TD, some authors have continued to speculate on the relationship [7,37,38]. It is estimated that among individuals treated with neuroleptics, the prevalence of TD is of the order of 10–15% in the young population, 15–25% in slightly more chronic patients, and 25–45% in very chronic patients [39]. Yassa and Jeste found in a meta-analysis of 76 studies, including 39,187 patients with history of neuroleptic exposure, a mean prevalence rate of 24.2% [40]. Van Putten et al. estimate that between 400,000 and 1 million Americans have TD, and 4–6% of these are considered to have meaningful disability as a result of the movement disorder [39,41]. Several studies have concluded that age is a significant risk factor in TD. One study showed that during the first year of neuroleptic treatment, 50–70% of patients over 55 years develop TD [39]. Epidemiological studies of drug-induced movement disorders are difficult to interpret and compare largely because of nosological and methodological differences. For example, many studies fail to differentiate the various types of drug-induced movement disorders, and some use the term ‘‘extrapyramidal’’ to

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‘‘lump’’ any or all movement disorders occurring with or after exposure to DRBDs into the same category. Furthermore, hospital-based studies are more likely to unveil higher prevalence rate of TD than community-based surveys [42]. Therefore, not only differences in definition of TD, but the studied populations themselves may account for the discrepancy in the reported prevalence figures. Prospective studies have shown an annual incidence range from 3.7% to 12% [43,44]. According to Woerner et al. [42], spontaneous dyskinesias were observed in 1.3% of 400 healthy elderly people. At the same time, the rate among inpatient elderly individuals was three times as high (4.8%). The neuroleptic-associated dyskinesias, on the other hand, were found to be much higher, ranging from 13.3% to 36.1% depending on whether they were in voluntary or state psychiatric institutions, respectively [42]. In a recent review of cumulative incidence of tardive dyskinesia after exposure to neuroleptics in patients over age 45, the mean incidence at 1, 3, and 12 months were found to be 3.4%, 5.9%, and 22.3%, respectively [43]. Risk factors for development of TD most consistently defined by various epidemiological studies include affective disorder, advanced age, female gender, total cumulative drug exposure, diabetes, alcohol, cocaine intake, and persistence of neuroleptic drug use after the development of TD symptomatology and history of electroconvulsive treatment (ECT) treatment [44–52]. Miller and Jankovic studied 125 patients with drug-induced movement disorders and found 4- to-1 female preponderance for all tardive syndromes (i.e., tardive dyskinesia, akathisia, tremor, and parkinsonism) except tardive dystonia [53]. The study showed that while elderly women carry a higher risk for classic TD, young men are at a higher risk for tardive dystonia. More recently, Van Os et al. [54] noted that among younger patients, men had higher rates of TD, but higher rates were observed in women 40 years and older. Furthermore, spontaneous remissions are said to occur more readily in younger patients. Patients with drug-induced movement disorders prior to age 60 improve three times more often than older patients, over the age of 65 [55]. While age has been associated with an increase risk for TD, young age does not necessarily confer protection [56]. TD is quite rare in children [53,57,58], although withdrawal-emergent syndrome (discussed below) occurs almost exclusively in children. Diabetics were found to have more than twice the risk of developing TD than nondiabetics [50]. A long history of alcohol abuse or dependence also appears to be associated with an increased risk for developing TD, particularly the orofacial subtype [59–62]. Dixon and colleagues [63] reported that alcohol still accounts for a significant risk in TD even after correction for the other risk factors such as gender, age, dose of neuroleptics, and lifetime neuroleptic exposure [59]. The mechanisms by which alcohol contributes to the risk of TD are not clear but probably involve direct neurotoxicity in certain regions of the brain and perhaps a yet-unexplained pharmokinetic effect of alcohol in conjunction with neuroleptic levels [64]. Since the advent of neuroimaging, struc-

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tural brain lesions have been documented in patients with TD and a history of chronic alcohol consumption [64]. There is a paucity of epidemiological studies on TD, but it seems that the incidence and prevalence of TD has been decreasing since the advent of the new atypical neuroleptics. Drug-induced movement disorders, however, continue to be a major concern to all clinicians treating patients with behavioral or psychiatric disorders. Therefore, early recognition and correct categorization of the druginduced movement disorders is critical. Until a specific biological marker is identified to aid in the differentiation among the various types of drug-induced movement disorders, the diagnosis will rely on the recognition of clinically distinguishable phenomenology of the diverse tardive syndromes [65–67].

TARDIVE STEREOTYPY The term ‘‘tardive dyskinesia’’ was initially used to describe the most common form of persistent, abnormal, involuntary movements induced by chronic exposure to neuroleptics. The classic form of TD is characterized by stereotypic movements involving the oro-facial-lingual-masticatory muscles, producing the socalled bucco-linguo-masticatory syndrome. The patient may also exhibit choreic movements of the trunk or extremities, but since the stereotypy is usually the dominant and most troublesome feature, the classic form of TD is usually classified as tardive stereotypy [22]. Tardive stereotypy usually consists of repetitive movements of tongue, lips, and mouth, producing stereotypic tongue protrusion and retraction, lip smacking and puckering, and chewing movements [18,68] (Fig. 1). The upper facial muscles are less frequently affected by the involuntary movements, but some patients exhibit increased blinking, blepharospasm, arching of the eyebrows, and oculogyric movements [69]. Many patients also produce repetitive grunting and moaning, which are thought to be due to involuntary contractions of the muscles of the airway passages [70]. In addition to the classic orofacial stereotypy, TD patients frequently display signs of akathisia, manifested by restlessness, including pacing, shifting of weights, hand and face rubbing, and picking and pulling at clothes. Typically, the oral movements worsen under emotional duress but are abolished during sleep [71]. In some instances, TD can exist concommitantly with other tardive syndromes such as dystonia, parkinsonism, and chorea. Thus, choreaothetosis may occur in isolation or in conjunction with a dystonic posture [16]. As mentioned previously, TD can similarly manifest itself in the presence of parkinsonism. In a study involving 132 patients, 17.4% were found to have concomitant parkinsonism with TD [72], while another study revealed a 33% (15/46) concurrence [35]. Several studies have attempted to unravel the relationship between these, seemingly opposite, entities in the general population. In patients diagnosed with parkinsonism and TD, TD has a tendency

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to develop much later in the subset of patients with Parkinson’s disease in comparison to patients without previous Parkinson’s symptoms [35,73]. TD is typically a persistent disorder, but spontaneous remissions may occur, especially in the younger population. Patients younger than 60 years have a threefold chance of improving, compared to patients who are older [74]. An inverse correlation between rates of spontaneous remissions and age has been noted by a number of studies [18]. In a study conducted over 5 years in 27 psychiatric patients, patients with TD improve at least 50% with adjustment or elimination of neuroleptics [75]. WITHDRAWAL-EMERGENT SYNDROME The withdrawal-emergent syndrome, typically seen in children, is analogous to classic TD (tardive stereotypy) manifested in adults with the exception of the more generalized movements mimicking Syndeham’s chorea [76]. The entity was first described in children who were treated with antipsychotics for an extensive period and subsequently underwent an abrupt cessation of the medication [77]. In contrast to classical TD, the hyperkinesias seen in withdrawal-emergent syndrome involve the limbs, neck, and trunk primarily, and seldom the lower facial region [1]. The course of illness is usually shorter and more benign compared to tardive stereotypy. Less frequently, this syndrome, referred to as withdrawal dyskinesias [78], it may occur in adults after an acute withdrawal of long-term use of antipsychotics. It typically disappears within 3 months. This withdrawal-emergent syndrome, while similar to classic TD [79], may have a different mechanism since it appears only after an abrupt withdrawal of the offending drug, whereas classic TD may appear while the patient is still taking the drug [18]. The withdrawalemergent syndrome is believed to be self-limiting, but it may last for several weeks. Usually, reexposing the patient to the offending agent followed by a slow taper can eliminate the abnormal choreic movements [1]. Cases of withdrawalemergent dyskinesias and dystonias have been reported after acute withdrawal of clozapine and other drugs [4,76,80]. ACUTE AND TARDIVE DYSTONIA Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal posture [81]. Although dystonic movements are typically slow and at least transiently sustained, they may be fast and brief. One of the characteristic features is the ‘‘patterned’’ aspect of the contractions. This implies involvement of the same muscle groups time after time to produce the abnormal posture. Dystonic spasms and postures may be quite painful. The dystonic movements may develop within hours after administration of the offending drug, and this ‘‘acute dystonic reaction’’ can present

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as the first ‘‘extrapyramidal’’ side effect of neuroleptic treatment. About 50% of patients experience the first signs of dystonia within 48 hr of drug intake, and 90% show signs within 5 days of drug treatment [16]. Tardive dystonia differs from the acute transient dystonic reaction by its persistence [16,82–85]. Besides the temporal relationship between DRBD exposure and the onset and persistence of the movement disorder, criteria for the diagnosis of tardive dystonia include exclusion of genetic form of dystonia and other known causes of secondary dystonia [85]. Common forms of dystonic reactions include oculogyric deviations, blepharospasm, jaw deviation, torticollis, retrocollis, tongue protrusion, abnormal trunk posturing such as lordosis or scoliosis, opisthotonous, trismus, and bruxism. Oculogyric crisis which can manifest as both acute and tardive dystonia is indistinguishable from cases reported occurring in postencephalitic parkinsonism [18]. Acute dystonic reactions often have dramatic presentations. About 90% occur within 4 days of commencing drug therapy [86]. At times the acute dystonic reactions are severe enough to warrant life-saving measures. A classic example is the phenomenon known as ‘‘laryngeal dystonia,’’ which may compromise the respiratory system [87]. Blepharospasm, another focal dystonia involving the orbicularis oculi, may render a patient functionally blind [88,89] This is manifested by an involuntary, bilateral, spasmodic closing of eyelids due to contractions of the orbicularis oculi muscles [90]. Blepharospasm may be accompanied by oromandibular (cranial) and neck (cervical) dystonia [91–93]. Idiopathic (primary or essential) blepharospasm and oromandibular dystonia are at times be misdiagnosed as tardive dystonia despite a lack of neuroleptic exposure in these patients [94]. In addition to the involvement of the cranial-cervical region, patients with tardive dystonia typically exhibit spasms of the thoracic paraspinal muscles resulting in opisthotonic arching of their trunk usually accompanied by a pronation and adduction of the shoulders and extension of the elbows (Figs. 2 and 3). Depending on a particular study, the frequency of acute drug-induced dystonic reactions varies widely from 3% to 63% [86,95]. Risk factors for dystonia in this particular setting include male gender, young age (under 30), potency and dose of neuroleptics used, familial predisposition, underlying psychiatric illness, mental retardation, and a history of ECT [96]. There is a 2:1 risk of drug-induced dystonia in men compared to women. The same ratio holds true for young adults and children. For yet-unknown reasons, young people are more susceptible to developing dystonic reactions than the elderly [18]. It was thought that patients with mania had a higher incidence than those with schizophrenia when treated with neuroleptics [97]. However, this notion has been challenged in a prospective study of neuroleptic-induced dystonia in manic and schizophrenic patients. The study showed that peak neuroleptic dose and age, not underlying illness, correlated strongly with development of dystonic reactions [98]. The authors felt that perhaps the larger quantities of neuroleptics required in the treatment of mania

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versus schizophrenia could account for the discrepancies noted in the past between the two psychiatric disorders. There have also been reports of cocaine use as a predisposing factor for other movement disorders [47]. One study showed that cocaine use increased the risk of acute dystonic reactions in patients undergoing treatment with DRBDs [99]. Further, there have been a few reports of patients with ‘‘cocaine-induced dystonia’’ taking no other recreational drugs or prescription medications while on cocaine [99]. Although tardive dystonia is considered a persistent disorder, a long-term study of 107 patients followed for 23 years showed that 14% achieve a spontaneous remission [15]. Remission took place after a mean period of 5.2 years from onset and 2.6 years after cessation of neuroleptic intake. Discontinuation of DRBDs appeared to increase the probability of remission fourfold. Patients with a less than or equal to 10 years exposure had a fivefold greater chance of remission than those with duration of tardive dystonia for more than 10 years. TARDIVE TOURETTISM Tourette syndrome (TS) is a neurobehavioral disorder characterized by motor and vocal tics and a wide range of behavioral problems. Tics are abrupt, brief, coordinated involuntary movements (motor tics) or sounds (phonic tics) that are often preceded by a premonitory sensation [100,101]. Motor tics can be simple (e.g., eye blinking, head jerking, facial grimacing) or complex (e.g., self-hitting, jumping) or ‘‘echopraxia’’ (mimicking gestures). Similarly, phonic tics may be either simple sounds (e.g., sniffing, grunting, coughing) or complex vocalizations, such as ‘‘coprolalia’’ (use of obscene words), ‘‘palilalia’’ (repetition of one’s own phrases), or ‘‘echolalia’’ (repetition of other’s phrases). Coprolalia, one of the most recognized symptoms of Tourette syndrome, is actually present in less than half of afflicted patients [90]. There are many behavioral symptoms associated with Tourette syndrome, including attention deficit with hyperactivity disorder, obsessive-compulsive behavior, impulse-control problems, learning deficits, and sleep disturbances [102–104]. A possible underlying pathophysiological mechanism such as dopamine receptor hypersensitivity is supported by the finding of low levels of homovanillic acid (a dopamine metabolite) in the cerebrospinal fluid, as well as a favorable response to dopamine-depleting and -obstructing agents in patients with Tourette syndrome [105]. There are many causes of tics [101,106], but Tourette syndrome is clearly the most common. Tardive tourettism has been recognized as one of the acquired tourettisms [107–109]. All three individuals in the original report were adults with an acute onset of abnormal movements and vocalizations following chronic neuroleptic treatment. There was no history of abnormal tics (motor or phonic) in these patients or in their families prior to exposure to the dopamine-depleting drugs [109]. Further, the symptoms exhibited by the patients were indistinguishable

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from those of classic Tourette syndrome. However, unlike primary Tourette syndrome, the symptoms of which usually begin between the ages of 2 and 15 years, tardive tourettism may not present until later in life [110]. The neuropharmacology underlying tardive tourettism parallels that of TD and idiopathic Tourette syndrome [111]. All three disorders may represent dysregulation of the dopaminergic system [48]. Subsequently, tardive dystonia and TD may be a side effect of neuroleptic treatment in patients with Tourette syndrome [58]. Although most patients with troublesome tics are treated with neuroleptics, the occurrence of TD in patients with Tourette syndrome is quite rare and only a few dozen cases have been documented in the world literature [112]. Several drugs, particularly the CNS stimulants used in the treatment of associated attention deficit and cocaine, have been known to play a role in the exacerbation of tics in patients with Tourette syndrome [47,48,101]. The occurrence of tardive tourettism following neuroleptic therapy highlights the importance of weighing the advantages and disadvantages in making a decision about the use of DRBD in the treatment of Tourette syndrome. Hence, the decision to employ such drugs in the standard treatment for Tourette syndrome must not be taken lightly, and the potential risk of TD and tardive dystonia should be fully disclosed to patients in whom such therapy is planned [58]. TARDIVE MYOCLONUS In a small number of cases, myoclonus is the predominant feature of TD [113]. Myoclonus is a movement disorder characterized by abrupt, brisk, shocklike, involuntary, repetitive, synchronous or asynchronous contractions of a muscle group of axial or appendicular muscles [114,115]. These involuntary movements may be sufficiently forceful to displace the affected part or entire body. Myoclonus may be focal, multifocal, or generalized. It may also occur spontaneously or on attempted action (‘‘action myoclonus’’) [116] and may be triggered by auditory, visual, tactile, or muscular stimuli (‘‘stimulus-sensitive myoclonus’’). Myoclonus arises from cortical, subcortical, and spinal cord regions [117]. The original report of tardive myoclonus detailed prominent postural myoclonus in the upper extremities in 32 of 133 psychiatric patients who had been treated with neuroleptics for at least 3 months. The study revealed a slight maleto-female preponderance [113]. However, since the phenomenology was not well documented, it is possible that some of the patients exhibited other brief, jerklike movements, such as chorea and tics, that are sometimes confused with myoclonus. Late-onset (tardive) myoclonus represents a distinct movement disorder secondary to neuroleptic exposure. In the original report of a case of tardive myoclonus, noted in a 46-year-old psychotic female, the movement disorder appeared within 5 months after discontinuation of neuroleptic therapy [118]. The movement disorder was characterized by rhythmic 1- to 2-Hz neck jerks accompanied by syn-

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chronous contractions of the frontalis, platysma, and the sternocleidomastoid muscles. The myoclonus persisted for 7 months, then ceased after reinstitution of neuroleptic treatment. TARDIVE TREMOR Tremor, is characterized by an involuntary, ‘‘rhythmic,’’ oscillatory movement, typically involves the distal extremities, less often the head and neck [119–121]. Stacy and Jankovic initialy described tardive tremor as a distinct clinical variant of TD [122–124]. The risk factors are still unclear, but some believe that patients with essential tremor, women, and older individuals are more at risk to develop tardive tremors [120]. In the five reported patients, tremor, described as an oscillatory 3–5-Hz movement occurring at rest and with action and involving all extremities, developed during the course of chronic neuroleptic exposure. The tremor was aggravated by and persisted after withdrawal of the medication. The lack of other parkinsonian features, lack of response to conventional medications typically used for essential tremor or parkinsonism, and marked improvement with tetrabenazine, a monoamine-depleting drug and DRBD, differentiated this tremor from all other types of hereto-described rhythmic movement disorders [122]. In the absence of an underlying potential cause of tremor, the diagnosis of ‘‘tardive tremor’’ should be entertained in all patients exposed to neuroleptic drugs. The more common cause of tremor in patients currently treated with neuroleptic drugs, however, is drug-induced parkinsonism (discussed elsewhere in this volume). NEUROLEPTIC MALIGNANT SYNDROME Neuroleptic malignant syndrome (NMS), first recognized in 1960, was subsequently characterized by Delay and Deniker [125]. A similar condition, known as lethal catatonia, has been recognized in untreated psychiatric patients since the nineteenth century [126]. A universally accepted consensus on the definition NMS is lacking, but most agree that a movement disorder and fever are the essential elements for the diagnosis of this potentially fatal iatrogenic disorder. According to the American Psychiatric Association, the diagnostic criteria include severe rigidity and fever along with 2 of 10 minor features which include tremor, diaphoresis, altered mentation, dysphagia, incontinence, tachycardia, mutism, labile or elevated blood pressure, leukocytosis, and elevated creatinine phosphokinase [127]. In a study conducted by Kurlan et al. [128] it was determined that most patients presumed to have this syndrome had a constellation of symptoms including fever, autonomic dysfunction, and a movement disorder. In another review it was found that 92% of 115 patients with diagnosis of NMS had temperature above 100.4⬚F and 91% showed signs of rigidity [129]. According to experts,

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most cases of altered mental status and rigidity presented with or preceded the fever [76,129]. NMS typically occurs in the setting of exposure to DRBDs. However, there have been many reports of a similar syndrome in patients who have never been exposed to neuroleptics in whom NMS was precipitated by an abrupt withdrawal of dopaminergic agents [130]. Pfeiffer and Sucha [131] reported a similar phenomenon as an ‘‘off’’ symptom in Parkinson’s patients experiencing ‘‘on-off’’ fluctuations. Tetrabenazine, a dopamine-depleting drug, has also been implicated in the production of an NMS-like syndrome [132]. Burke et al. [133] reported reserpine to cause a similar disorder as well. Rarely, drugs that do not seem to affect the dopamine system directly, such as carbamazepine [134] and trimiprimine [135], have been reported to cause an NMS-like syndrome. Selective serotonin reuptake inhibitors (SSRI) and monoamine oxidaze inhibitors (MAO) can cause a drug-induced, hyperthermic agitated mental state, known as the ‘‘serotonin syndrome,’’ which closely resembles NMS [136,137]. Only about 0.1%–1.8% of patients exposed to DRBDs develop NMS [138,139]. There is no adequate explanation why some patients suddenly develop the syndrome after long-term (months to years) neuroleptic use. Ram et al. [140] evaluated the structure of D2 receptor gene in 12 patients with history of NMS and found a nucleotide substitution in the D2 gene exon in one patient. The significance of this finding is unknown, but it is intriguing to consider genetic predisposition in some of these patients. NMS typically occurs 3–9 days following neuroleptic administration [141], but it can occur on the same day [129,141] and it may even occur years after initiating neuroleptics. Only a small percentage (3%) develop the syndrome after 6 months of stable doses of neuroleptic medication. NMS may present at any age, but there appears to be a special predilection among young adults [142]. NMS also appears to favor men compared to women in a 1.5–2:1 ratio. The presentation is usually subacute (24–72 hr), but it can occur precipitously over hours [143]. Duration is about 10–13 days when caused by oral neuroleptics and twice as long when depot agents are employed [129]. According to previous prospective studies, the incidence of NMS appears to be about 0.5% per year [138,144,145]. This estimate has been confirmed in an examination of 21 reports published as of 1999, in which the incidence of NMS has been estimated to be less than 1% per year [146]. Risk factors for the development of NMS include young age, male gender, high-potency neuroleptics [147], rate of dose increase [148], use of depot drug [145,147], genetic predisposition [149], affective disorder [147], and associated agitation and dehydration [148]. Other reported risk factors which have not yet been validated include concomitant use of lithium, stress, and brain damage, as well as multiple neuroleptic use [150]. Because of poor understanding regarding the pathophysiology and the risk factors leading to NMS, there is no clear method for preventing this illness. It is

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believed that once a patient has suffered from NMS, that patient is at greater risk of recurrence [150]. However, there have been few reports confirming this notion. In one study involving 54 patients, it was found that 37% (20/54) had recurrent NMS after reexposure, but the authors did not mention which neuroleptics were involved [141]. According to another study, however 13 of 15 patients did not develop NMS even after being rechallenged with various neuroleptics [151]. Mortality from NMS has been reported to range from 4% to 22% [152]. The mortality in each case is typically secondary to myoglobinuria, resulting in renal failure or pneumonia [150]. Thus far, risk factors for death have not been clearly elucidated despite much speculation [152]. Conventional wisdom mandates prompt recognition of this syndrome along with drug withdrawal and appropriate management (see below).

ACUTE AND TARDIVE AKATHISIA Akathisia has been described for over a hundred years, and it may be the most common condition associated with exposure to DRBDs. According to Haskovec [153], the term was coined in reference to psychotic patients unable to remain seated and believed to suffer from a type of hysteria. The syndrome akathisia consists of a subjective feeling of muscular discomfort that causes a patient to be agitated, pace relentlessly, alternately sit and stand in rapid succession, and feel dysphoric. This symptom complex was first described in the nineteenth century in idiopathic Parkinson’s disease [154]. The movements are primarily motor and cannot be controlled by the patient’s will. Akathisia shares some clinical features with restless legs syndrome, but despite the overlap, several clinical features differentiate the two disorders [155]. Restless legs syndrome typically is most prominent in the evening and at night, whereas akathisia patients generally have milder sleep complaints. Akathisia tends to be associated with whole-body, predominantly axial, rocking movements; patients with restless legs syndrome, on the other hand, demonstrate restless, stereotypic movements chiefly in the legs and occasionally in the arms. Frequently, treating physicians misdiagnose akathisia as anxiety, agitation, or hyperactivity related to an underlying primary illness. Akathetic patients often engage in seemingly purposeless activities such as folding and unfolding arms, repetitively touching their face and scalp, picking at clothes, shifting weights, rocking, pacing, or marching in place [16]. Leg movements may include crossing, and uncrossing, abducting and adducting, and pumping the legs up and down. While sitting, they may spontaneously arise from the chair. Usually, family and patients themselves describe an inability to engage in conversations, read, watch television, or even sleep secondary to difficulty in remaining still. Akathisia can also manifest itself as focal pain or burning in the genital or oral regions typically

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[156]. Likewise moaning may be a verbal expression of a patient’s subjective inner feelings of restlessness and akathisia. The diagnosis of akathisia should only be entertained when patients complain of inner restlessness and objective clinical signs are present. There appears to be no age or gender predilection in the diagnosis of akathisia [157,158]. According to Marsden et al. [159], akathisia is more common with high-potency neuroleptics, high doses of drugs, and depot injections. The prevalence is thought to be between 10% and 70%, with a figure of 20% most commonly accepted [160]. The true incidence, however, is uncertain secondary to poor recognition or underdiagnosis by physicians. Kahn et al. [161] found akathisia in 36% of patients undergoing neuroleptic treatment, independent of other drug-induced movement disorders. In 50% of cases with this disorder, symptoms developed within the first month of therapy. One study found that within 73 days of commencing neuroleptic treatment, nearly 90% developed akathisia [162]. However, some patients may display symptoms of akathisia within minutes of drug treatment, especially if treated with intravenous neuroleptics [162]. In a recent review, Drotts and Vinson revealed that 44% of patients who received prochlorperazine 1 hr postintravenous infusion developed acute akathisia [163], while only 3 patients manifested symptoms at 48 hr postinfusion compared to patients receiving other infusions with saline or antibiotics. None of the second group developed akathisias, acute or tardive [163]. It is important to note that secondary complications of akathisia such as behavioral disturbances and even suicide are not trivial [164–165]. Akathisia is a very common side effect of neuroleptics, frequently manifesting within the first 3 months of commencing antipsychotic therapy (acute akathisia), but the symptoms may persist for a long time if neuroleptics are continued or after they are discontinued (tardive akathisia) [16]. The development of akathisia may coincide with an increase in dosage or emerge while the neuroleptic is replaced by a more potent one or after a prolonged exposure to DRBDs [18]. The pathophysiology of akathisia is not well understood at present, nor is the benefit of prophylaxis. Iron deficiency has been implicated in the development of acute akathisia because of its influence on dopamine D2 receptor sensitivity. However, the precise mechanism is yet unknown [164]. Structural brain abnormalities as the underlying etiology of akathisia are being carefully considered after a report in the literature of basal ganglia destruction (from carbon monoxide poison) leading to akathisia [166]. An alternative hypothesis is the blockade of mesocortical dopaminergic or noradrenergic receptors and opiod mechanisms [164,167]. Akathisia can accompany idiopathic Parkinson’s disease and it is therefore believed that akathisia in represents an expression of an underlying need to relieve discomfort from rigidity and bradykinesia. Finally, akathisia was found to be

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more frequent in the akinetic-rigid type of Parkinson’s disease compared to the tremor-dominant type [168]. A review of the literature revealed that SSRIs may play a role in the induction of ‘‘extrapyramidal’’ side effects in susceptible individuals suffering from depressive disorders [169–172]. Among 71 cases of SSRI-induced ‘‘extrapyramidal’’ symptoms (EPS) reported in the literature, the most common side effects were akathisia (45.1%), dystonia (28.2%), parkinsonism (14.1%), and tardive dyskinesia (11.3%) [173]. Fluoxetine (Prozac), the most commonly prescribed SSRI to date, was implicated in 53 (74.6%) of the 71 reported cases. However, several reports (57.7%) were confounded by concomitant use of other medications that can contribute to the development of EPS. Of the 30 cases of akathisia described, 24 patients had been treated with neuroleptics previously or were taking at least one concurrently along with the SSRI [174]. In this study, akathisia developed from 12 hr to 12 weeks following the initiation of SSRI therapy, and in 6 patients the symptoms occurred after a dosage increase [174]. All cases resolved within 14 days of discontinuing or decreasing the dosage of medication. The majority of reported SSRI-related reactions occurred within the first month of drug exposure [175]. The propensity for the SSRIs to induce these effects in individual patients may vary within the drug class, depending, for instance, on their selectivity for serotonin relative to other monoamines, affinity for the 5HT2C receptor, potential for pharmacokinetic drug interaction with concomitantly administered neuroleptics, and potential for accumulation due to a long half-life. However, relative risk for akathisia associated with SSRIs has yet to be clearly established, although there appear to be some factors that increase the risk for akathisia, such as the total SSRI daily dose, rapid dose escalations, increased age, female gender, concurrent administration of DRBDs, and coexisting disease states such as Parkinson’s disease [175]. Since SSRI-related akathisias have occurred in diverse situations with different possible contributing factors, practitioners and other health care providers should remain aware of this drug class’s potential for drug-induced dyskinesias. MANAGEMENT Since, by definition, tardive syndromes are iatrogenic disorders, the best treatment is prevention. Patients should be advised of the inherent risk of developing tardive syndromes prior to commencing drug therapy with neuroleptics (particularly those blocking D2 and D3 receptors) (Table 1). In a survey conducted by Kennedy and Sanborn [176] of 520 psychiatrists, it was reported that only 54% of them disclosed the risk of developing TD. The American Psychiatric Association Task Force on Tardive Dyskinesia recommends a reduction or discontinuation of neuroleptics when possible. This act alone may result in improvement up to 50% of patients where TD is recognized in its early stages [177]. Unfortunately, when

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TABLE 1 Drugs Implicated in Tardive Syndromes 1. Phenothiazines A. Aliphatic B. Piperidine C. Piperazine

2. Thioxanthenes A. Aliphatic B. Piperazine 3. Butyrophenones 4. Diphenylbutylpiperidine 5. Dibenzazepine 6. Dibenzodiazepine 7. Thienobenzodiazepine 8. Substituted benzamides

9. 10. 11. 12.

Indolones Pyrimidinone Tricyclic Calcium channel blockers

Chlorpromazine Triflupromazine Thioridazine Mesoridazine Trifluoperazine Prochlorperazine Perphenazine Fluphenazine Perazine Chloprothixene Thiothixene Haloperidol Droperidol Pimozide Loxapine Clozapine Quetiapine Olanzapine Metoclopramide Tiapride Sulpiride Clebopride Remoxipride Veralipride Molindone Risperidone Amoxapine Flunarizine Cinnarizine

neuroleptics are required to manage the underlying condition, a reduction or cessation of the offending drug may not be possible. Patients receiving antipsychotics should undergo periodic reevaluation of the need for treatment continuation. Early diagnosis of drug-induced movement disorders is imperative, as is prompt intervention to try to curtail and reverse the abnormal movements. In some instances drug withdrawal may induce spontaneous remissions. The possibility of this should always be kept in mind before to considering other specific drug treatments.

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Tardive Stereotypy Treatment of drug-induced movement disorders, especially TD, has proven quite challenging. Drugs used in the treatment of TD include dopamine-depleting agents (e.g., reserpine and tetrabenazine), GABA agonists (e.g., baclofen, vigabatrin, sodium valproate, and tiagabine), and benzodiazapines (clonazepam) [178–182]. Clonazepam has been reported to exert efficacy in certain types of TD, in particular the milder forms, possibly via its indirect effect at GABA receptors [182]. Caution, however, is advised when introducing clonazepam to a patient taking antipsychotic drugs, since this combination may cause respiratory depression [7]. Other medications with presumed GABAergic properties have also been tried in the treatment of TD. Baclofen (Lioresal) is a putative GABA-B receptor agonist which has been used alone or in combination with antidopaminergic drugs with limited success [178]. The improvement of dyskinesias with baclofen may have been influenced by the neuroleptic properties or by a synergistic effect of the two drugs, since baclofen treatment alone is ineffective once the neuroleptic drug is withdrawn [183]. Nevertheless, baclofen infused intrathecally may prove efficacious for intractable forms of dystonia [184–187]. Another GABAergic drug, gamma-vinyl-GABA, which inhibits GABA transaminase, has been reported to alleviate symptoms of TD [188]. Furthermore, sodium valproate and vigabatrin have been reported to have mild efficacy in a small cohort of patients with TD [179]. Tiagabine prevented haloperidol-induced oral dyskinesias in rats [181]. However, to date no human trials have been reported. Atypical neuroleptics are associated with a lower rate of TD than the traditional typical neuroleptics. Examples of atypical neuroleptics include clozapine (Clozaril), quetiapine (Seroquel), and olanzapine (Zyprexa) to a lesser degree. Olanzapine (Zyprexa) has selective monoaminergic antagonist activity and high affinity for histamine, dopamine, and serotonin receptors [189]. In a study of 15 patients with TD treated with olanzapine, 4 had a greater than 50% improvement in TD [189]. After 6 months the Abnormal Involuntary Movement Scale (AIMS) score decreased from 21–24 to 5–10 at a dose of 20 mg/day [189]. Olanzapine has been also reported to suppress flupenazine- and haloperidol-induced tremors, possibly as a result of its agonistic action on muscarinic acetylcholine receptors [190]. Although risperidone (Risperdal) has been promoted as an atypical neuroleptic, it resembles the traditional neuroleptics in causing parkinsonism and TD [191,192]. Clozapine, the most typical of the atypical neuroleptics, has been reported to ameliorate TD, tardive akathisia, and tardive dystonia [6,41,193,194], but it may also cause tardive dystonia [195]. A number of medications, such as clonidine, propranolol, tryptophan, and carbamazapine, have been reported to be effective in the treatment of TD, but

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most of the studies are flawed because of poor, uncontrolled design and small sample size. Clonidine at 0.15 mg/day to 0.45 mg/day has been reported to produce moderate improvement in symptoms of TD in 75% of patients [196]. Nearly 50% of patients treated with clonidine reportedly exhibited full resolution of their abnormal movements. Verapamil, a calcium channel blocker, has been reported to improve TD markedly in 3 patients who were refractory to other treatments [197]. Dopamine-depleting drugs, such as reserpine and tetrabenazine, have been considered by many as the most effective treatment of TD [198–203]. Tetrabenazine has a dual action as a presynaptic monoamine depleting agent and as a DRBD postsynaptically. Tetrabenazine, however, is not readily available in the United States, so another monoamine-depleting, reserpine, may be a useful alternative [198]. Both medications should be initially introduced at low doses (tetrabenazine at 25 mg/day and reserpine at 0.25 mg/day) and gradually titrated until an adequate dose is achieved or undesirable side effects occur. Doses of reserpine required to adequately control the symptoms of TD are usually in the range of 3–5 mg/day, while the dose of tetrabenazine is typically 100–300 mg/day. In one study of 25 patients, mean age 65.2, diagnosed with TD and prospectively evaluated with videotapes that were randomized and ‘‘blindly’’ rated using the motor subset of the AIMS, tetrabenazine was found to have a robust effect on TD [200]. After a mean of of 20.5 weeks at a mean dose of 57.6 mg/day, the AIMS subscores improved from 9.1 to 3.6 (p ⬍ 0.001) and videotaped motor subscores improved from 17.8 to 8.4 (p ⬍ 0.001). The most common side effects of tetrabenazine included drowsiness, parkinsonism, and depression. A variety of other drugs and neurotransmitters have been implicated in the pathophysiology of dyskinetic movements and could potentially play a role in the suppression of drug-induced movement disorders [204,205]. However, many putative therapeutic agents have been described only anecdotally or have been studied in small series or unblinded trials, making conclusions difficult to interpret. For instance, lithium is mentioned frequently as a potential therapeutic agent in TD, despite limited data on its effects. In humans, epidemiological data suggest that when lithium is administered in combination with neuroleptics or tetrabenazine, the incidence of TD is reduced [199], but when used alone, lithium therapy has not been effective in suppressing TD [206]. On the other hand, there has been mounting evidence over the past few years implicating lithium in the development of chorea in the absence of concomitant neuroleptic therapy [207]. The generalized choreiform disorder resolves spontaneously with declining serum levels [207]. Tardive Dystonia Tardive dystonia often requires a different therapeutic approach from that of the classic form of TD [84]. Because reserpine and tetrabenazine are usually of limited

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value, anticholinergics are often required to control the involuntary movement and posture. In 50% of patients with tardive dystonia the simultaneous administration of both dopamine-depleting agents and anticholinergics was found to be effective [18]. The observed improvement with anticholinergics in the involuntary movements associated with tardive dystonia as compared to tardive stereotypy (which often worsens with anticholinergics) is one primary and crucial difference between classic tardive stereotypy and tardive dystonia [208]. In one study [84], a 46% improvement was noted with antimuscarinics such as trihexyphenidyl (Artane). The authors recommend a maximum dose of 32 mg of trihexyphenidyl or 450 mg of ethopropazine [84]. The use of these medications is limited only by their side effects (orthostatic hypotension, blurred vision, dry mouth). Peripheral side effects are typically controlled by the administration of peripheral cholinergic drugs such as pyridostigmine and pilocarpine eye drops. Ethopropazine may be better tolerated than trihexyphenidyl by the elderly, despite the fact that they are equally efficacious. The treatment of tardive dystonia is similar to the treatment of primary dystonia [209,210]. The dopamine-depleting agents, such as reserpine and tetrabenazine [84], are considered the most effective drugs, although their effects are less dramatic than in patients with classic tardive stereotypy. Clonazepam has been also reported to exert beneficial effects on dystonic symptoms, and this drug appears to be more effective in tardive dystonia than in the bucco-lingualmandibular syndrome [182]. Clozapine has been reported to be effective in the treatment of idiopathic (primary) dystonia [6] and in tardive dystonia [6,194,211,212]. Further, the combination of clozapine and clonazepam has resulted in successful treatment of tardive dystonia in instances where neither drug alone had much benefit [213]. Botulinum toxin injections are considered the treatment of choice for focal tardive dystonias unresponsive to medical management [214,215]. Botulinum toxin is a polypeptide produced by the bacterium Clostridium botulinum. This potent biological toxin exerts its effects by blocking acetylcholine release at the neuromuscular junction, producing local chemical denervation [7]. The clinical efficacy and duration is related directly to the time it takes for reinervation to occur, usually in 3–4 months. There are seven serologically different types of botulinum toxin, but only type A is currently available for clinical use. In 1989 the U.S. Food and Drug Administration (FDA) approved the use of botulinum toxin A injections for the treatment of hemifacial spasm and blepharospasm. Since that time its use has expanded to include other focal dystonias, including tardive dystonia [216–218]. Immunoresistance develops in about 5% of patients receiving repeat injections [219,220]. In these patients who develop blocking antibodies other serotypes (e.g., types B and F) may be effective. However, duration of action of type F is approximately half that of type A, thus requiring more frequent injections. Type B botulinum toxin is currently being investigated as a

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treatment in patients with cervical dystonia (spasmodic torticollis) and should be approved by the FDA in the near future [221]. In otherwise medically intractable cases of tardive dystonia, a variety of alternatives can be employed, such as ECT [222], thalamotomy, pallidotomy, and intrathecal baclofen [223]. Nisijima et al, [224] reported a single patient with tardive dystonia who had a good response to eperisone, a centrally acting muscle relaxant. Thalamotomy, which was introduced in 1958, is another useful therapeutic modality employed in selective cases of intractable dystonia. One study demonstrated benefit from stereotactic thalamotomy to occur in approximately 50% of carefully selected patients previously unresponsive to optimal medical treatment [225]. Other surgical interventions used in the treatment of dystonia, including intractable tardive dystonia, include pallidotomy and pallidal deep brain stimulation [226–228]. Acute and Tardive Akathisia Despite a growing body of literature, there is still some confusion between acute and tardive akathisia. Thus few studies have focused on the treatment of tardive akathisia. Tardive akathisia does not respond consistently to any pharmacological therapy, and patients afflicted with this syndrome often express symptoms of distress, violence, and even suicidal ideation [163,164,229]. Burke et al., however, found that 87% of patients showed improvement with reserpine and 58% with tetrabenazine [229]. They reported complete resolution of symptoms in one-third of patients. According to these authors, opiates may also exert a beneficial effect in tardive akathisia, but the benefit appears to be transient. Iron supplementation has also been suggested as a possible treatment for akathisias, based on the observation that correction of iron deficiencies in patients with akathisia and restless legs syndrome [155], phenomenologically similar disorders, improves the troublesome restlessness and other symptoms [230]. Chenpagga et al. [231] proposed iron supplementation even in the absence of overt iron deficiency, in an attempt to ameliorate symptoms of drug-induced akathisia. This recommendation is based largely on the observation that serum iron and transferrin are reduced in patients treated with neuroleptics who develop akathisia [232]. Furthermore, below, normal levels of iron have been detected in a subgroup of catatonic patients who later develop NMS [233]. Since the exact role of iron in akathisia is still obscure, iron supplementation in this condition is considered controversial. Moreover, measurements of peripheral iron stores may be inadequate because of poor correlation between levels of iron and severity of akathisia [232]. Supplementing iron indeed may be potentially damaging, since it is believed that iron can trigger the onset of TD by increasing oxidative stress and hence accelerate neuronal damage. Further research is recommended before recommending iron tablets to patients afflicted with abnormal movement disorders

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[230]. Finally, Hermesh et al. [234] have reported benefits of ECT in a patient with intractable akathisia. Neuroleptic Malignant Syndrome Management of NMS requires much greater urgency than the treatment of the other drug-induced movement disorders because of its high risk of morbidity and mortality. For many years, dantrolene [235] and bromocriptine [236] alone and in combination [237], and even ECT [238], have been employed in the treatment of NMS. Recently, however, doubts have been raised regarding these modalities. According to Rosebush and associates, the course of NMS was actually prolonged by the use of dantrolene and bromocriptine as compared to supportive therapy alone [239]. There was, however, a considerable discrepancy in baseline or premorbid state (health) among those treated with medication versus those treated only with supportive care. ECT has been reported to reverse the symptoms within minutes, leading to a full recovery within days [238]. Despite the uncertainty, most experts agree that, in addition to supportive measures (e.g., hydration, respiratory support), NMS should be initially treated with dopamine agonists. The drug most frequently mentioned is bromocriptine (at doses of 5–15 mg three times a day), but other dopaminergic drugs, including other dopamine agonists and levodopa, may be equally effective [150,240,241]. A recent report has described a beneficial response with carbamazapine [242]. Because of the possibility that some effects of neuroleptics are mediated via formation of free radicals, antioxidants such as vitamin E have been studied extensively in the treatment of tardive syndromes [243]. A recent double-blind controlled study, however, showed no benefit from vitamin E in 158 patients with TD [244]. SUMMARY Currently it is virtually impossible to predict with any degree of certainty which individuals will develop drug-induced movement disorders when exposed to any given neuroleptic. Nevertheless, awareness of risk factors associated with the development of TD and drug-induced abnormal movements should be taken into consideration when prescribing neuroleptics in high-risk groups. An accurate and early diagnosis and correct categorization of the tardive syndromes is crucial in overall patient management. Despite the promise of a new generation of antipsychotics having lower rates of drug-induced movement disorders, the tardive syndromes continue to present a vexing clinical dilemma. Prevention remains the most important tool in treatment of these syndromes. Furthermore, withdrawal of the offending drug may bring full remission in some instances. Effective symptomatic, medical, and

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surgical treatments are available to those patients who experience troublesome or disabling symptoms. REFERENCES 1. Fahn S. The tardive dyskinesias. In: Matthews WB, Glaser GH, Eds. Recent Advances in Clinical Neurology. Vol. 4. Edinburg: Churchill Livingstone, 1984: 229–260. 2. Stacy M, Jankovic J. Tardive dyskinesia. Curr Opin Neurol Neurosurg 1991; 4: 343–349. 3. Baldessarini RJ, Cole JO, Davis JM, et al. Tardive dyskinesia: Summary of a Task Force Report of the American Psychiatric Association. Am J Psychiatry 1980; 137: 1163–1172. 4. Jeste DV, Lacro JP, Palmer B, Rockwell E, Harris J, Calguri MP. Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients. Am J Psychiatry 1999; 156:309–311. 5. Deniker K. Introduction to neuroleptic chemotherapy into psychiatry. In: Ayd FJ, Blackwell B, Eds. Discoveries in Biological Psychiatry. Philadelphia: Lippincott, 1970:155–164. 6. Raja M, Maisto G, Altavista MC, Albanese A. Tardive lingual dystonia treated with clozapine. Move Disord 1996; 11:585–586. 7. Egan MF, Apud J, Wyatt RJ. Treatment of tardive dyskinesia. Schizophrenia Bull 1997; 23:583–603. 8. Tollefson GD, Beasley CM, Tamura RN, Tran PV, Potvin JH. Blind, Controlled, long-term study of the comparativve incidence of treatment-emergent tardive syskinesia with olanzapine or haloperidol. Am J Psychiatry 1997; 154:1248–1254. 9. Seeman P, Tallerico T. Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors. Molec Psychiatry 1998; 3:123–134. 10. Casey DE. Effects of clozapine therapy in schizophrenic individuals at risk for tardive dyskinesia. J Clin Psychiatry 1998; 59(suppl 3):31–37. 11. Dresel S, Tatsch K, Dahne I, et al. Iodine-123-iodobenzamide SPECT assessment of dopamine D2 receptor occupancy in resperidone-treated schizophrenic patients. J Nuclear Med 1998; 39:1138–1142. 12. Jibson MD, Tandon R. New atypical antipsychotic medications. J Psychiatr Res 1998; 32:215–228. 13. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999; 156:286–293. 14. Miller LG, Jankovic J. Sulpiride-induced tardive dystonia. Move Disord 1990; 5: 83–84. 15. Kiriakakis V, Bhatia KP, Quinn NP, Marsden CD. The natural history of tardive dystonia. A long term follow-up study of 107 cases. Brain 1998; 121:2053–2066. 16. Miller LG, Jankovic J. Drug-induced dyskinesias. An overview. In: Anthony JB, Young RB, Eds. Disorders of Movement in Neurology and Neuropsychiatry. 2nd ed.. Cambridge. MA: Blackwell Scientific, 1999:5–30.

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181. Gao XM, Kakigi T, Friedman MB, Tamminga CA. Tiagabine inhibits haloperidolinduced oral dyskinesias in rats. J Neurol Trans Gen Sect 1994; 95:63–69. 182. Thaker GK, Nguyen JA, Strauss ME. Clonazepam treatment of tardive dyskinesias: A practical GABA mimetic strategy. Am J Psychiatry 1990; 147:445–451. 183. Stewart RM, Rollins J, Beckham B, et al. Baclofen in tardive dyskinesia patients maintained on neuroleptics. Clin Neuropharmacol 1982; 4:365–373. 184. Ford B, Greene P, Louis ED, et al. Intrathecal baclofen in the treatment of dystonia. Adv Neurol 1998; 78:199–210. 185. Narayan RK, Loubsser PG, Jankovic J, et al. Intrathecal baclofen for intractable axial dystonia. Neurology 1991; 41:1141–1142. 186. Penn RD, Gianino JM, York MM. Intrathecal baclofen for motor disorders. Move Disord 1995; 10:675–677. 187. Albright AL, Barry MJ, Painter MJ, Shultz B. Infusion of intrathecal baclofen for generalized dystonia in cerebral palsy. J Neurosurg 1998; 88:73–76. 188. Tell GP, Shecter PJ, Kach-Weser J, et al. Effects of gamma vinyl GABA (letter). N Engl J Med 1981; 302:581–582. 189. Littrell KH, Johnson CG, Littrell S, Peabody CD. Marked reduction of tardive dyskinesia with olanzapine. Arch Gen Psychiatry 1998; 55:279–280. 190. Strauss AJL, Bailey RK, Dralle PW, et al. Conventional psychotropic-induced tremor extinguished by olanzapine. Am J Psychiatry 1998; 155:1132. 191. Buzan RD. Risperidone-induced tardive dyskinesia. Am J Psychiatry 1996; 153: 734–735. 192. Rosebush PI, Mazurek MF. Neurologic side effects in neuroleptic-naive patients treated with haloperidol or risperidone. Neurology 1999; 52:782–785. 193. Bassitt DP, Neto MRL. Clozapine efficacy in tardive dyskinesia in schizophrenic patients. Eur Arch Psychiatr Clin Neurosurg 1998; 248:209–211. 194. Trugman JM, Leadbetter R, Zalis ME, Burgdorf RO, Wooten GF. Treatment of severe axial tardive dystonia with clozapine: A case report and hypothesis. Move Disord 1994; 9:441–446. 195. Molho ES, Factor S. Possible tardive dystonia resulting from clozapine therapy. Move Disord 1999; 14:872–889. 196. Nishikawa T, Tanaka M, Tsuda A, et al. Clonidine therapy for tardive dyskinesia and related syndromes. Clin Neuropharmacol 1984; 7:239–245. 197. Ovsiew F, Meador K, Sethi K. Verapamil for severe hyperkinetic movement disorders. Move Disord 1998; 13:341–344. 198. Sato S, Daly R, Peters H. Reserpine therapy of phenothiazine induced dyskinesia. Dis Nerv Syst 1971; 32:680–685. 199. Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology 1988; 38:391–394. 200. Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment for tardive dyskinesia: Assessment by randomized videotape protocol. Am J Psychiatry 1999; 156: 1279–1281. 201. Asher SW, Aminoff MJ. Tetrabenazine and movement disorders. Neurology 1981; 31:1051–1054. 202. Jankovic J, Beach J. Long-term effects of tetrabenazine in in hyperkinetic movement disorders. Neurology 1997; 48:358–362.

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203. Lang AE, Marsden CD. Alphamethylparatyrosine and tetrabenazine in movement disorders. Clin Neuropharmacol 1982; 5:375–387. 204. Penney JB, Young AB. Movement disorders. In: Johnston MV, Macdonald RL, Young AB, Eds. Principles of Drug Therapy in Neurology. Contemporary Neurology Series. Philadelphia: Davis, 1992:50–86. 205. Kane JM. Tardive dyskinesia: Epidemiological and clinical presentation. In: Bloom FE, Kupfer DJ, Eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven, 1995:1485–1496. 206. Gardos G, Cole JO. The treatment of tardive dyskinesia. In: Bloom FE, Kupfer DJ, Eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven, 1995:1503–1511. 207. Podskalny GD, Factor SA. Chorea caused by lithium intoxication: A case report and literature review. Move Diord 1996; 11:733–737. 208. Yassa R, Iskandar H, Ally J. The prevelance of tardive dyskinesia in fluphenazinetreated patients. J Clin Psychopharmacol 1988; 8:17S–20S. 209. Jankovic J. Dystonia: Medical therapy and botulinum toxin in dystonia. In: Fahn S, Marsden CD, DeLong DR, Eds. Dystonia 3. Adv Neurol, Lippincott-Raven 1998; 78:169–184. 210. Jankovic J. Re-emergence of surgery for dystonia. Editorial commentary. J Neurol Neurosurg Psychiatry 1998; 65:434. 211. Wolf ME, Mosnaim AD. Improvement of axial dystonia with the administration of clozapine. Int J Clin Pharm Therapeut 1994; 32:282–283. 212. Van Harten PN, Kamphuis DJ, Matroos GE. Use of clozapine in tardive dystonia. Prog Neuro-Psychiatry Biol Psychiatry 1996a; 20:263–274. 213. Shapleske J, McKay AP, McKenna PJ. Successful treatment of tardive dystonia with clozapine and clonazepam. Br J Psychiatry 1996; 168:516–518. 214. Tarsy D, Kaufman D, Sethi D, Rivner MH, Molho E, Factor S. An open-label study of botulinum toxin A for treatment of tardive dystonia. Clin Neuropharmacol 1997; 20:90–93. 215. Chatterjee A, Gordon MF, Giladi N, Trosh R. Botulinum toxin in the treatment of tardive dystonia. J Clin Psychopharmacol 1997; 17:497–498. 216. Jankovic J, Hallett M, eds. Therapy with Botulinum Toxin. New York: Marcel Dekker, 1994. 217. Jankovic J, Brin M. Botulinum toxin: Historical perspective and potential new indications. Muscle & Nerve 1997; 20(suppl 6):S129–S145. 218. Hallett M. One man’s poison—clinical applications of botulinum toxin. N Engl J Med 1999; 341:118–120. 219. Jankovic J, Schwartz K. Response and immunoresistance to botulinum toxin injections. Neurology 1995; 45:1743–1746. 220. Hanna PA, Jankovic J, Vincent A. Comparison of mouse bioassay and immunoprecipitation assay for botulinum toxin antibodies. J Neurol Neurosurg Psychiatry(. J Neurol Neurosurg Psychiatry) 1999; 67:133. 221. Brin MF, Lew MF, Adler CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999; 53:1431–1438. 222. Yoshida K, Hasebe T, Higuchi H, Shimizu T, Hishikawa Y. Marked improvement of tardive dystonia in a schizophrenic patient after electroconvulsive therapy. Hum Psychopharmacol Clin Exp 1996; 11:421–423.

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243. Dabiri LM, Pasta D, Darby JK, Mosbacher D. Effectiveness of vitamin E for treatment of long-term tardive dyskinesia. Am J Psychiatry 1994; 151:925–926. 244. Adler LA, Rotrosen J, Edson R, et al. and the Veterans Affairs Cooperative Study 噛394 Study Group. Vitamin E treatment for tardive dyskinesia. Arch Gen Psychiatry 1999; 56:836–841.

6 Acute and Tardive Dystonia Mohit Bhatt Jaslok Hospital and Research Centre Mumbai, India

Kapil D. Sethi Medical College of Georgia Augusta, Georgia, U.S.A.

Kailash Bhatia Institute of Neurology London, England

INTRODUCTION The involuntary movements induced by dopamine blocking agents (DBAs) may arise immediately upon their initiation or be delayed (tardive). The acute manifestations include acute dystonia, akathisia, and drug-induced parkinsonism. The tardive manifestations can take a variety of forms, including tardive dystonia. This chapter reviews acute and tardive dystonia. ACUTE DYSTONIA Acute dystonia occurs shortly after the introduction of DBAs and occasionally after a dose increase. This reaction is particularly common with injectable DBAs. 111

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The dystonia does not become obvious immediately upon the administration of the DBA, and there is a lag time that may relate to the drop in the blood level of the drug. About 50% of patients experience the first signs of dystonia within 48 hr of drug intake, and 90% show signs within 5 days of drug treatment (Keepers and Casey, 1983). The introduction of the newer atypical neuroleptics has been a significant advance in psychiatry. In general, these drugs are associated with a significantly lower incidence of tardive dyskinesia. However, all the atypical drugs, including clozapine, are associated with a small risk of inducing acute dystonia (Raza and Azzoni, 2000). The dystonic reaction can take many forms and can be very dramatic. Dystonic spasms and postures may be quite painful. The usual manifestations are orofacial dystonia, back arching, neck extension, and occasional laryngospasm that can be life-threatening (Flaherty and Lahmeyer, 1978). Rhabdomyolysis due to acute dystonic reaction to antipsychotic drugs has been reported (Cavanaugh and Finlayson, 1984). Repeated acute dystonic reactions even with a single dose of DBA have been observed but are uncommon. One form of acute dystonic reaction appearing 3–10 days after starting DBAs has been called Pisa syndrome and is characterized by tonic lateroflexion of the trunk (Suzuki et al., 1990). However, Pisa syndrome may be seen as a manifestation of tardive dystonia (Suzuki and Mazakoa, 2002). Oculogyric crises (OGCs) are characterized by tonic conjugate ocular deviation that may last minutes to hours. These may be accompanied by psychotic features including obcessional thoughts and hallucinations. (Sachdev, 1993b). OGCs can manifest as both acute and tardive dystonia, and the clinical features may be indistinguishable from cases reported in postencephalitic parkinsonism (Sachdev, 1993b). Frequency and Risk Factors The frequency of acute drug-induced dystonic reactions varies widely, from 2.3% (Ayd, 1961) to 94% (Chiles, 1978; Ayer and Dawson, 1980). Risk factors for dystonia in this particular setting include male gender, young age (under 30), potency and dose of neuroleptics used, familial predisposition, underlying psychiatric illness, mental retardation, and a history of ECT (Keepers and Casey, 1987; Priori, 1994). There is a 2:1 risk of drug-induced dystonia in men compared to women. The same ratio holds true for young adults and children. For yet unknown reasons, young people are more susceptible to developing dystonic reactions than the elderly. It was thought that the dystonic reactions occur more frequently in patients with bipolar disease. However, this notion has been challenged in a prospective study of neuroleptic-induced dystonia in manic and schizophrenic patients. The study showed that peak neuroleptic dose and age, and not the under-

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lying illness, correlated with development of dystonic reactions (Khanna et al., 1992). These authors felt that the larger quantities of DBA in the treatment of mania accounted for the apparent difference. Cocaine abuse may predispose to acute dystonic reaction (Van Harten, 1986). AIDS has also been associated with increased risk (Kleij der Van, 1996). Inhibition of CYP2D6 and CYP3A4 by ritonavir and indinavir in AIDS patients may result in an accumulation of the active moiety of risperidone, which can result in acute dystonia (Kelly et al., 2002). Mechanism The mechanism of acute dystonia is unclear. Two opposing hypotheses have been presented. One is dopamine hypofunction, which results in a relative overactivity of the cholinergic mechanisms (Nealer et al., 1984). This hypothesis is supported by consistent response to anticholinergic drugs in patients. Also, in primates, acute dystonia may be suppressed by the preadministration of dopamine agonist such as L-dopa or apomorphine. Further support for this hypothesis comes from a marmoset model of tardive dyskinesia. In this model, acute administration of haloperidol results in a syndrome of excitation with sustained retrocollis, climbing upside down, biting the perch, repetitive turning, and frequent backward movements. These dystonic movements may be ameliorated by an anticholinergic drug, biperiden (Klintenberg, 2002). On the other hand, it has been proposed that neuroleptics induce a paradoxical dopaminergic hyperfunction by preferentially blocking presynaptic receptors. Moreover, as the level of the DBA falls off, the postsynaptic receptors are exposed to the natural release of dopamine from the presynaptic terminals (Marsden and Jenner, 1980). The possible contribution of other neurotransmitter systems such as GABA is unknown. Recently the role of sigma receptors has been explored. It has been reported that the unilateral microinjection of sigma ligands into the red nucleus induces torticollis in the rats (Matsumoto, 1990). Sigma1 and sigma2 receptors are differentially expressed in the motor areas. However, the tendency of the drugs to produce acute dystonic reactions is not preferentially associated with binding to either receptor but correlates with both subtypes (Matsumoto and Pouw, 2000). In animal models an anticholinergic drug, biperiden, dose-dependently ameliorates dystonia induced by two sigma ligands, whether each sigma ligand had dopaminergic affinity or not (Yashida et al., 2000). This suggests that this animal model of dystonia appears to be a model of acute dystonia. It appears that, in addition to the dopaminergic and the cholinergic systems, the sigma system may play a role in the genesis of acute dystonia. Moreover, not only the striatum but also the red nucleus may play an important role in the pathophysiology of acute dystonia.

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Management There is some evidence to suggest that acute dystonic reactions may be prevented by the use of anticholinergic drugs (Keepers, 1983; Winslow, 1986). It is recommended by some that patients at a high risk for dystonia, such as the young, cocaine abusers, and AIDS patients who require DBAs also receive prophylactic anticholinergics. Acute dystonia can be treated effectively with injectable anticholinergic drugs (Medina et al., 1962; Keepers, 1986; Arana et al., 1998) or diphenhydramine (Waugh and Metts, 1960). The response to anticholinergics is so consistent that if a patient with suspected DBA-induced acute dystionia fails to respond, one should consider alternative drugs such as PCP as an etiology (Piecuch et al., 1999). Occasionally, diazepam has been used successfully (Gagrat et al. Belmaker, 1978). At times, acute dystonic reactions such as laryngeal dystonia are severe enough to warrant life-saving measures such as tracheostomy.

TARDIVE DYSTONIA: INTRODUCTION AND DEFINITIONS Soon after the introduction of the dopamine-blocking agents or neuroleptics in the treatment of schizophrenia and other psychiatric disorders, it became clear that involuntary movements might result with the use of these drugs (Faurbye et al., 1964; Crane et al., 1973). The movements typically involved the oro-buccolingual region, and the syndrome was called tardive (delayed) dyskinesia (TDk), as usually it seemed to occur after prolonged use of DBAs. Soon other reports of abnormal sustained postures or dystonia related to chronic use of DBAs also appeared in the literature (Druckman et al., 1962; Angle and McIntire, 1968). Keegan and Rajput (1973), however, were the first to clearly describe this latter entity and coined the term ‘‘dystonia tarda’’ when reporting a patient with torticollis and axial dystonia due to DBAs. The literature about tardive dystonia, however, remains relatively scarce compared to that about tardive dyskinesia. Only three large series, by Burke et al. (1982), Kang et al. 1988 and Kiriakakis et al. (1998), have reported on a total of about 200 patients. One possible reason for this could be lack of recognition and the tendency to describe all cases with involuntary movements related to DBAs as tardive dyskinesia. Although tardive dystonia (TDt) can coexist with TDk, it is now clear that TDt differs from TDk in its epidemiology, prevalence, risk factors, clinical aspects, prognosis, treatment response, and pathophysiology and hence these two entities need to be differentiated. In TDt the dystonia is the sole or the main feature even if other associated involuntary movements (e.g., tardive dyskinesia) are present. With this in mind, Burke et al. (1982) formulated the first clear criteria for TDt. Thus, tardive dystonia is defined as ‘‘an involuntary movement predominated by dystonia and associ-

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ated with use of DBA. The dystonia must be present for more than a month and occur either during ongoing treatment with a DBA or within 3 months of its discontinuation.’’ Patients may have associated choreiform movements as seen in tardive dyskinesia, but the dominant involuntary movement must be dystonia. There should not be a family history of dystonia, and other known causes of dystonia have to be excluded. Like tardive dyskinesia, tardive dystonia may persist and even be aggravated despite withdrawal of the offending DBA (Burke et al., 1982). Because in some patients other movement disorders may coexist, Adityanjee et al. (1999) have suggested a subtypic classification based on the purity of the dystonic symptoms as follows: type 1, pure Tdt in the absence of any other movement disorder; type II, where dystonia coexists with dyskinetic movements in the same body part but dystonia is predominant; type III, where dystonia coexists with other dyskinetic movements in the same or different body parts but dystonia is less prominent then dyskinesia; type IV, where dystonia coexists with a variety of movement disorders disorders including parkinsonism, akathisia, myoclonus, tics, etc. The authors suggest using this classification to identify prognostic and other differences between subgroups in future studies. However, this may not be possible practically, as Tdt is often an evolving and progressive condition, at least in the initial phases. EPIDEMIOLOGY AND RISK FACTORS Epidemiological studies estimating the prevalence of TDt are difficult to interpret because quite a few studies have included some cases with TDk. Also, most studies are retrospective and are difficult to compare, as different population samples have been studied—for example, inpatient versus outpatient and psychiatric versus mixed populations. Nevertheless, some impressions can be made regarding prevalence by looking at a total of 11 cross-sectional studies in psychiatric patients (Friedman et al., 1987; Gureje, 1989; Sethi et al., 1990; Inada et al., 1991; Chiu et al., 1992, Micheli et al., 1993; Pourcher et al., 1995; Raja, 1995; Van Harten et al., 1996; Sachdev, 1991; Yassa et al., 1986). The prevalence of TDt in these studies ranged from 0.5% to 21.6% with a mean of 2.7% for a total of 4166 psychiatric patients exposed to DBAs. Among these, of interest is the study of Sethi et al. (1990), which had the highest reported rate of TDt of 21% of 125 inpatient veterans exposed to DBAs. The authors suggested that their observed high rate was due to their detailed and systemic examination, thus implying that the lower rates in many earlier studies could be due (at least in part) to lack of awareness and recognition skill about this movement disorder. Overall within the drug-induced movement disorders, tardive dystonia is quite common, constituting 24% of 125 patients with drug-induced movement disorders in one report (Miller and Jankovic, 1990). However, this report comes from a

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tertiary referral movement disorders clinic, where TDt patients are more likely to be referred than TDk patients. Risk Factors for Developing TDt Primary Diagnosis and Drug Patients with psychiatric disorders in whom DBAs are in common use are at greatest risk of developing TD. However, there does not appear to be any particular psychiatric disorder that has an additional risk for developing TDt, nor any that is immune (Kiriakakis et al., 1998; Raja et al., 1995). Patients with all forms of psychiatric disorders can develop TDt, and thus there is no ‘‘safe’’ diagnosis. Overall, in a total of 299 TD patients from 7 studies (Burke et al. 1982; Kang et al., 1986; Kiriakakis et al., 1998; Gardos et al. 1987; Gimenez-Roldan et al., 1985; Sachdev, 1993a; Wojcik et al., 1991), 51% had schizophrenia, 30% had mood disorders, and 19% had minor psychiatric disorders. However, this apparent increased prevalence for schizophrenia is an aberration of more widespread and early use of DBAs for this condition. Prevalence of TDt in 835 schizophrenia patients of about 2.8% (Gureje, 1989; Inada et al., 1991, Raja, 1995; Sachdev, 1991) is similar to the psychiatry patients in general. It has been suggested that mood disorders may predispose patients to classic TDk and perhaps also TDt. However, none of the patients with mood disorders in three prevalence studies developed TDt, and Raja et al., in a study of 200 psychiatric inpatients, concluded that psychiatric diagnosis was not associated with an increased risk of developing TDt (or TDy). Unfortunately, the list of diagnoses in which DBAs were used and caused TDt includes conditions for which more appropriate treatments are available and the use of DBAs could have been avoided. These include cases of depression and anxiety disorders treated with DBAs instead of appropriate antidepressants as well as patients with vertigo and patients with gastrointestinal symptoms who were treated with DBAs such as prochlorpromazine, promethazine, and metoclopramide and then developed TDt. Overall, Kiriakakis et al. (1998) pointed out that nearly 21% percent of patients with TDt were given DBAs for conditions that could have been treated with safer drugs. All classes of DBA are implicated in producing TDt. In an analysis of 107 patients with TDt, Kiriakakis et al. (1998) found trifluoperazine chlorpromazine, fluphenazine, thioridazine, and haloperidol as the most common ‘‘offending agents’’ (drug used alone or concurrently with or just prior to dystonia onset). However, this may just be a reflection of the higher frequency of prescription of these drugs. What is clear is that some DBAs conventionally believed to be safe in the recent past, such as sulpiride or thioridazine (Miller and Jankovic, 1990; Kiriakakis et al., 1998), as well as the so-called atypical neuroleptics such as risperidone (Saran, 1998; Tachikawa et al., 2000, Narenderan et al., 2000) and

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olanzapine (Gunal et al., 2001), can produce TDt. There are no reports of TDt with quetiapine, but that may be due to limited experience with this drug. Clozapine appears to be the least likely to produce TDt. However, even clozapine has been incriminated (Molho and Factor, 1999), and there is a report of patients said to have developed the Pisa syndrome on clozapine therapy (Kurtz et al., 1993). Thus, there does not appear to be any totally safe DBA. There is also no evidence that any other drugs (e.g., anticholinergics) given concurrently with the DBA increase or decrease the risk of developing TDt. Duration of Exposure There does not appear to be any clear relationship between the duration of exposure and the onset, prevalence, and severity of dystonia (Sethi et al., 1990; Burke et al., 1982; Kiriakakis et al., 1998). What seems clear is that there does not appear to be any safe period, and sometimes a relatively short exposure of a few days may result in TDt. On the other hand, TDt may appear only after receiving the DBA for many years. For example, in the study of Kiriakakis et al. (1998), the duration of exposure of DBA ranged from as short as 4 days to as long as 23 years, with a mean of 6.2 years (Fig. 1). It was suggested in the same study that younger patients tended to have a shorter duration of exposure to neuroleptics. Sometimes, in those on long-term treatment with one (or more) DBA over many years, the TDt onset seems to be triggered by a change in treatment, for example, switching to or adding another DBA or even adjusting the dose of the DBA after a long stable period of treatment. Age of Onset and Sex Over the years there has been a lot of interest with regard to the age of onset and the severity and type of tardive disorder. An earlier mean age of onset has been reported for TDt (mean 36 years) compared with TDk (mean 61 years) (Gimenez-Roldan et al., 1985). Children exposed to DBAs are more likely to get TDt (Mclean and Casey, 1978), and the higher the age the less are the chances of getting generalized dystonia (Burke et al., 1982). A study by Kiriakakis et al. (1998) found that men were significantly younger at onset of dystonia (33.5 years) than women (43 years), with the mean age at onset of TDt being 38 years (Fig. 2), a figure similar to that reported by others (Burke et al., 1982; Gimenez-Roldan et al., 1987; Kang et al., 1986, Wojcik et al., 1991). Male predominance has also been a consistent finding in most studies (M: F about 2:1). Both findings regarding the onset age in men and the male predominance, however, could simply reflect the sex difference in age of onset of schizophrenia/schizoaffective disorders, which are the most frequent diagnosis in psychiatric patients with DBA-related complications. Both these disorders (but not affective psychosis) occur earlier in men, and men are likely to be given DBA earlier than women (Loranger, 1984; Channon, 1993). This could explain

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FIGURE 1 Cumulative percentage of tardive dystonia patients as a function of exposure to neuroleptics prior to dystonia onset. Males (Ⳮ) have a shorter exposure than females (*); curve without symbols ⳱ all patients. There was no safe duration of exposure to BDAS. (Adapted from Kiriakakis et al. 1998)

why men develop TDt earlier than women. In this regard, in the study of Kiriakakis et al., the mean age at first exposure to DBA was 31 years, but males had a younger mean age at first exposure than females (males 27 years; women 36 years). CLINICAL PICTURE Onset of Dystonia and Its Course The onset tends to be insidious, usually developing over a period of weeks and sometimes months. At the onset the dystonia usually starts in one body part, but it then spreads to become segmental (affecting contiguous body parts) or even

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FIGURE 2 The cumulative percentage of tardive dystonia patients increases linearly with age at onset of dystonia. Males (Ⳮ) are younger at onset of dystonia than females (*); curve without symbols ⳱ all patients. (From Kiriakakis et al. 1998)

generalized when the dystonic syndrome is fully developed. The cranial and cervical areas are the most common areas of onset of the dystonia, and 80% of TDt patients have involvement of these areas. Common presentations at onset are blepharospasm and cervical dystonia. Other manifestations include oromandibular, lingual, labial, and pharyngeal dystonia. A few patients report sensory symptoms or strange somatic sensations at a site before the onset of dystonia at that site. Neck pain before the onset of cervical dystonia is also known. Presentation with arm, trunk, or leg dystonia is less common. After onset, the dystonia can worsen and progress for months to a few years in a stepwise fashion. In the study by Kiriakakis et al., the dystonia progressed for a mean of 1.8 years (range 1 month to 14 years). Younger patients tended to have a more rapid spread compared to older patients with TDt. In those with rapid spread (⬍1 year), the mean age at onset was 32 years, compared to those patients in whom

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dystonia spread for more slowly (than a year), who had a mean age of 42 years. Although no clear relationship between the age of onset and distribution of dystonia has been established, in the study of Kiriakakis et al. it was observed that there was a trend for younger patients to have dystonia involving the legs, while in those who were older the onset of the dystonia involved a higher body part, for example, the trunk or arms, with the oldest having cranial cervical dystonia alone. Thus patients with generalized dystonia tended to be younger at onset of dystonia than those with focal or segmental dystonia (Fig. 2). Curiously, this picture mirrors what is seen in idiopathic dystonia. Overall, the phenomenology of TDt may be indistinguishable from idiopathic dystonia (Kang et al., 1986). However, some interesting differences have been noted. For example, retrocollis appears to be more common in TDt than primary cervical dystonia, as was torticollis to the right side in TDt as compared with left-sided predominance in primary cervical dystonia (Kiriakakis et al., 1998). Molho et al. (1998) mentioned that torticollis, laterocollis, and sensory ticks as well as muscle hypertrophy were more common in the idiopathic group compared to tardive dystonia, as was head tremor and family history. No difference was found in response to treatment with botulinum toxin (BTX) injections in the two groups. Tan and Jankovic (2000) compared tardive oromanibular dystonia (OMD) with idiopathic OMD. They found that oro-facial-lingual stereotypies were significantly more frequent in the tardive than the idiopathic group. Presence of stereotypic movements in the limbs, akathisia, and respiratory dyskinesias in patients with OMD strongly suggested prior neuroleptic exposure. Dystonia in tardive OMD was more likely to be restricted to the oromandibular region, whereas in patients with idiopathic OMD, there was often coexistent cervical dystonia. BTX is equally effective in both groups of patients. Axial truncal involvement in TDt is common but more often than not causes hyperextension of the trunk, in contrast to mainly forward truncal flexion or rotation, which is more common in primary axial segmental dystonia (Bhatia et al., 1997). Lateral flexion of the trunk or the Pisa syndrome can occur in TDt and less commonly in idiopathic dystonia (Suzuki and Matzuoaka, 2002). After the intial spread there is some stabilization of the clinical picture. Stress and other factors may cause day-to-day variation. Occasionally the dystonic spasms, particularly in those with generalized dystonia, can get inexplicably severe, sometimes triggered due to an infection or some other illness. This is referred to as ‘‘status dystonicus’’ or ‘‘dystonic storm,’’ and the severity of the spasms can result in myoglobuinuria and resultant renal failure (Manji et al., 1998). Management in an intensive care setting is critical, as the episodes are selflimiting, lasting many days, and will pass with appropriate maintenance. Associated Movement Disorders Associated drug-induced movement disorders are not common in patients with TDt. Oral stereotypies of TDk, akathisia, and parkinsonism were present in about

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65% patients presenting with TDt. Of these, tardive dyskinesia is the most common associated movement disorder, presenting as oral stereotypies. These patients with associated TDk tend to be older when compared to patients with TDt alone. OUTCOME AND CHANCES OF REMISSION OF TDT Unfortunately,TDt is a rather persistent disorder, and remissions are relatively infrequent. This is evident when putting together six reported large series as shown in Table 1. The remission rate of TDt was very low at 10% (21 of 231 patients) after a mean follow-up period of 6.6 years (Burke et al., 1982; Kang et al., 1986; Gardos et al., 1987; Gimenez-Roldan et al., 1985; Wojcik et al., 1992; Kiriakakis et al., 1998). None of the variables, including age at onset, sex, type of neuroleptic, and distribution of dystonia, seem to affect remission. Discontinuation of the DBA seems to be the only important factor related to remission. In the study of Kiriakakis et al., 12 of 54 patients who discontinued DBAs went into remission, versus only 3 of 52 patients who continued with them. Another factor relating to remission is the total duration of DBA treatment. Patients on long-duration (ⱖ 10 years) use of DBAs had a five times lesser chance of remission compared to those in whom the drug had been in use for a shorter period (ⱕ 1 year). A variety of drugs have been tried in patients with TDt. Although some can produce some symptomatic benefit (see treatment section below), none of the different drug treatment modalities seem to influence the final outcome of TDt with regard to permanent or lasting remission. There have been suggestions that clozapine may have a therapeutic role in alleviating TDt, but this is debated and the evidence is inconclusive (Friedman, 1994; Carroll et al., 1997). It is possible that withdrawal of the ‘‘offending’’ DBA when the clozapine was initi-

TABLE 1

Study Burke et al. (1982) Gimenez-Roldan et al. (1985) Kang et al. (1986) Gardos et al. (1987) Wojcik et al. (1991) Kiriakakis et al. (1997) Legend: ns = not stated.

Patients (n)

Follow-up from onset (years)a

Follow-up from DRA with drawal (years)a

Remitting patients (n)

42 9

3.1 4.7

1.5 n.s.

5 0

67 10 29 107

4.8 5.2 7.3 8.3

2.8 n.s. n.s. 3.9

5 0 0 15

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ated may have accounted for the apparent benefit at least in some cases (Friedman, 1994). DIFFERENTIAL DIAGNOSIS It is important to keep in mind conditions in which psychiatric disturbances and a dystonia coexist. The patient may be treated with a DBA for the psychiatric disorder and then develop dystonia as part of his or her original condition. An example is Wilson’s disease (WD), as it can manifest in young patients as dystonia and psychiatric disturbances. Slit lamp examination for Kayser-Fleischer corneal rings and serum ceruloplasmin and copper are essential even if there is a clear history of DBA exposure. Other conditions to be considered are Huntington’s disease and dentatorubropallidal luysian atrophy (DRPLA), and a family history should be sought. Both of these conditions, particularly Huntington’s disease, can cause psychiatric manifestations and a movement disorder and if suspected can be excluded by appropriate genetic tests. Imaging may be useful, and brain MRI may show abnormalities suggesting an alternate diagnosis, as the scans in TDt are normal. Hallervorden Spatz syndrome, which can cause dystonia and psychosis, has a typical MRI picture with a characteristic ‘‘eye of the tiger sign’’ (Sethi et al., 1988) in the basal ganglia. Other conditions with dystonia and an abnormal MRI scan include delayed-onset dystonia due to birth injury, metachromatic leukodystrophy, Huntington’s disease and Wilson’s disease. Finally, as patients with TDt may have no other abnormal features apart from dystonia, the question can arise whether the patient could have idiopathic dystonia. Up to 70–80% of young-onset primary dystonia affecting the limbs is due to the DYT-1 gene; however, the DYT-1 gene is known to be negative in patients with tardive dystonia (Bressman et al., 1997). From a practical point of view, in a given patient with a clear history of DBA use and dystonia suspected to be tardive dystonia with no other features, the only tests necessary are to exclude Wilson’s disease and do brain, imaging, either CT or MRI, as a screening tool. If this is abnormal, other appropriate investigations can be carried out. TREATMENT The most important aspect is prevention, particularly the avoidance of inappropriate use of DBAs. Treatment is essentially symptomatic.The remission rates are very poor, and it is likely that the patient will have a life-long condition of TDt. If the dystonia is focal (or segmental), botulinum toxin injections may be the most effective symptomatic treatment, particularly for cranio-cervical dystonia. Tarsy et al. (1997) reported moderate to marked improvement in 29 of 38

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affected body parts injected with botulinum toxin in 34 patients with TDt, all of whom had failed previous treatments with a variety of drugs. For generalized dystonia, a large number of drugs is available for symptomatic treatment. Drug responses can vary among patients, and often one needs to switch between various agents or even try two or more drugs to help intractable dystonia. Medications commonly used are anticholinergics, tetrabenazine, benzodiazepines, and baclofen. Less commonly used drugs are L-dopa, amantadine, ␤-blockers, and anticonvulsants. In our practice we suggest trying an anticholinergic first if possible (given the possible psychiatric problems), at increasing doses. Next, tetrabenazine or reserpine can be added to the anticholinergic drug, and if that had not been tolerated, tetrabenazine or reserpine may be used alone. Oral baclofen in increasing doses can be helpful, but depression as a side effect has to be kept in mind. Intrathecal baclofen for axial (truncal) dystonia can be very useful but may be tricky to use over the long term due to pump or delivery problems and risk of infection. Paradoxically, sometimes in severe dystonia without benefit from any drug, a neuroleptic such as pimozide or sulpiride has been used and found helpful, although there is the potential risk of worsening tardive dystonia. Atypical neuroleptics, particularly clozapine, have been reported to help tardive dystonia, but the evidence for this has not been conclusive. Lucetti et al. (2002) noted a moderate to marked improvement in dystonia in all 4 patients treated with olanzapine. Significant differences were observed in Toronto Western Spasmodic Torticollis Rating Scale scores and videotape ratings after 8 and 12 weeks of treatment compared with the basal values (p ⬍ 0.05). The average percentages of improvement in Toronto Western Spasmodic Torticollis Rating Scale score and visual analog scale were 26.4% and 42.6%, respectively. No serious side effects were reported at the maximum dosage of olanzapine reached, which was 7.5 mg/day. The authors suggested that this study warranted a larger controlled study to conclusively demonstrate the efficacy of olanzapine in Tdt. The literature regarding the improvement with clozapine is a bit clouded because of mixed inclusion of cases with tardive dyskinesia and tardive dystonia in some reports (Van Harten et al., 1996). Lieberman et al. (1991) mentioned improvement in 43% of cases of TDk, particularly those with dystonia, but others have not found clozapine beneficial in TDk (Caine et al., 1979; Carroll et al., 1977). It is still doubtful if clozapine has a special therapeutic effect in tardive dystonia, though it has been claimed by some authors (Van Putten et al., 1990; Trugman et al., 1994; Friedman, 1994). Controlled studies including clozapine washout studies need to be conducted. Nevertheless, one can recommend a trial of cloazapine in TDt patients with concurrent psychosis. Other suggestions have included morphine (Berg et al., 2001), and in the past it has been noted that electroconvulsive therapy (ECT) could be beneficial for TDt symptoms for a short while.

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Lastly, surgical options such as thalamotomy and pallidotomy have been tried as for idiopathic dystonia, but there is risk of swallowing and bulbar dysfunction, particularly with bilateral thalamotomies. Bilateral deep brain stimulation of the internal segment of the globus pallidus has shown excellent results in idiopathic generalized dystonia (Coubes et al., 2001). There are isolated case reports of tardive dystonia benefited by deep brain stimulation of the globus pallidus (Trottenberg et al., 2001). This procedure may be a promising option in the near future for severely affected TDt patients. CONCLUDING POINTS 1. TDt can emerge within days or after many years of use of DBAs, and there is no safe period. Young males may be at greater risk. 2. There are no safe DBAs, and all classes of neuroleptics can produce TDt. 3. Most patients start with focal dystonia that becomes segmental or generalized within 1–2 years. 4. Prevention is important, as TDt is resistant to treatment and the remission rate is as low as 14%. 5. Discontinuation of DBAs, increases the chances of remission by fourfold. 6. Botulinum toxin injections are the best form of treatment for symptomatic relief, particularly for focal or segmental dystonia. REFERENCES 1. Angle CR, McIntire MS. Persistent dystonia in a brain-damaged child after ingestion of phenothiazine. Pediatr Pharmacol Ther 1968; 73:124–126. 2. Arana GW, Goff DC, Baldessarini RJ, Keepers GA. Efficacy of anticholinergic prophylaxis for neuroleptic-induced acute dystonia. Am, J. Psychiatry 1988; 25: 993–996. 3. Ayd FJ. A survey of drug-induced extrapyramidal reactions. JAMA 1961; 175: 1054–1060. 4. Ayers JL, Dawson KP. Acute dystonic reactions in childhood. N.Z. Med. J 1980; 92:964–965. 5. Berg D, Becker G, Naumann M, Reiners K. Morphine in tardive and idiopathic dystonia. J Neural Transm 2001; 108:1035–1041. 6. Bhatia KP, Quinn NP, Marsden CD. Clinical features and natural history of axial predominant adult onset primary dystonia. J Neurol Neurosurg Psychiatry 1997; 63: 788–791. 7. Bressman SB, de Leon D, Raymond D, Greene PE, Brin MF, Fahn S, Ozelius LJ, Breakefield XO, Kramer PL, Risch NJ. Secondary dystonia and the DYTI gene. Neurology 1997; 48:1571–1577. 8. Burke RE, Fahn S, Jankovic J, Marsden CD, Lang AE, Gollomp S, et al. Tardive dystonia: Late-onset and persistent dystonia caused by antipsychotic drugs. Neurology 1982; 32:1335–1346.

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7 Acute and Tardive Drug-Induced Akathisia Perminder S. Sachdev University of New South Wales, Sydney, and The Prince of Wales Hospital Randwick, New South Wales, Australia

HISTORICAL BACKGROUND The term ‘‘akathisia’’ (from Greek, literally ‘‘not to sit’’) was introduced by Haskovec [1] in 1901, much before the introduction of neuroleptic drugs, to describe two patients with restlessness and an inability to sit still. Earlier descriptions of a similar syndrome can be traced back to the seventeenth century [2]. The first description of neuroleptic drug-induced akathisia is attributed to Sigwald et al. [3]. In the intervening period, restlessness had been described in association with Parkinson’s disease [4,5], and Ekbom [6] gave a detailed account of the restless legs syndrome (RLS). As neuroleptic drugs came into general use in the 1950s, the occurrence of akathisia began to be increasingly recognized. The early European authors considered akathisia to be an extrapyramidal reaction, although until the 1960s many authors continued to regard it as a psychogenic response to the medication or the fact of being medicated. It was not until the 1970s [7] that clinicians recognised that akathisia was common and could manifest itself in multiple ways. Detailed descriptions of the syndrome subsequently began to emerge [8,9]. While most reports of akathisia described it as an acute side effect of neuroleptics, it was also recognised that akathisia could develop as a delayed 129

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side effect, analogous to tardive dyskinesia. Akathisia has been described in association with a range of non-neuroleptic drugs. The distinction between druginduced akathisia and RLS has been firmly established, and the term akathisia has come to refer almost exclusively to the former.

DEFINING AKATHISIA From its earliest descriptions, the paradoxical nature of akathisia was apparent to clinicians and investigators alike: i.e., drugs that were generally recognised to produce a calming effect on psychotically disturbed individuals themselves produced ‘‘nervousness’’ and restlessness. Most investigators agree that there are two aspects to akathisia: a subjective report of restlessness or inner tension, particularly referable to the legs, with a consequent inability to maintain a posture for several minutes, and the objective (or observational) manifestations of restlessness in the form of semipurposeful or purposeless movements of the limbs, a tendency to shift body position in the chair while sitting or marching on the spot while standing, etc. A detailed description of the manifestations is provided later. There is disagreement about the relative importance of these two aspects [10–12], with emphasis on the subjective component (akathisia as a mental disorder) or the objective component (akathisia as a movement disorder) by different investigators. A combination of the two has been argued as being necessary for a definite diagnosis [13]—i.e., akathisia as both mental and movement disorder. A less certain diagnosis (probable or possible) of akathisia may sometimes be made if either the subjective or the objective features, but not both, are present. The temporal association with drug administration is an important aspect of the diagnosis as the syndrome is, by definition, drug-induced. Even when fairly characteristic features of akathisia are present, and the clinical situation is appropriate for the diagnosis, a clinical decision often has to be made to distinguish it from anxiety or agitation or restlessness due to other causes. As there are no laboratory measures to support the diagnosis, the latter must rely solely on clinical judgment. The proposed research diagnostic criteria for akathisia are presented in Table 1.

SUBTYPES OF AKATHISIA Akathisia associated with neuroleptics can be subtyped according to its onset in relation to the administration of the drug and its duration. Since the subtypes may have differing clinical characteristics, pharmacological profiles, and predisposing factors, it is important to consider them separately. Most research on akathisia deals with the acute subtype, and detailed information on the other subtypes is limited. Non-neuroleptic drugs (q.v.) are known to cause akathisia only in relation

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TABLE 1 Research Diagnosis of Drug-Induced Akathisia [13] Prerequisites (necessary for all diagnoses) 1. A history of exposure to drugs known to cause akathisia (antypsychotics can cause all subtypes; nonantipschotics can cause acute akathisia and chronic akathisia, acute onset) 2. Presence of characteristic subjective and/or objective features of akathisisa 3. Absence of other known causes of akathisia, e.g., restless legs syndrome, Parkinson’s disease, subthalamic lesion, etc., and absence of peripheral neuropathy, myelopathy, or myopathy Diagnosesa 1. Acute akathisia (antypsychotic or nonantypsychotic drug-induced; if has a duration of ⱖ 3 months, categories as chronic akathisia, acute onset) 2. Tardive akathisia (if has a duration of ⱖ 3 months, categorize as chronic akathisia, tardive onset) 3. Withdrawal akathisia (if has a duration of ⱖ 3 months, categorize as chronic akathisia, withdrawal onset) 4. Chronic akathisia (acute, tardive, or withdrawal onset; state if patient is not currently receiving antipsychotics) a

State if only subjective or objective features are present.

to their acute administration and, therefore, the other subtypes do not apply to them. The following three subtypes may be considered on the basis of the nature of onset. 1. Acute akathisia (AA). This most well-recognised type of akathisia can start within hours or days after the initiation or increase in dosage or change in type of the neuroleptic drug, and even a single exposure to the drug should be sufficient for the diagnosis [14]. It usually starts within the first 2 weeks [15,16] and almost always within the first 6 weeks [17]. The majority of the references in the literature to neuroleptic-induced, and all references to non-neurolepticinduced, akathisia are to this subtype. 2. Tardive akathisia (TA). There is now sufficient evidence [9,10,12] to suggest that akathisia may develop for the first time in a patient who is being chronically treated with neuroleptic medication, and has not had a recent change in dose or type of drug, or a withdrawal of potentially antiakathisia medication. We consider an onset after 3 months of stable medication as being tardive [13], but empirical data on a valid distinction between acute and tardive onsets are lacking. A number of parallels between TA and tardive dyskinesia (TD) have been drawn as will be discussed later. 3. Withdrawal akathisia (WA). That akathisia may develop within days or weeks of stopping or significantly reducing the dosage of a neuroleptic drug

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is supported by anecdotal reports [11,12,1819]. We consider a development within 6 weeks of the drug change as a withdrawal onset [13], and if the akathisia persists beyond 3 months after drug cessation or reduction, TA should be diagnosed. Akathisia that becomes apparent within 2 weeks of the discontinuation of an anticholinergic, ␤-adrenergic antagonist or other antiakathisia drug should be considered to have been ‘‘unmasked,’’ and classified according to its chronological relationship to the etiological agent. 4. Chronic akathisia (CA). Akathisia may also be categorized on the basis of its duration. We suggest that akathisia which continues for 3 months or longer should be referred to as chronic [13]. CA may therefore have an acute, tardive, or withdrawal onset, and at present there are no empirical data to decide whether this makes any difference to its clinical manifestations. CA is not a distinct subtype of akathisia but refers to its duration, and possibly represents a heterogeneous group. Furthermore, akathisia seen in patients on long-term neuroleptic medication, especially when they are examined cross-sectionally, is not all chronic, and is likely to be a mixture of acute, tardive, and withdrawal akathisias, some of which may also be chronic. A common mistake in the literature is to regard all akathisia in such patients as being CA or TA, without a distinction being made between the two. Other Descriptive Terms The published literature refers to some other terms and syndromes related to akathisia. 1. Pseudoakathisia. This term was introduced by Munetz and Cornes [20] to refer to lower-extremity TD, a forme fruste of TD, which was mistaken for akathisia, with the implication that it was a misdiagnosis. Barnes and Braude [9] applied a different meaning when they suggested that it be used to refer to patients who had the objective features of akathisia without the subjective complaints. For them, therefore, pseudoakathisia was a true akathisia but with limited manifestations. That akathisic restlessness may sometimes occur without its associated subjective distress is supported by the published literature, although this is more likely to occur in TA or CA rather than AA [9,16,21]. Since the urge to move, typically seen in akathisia, may not be reported by these patients, it may be difficult to distinguish akathisic from dyskinetic movements. The distinguishing features are the stereotypic nature of the akathisia (q.v.) and the ability to suppress the akathisic movements voluntarily, unlike dyskinesia. Sachdev [13] suggested that it be referred to as probable akathisia (objective), and that longitudinal studies were necessary to establish its true state with respect to the various subtypes of akathisia as well as TD. Furthermore, Haskovec [1] originally suggested that the inability to sit sometimes occurred as a conversion symptom in neurotic disorders,

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and pseudo-akathisia would perhaps be the appellation for such a presentation, although it must be exceedingly rare. We therefore are of the opinion that pseudoakathisia is an ambiguous term and its use should be discouraged [12]. 2. Acute persistent akathisia. This term has been used to describe akathisia that has an acute onset and persists for a long period while the offending drug is still present [9]. Sachdev [13] referred to this as CA with an acute onset. 3. Akathisia secondary to a general medical condition. Syndromes resembling drug-induced akathisia have been described secondary to encephalitis lethargica [22], Parkinson’s disease [23,24], brain trauma [25], lenticular infarction [26], and a subthalamic abscess [27]. Although described uncommonly, akathisia with organic brain disease is of heuristic importance and should be examined in greater detail. 4. Hemiakathisia and monoakathisia. The manifestations of akathisia may very rarely be restricted to one half of the body [27,28] or one limb [29], which should raise the suspicion of an organic brain lesion, although it can reportedly be drug-induced [28]. ACUTE AKATHISIA Epidemiology and Causes Neuroleptic Drugs Acute akathisia has been reported with both conventional and newer neuroleptic drugs. With the conventional neuroleptic drugs, rates of AA reported vary from 8% [30] to as high as 76% [31]. Three studies that examined the incidence rates of akathisia in psychotically ill individuals treated with the usual clinical doses of medication put the rates at 21.2% [17], 25% [15], and 31% (21% being moderate to severe) [16], respectively. A conservative estimate is therefore 20–30%, but this rate is significantly affected by treatment-related and other variables. AA, along with parkinsonian symptoms, is one of the commonest neurolepticrelated side effects. The risk with some of the atypical neuroleptics may be lower, but the published evidence for this is inconsistent because of the problems of carryover effects and equivalent doses not always being used. The reported rates of akathisia with clozapine vary from 0 [32] to 39% [33], with Sandoz Pharmaceutical Corporation [34] reporting a rate of 3% in 842 patients. In a recent study [35] of 41 patients on clozapine (mean dose 425 Ⳳ 197 mg/day) for at least 3 months, a point-prevalence rate of 7.3% was reported in comparison with 13% for risperidone (4.7 Ⳳ 2.1 mg/day) and 23.8% for conventional neuroleptics (476 Ⳳ 197 mg/day). In another study [36] of patients on clozapine at stable doses, 7% of patients on clozapine monotherapy had akathisia, whereas the rate was 36% in those on clozapine and another neuroleptic. A study [37] comparing akathisia

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in chronically medicated patients on clozapine monotherapy and conventional neuroleptics reported psychic and motor aspects of akathisia in 14% versus 40% and 7% versus 29% in favor of clozapine. These studies suggest that patients on clozapine do have lower rates of akathisia in comparison with conventional drugs and possible other atypical drugs as well. However, it must be appreciated that as these were stably medicated individuals and the studies cross-sectional, the akathisia reported is probably a combination of the subtypes discussed above. Lower rates have also been reported with olanzapine: 6.6% in comparison with 22% for haloperidol [38] and not significantly higher than placebo [39]. In two multicenter trials [40,41] of risperidone (up to 6 mg/day), the rate of akathisia was lower than with haloperidol (10–20 mg/day) and not greater than with placebo. This difference is not apparent at doses of risperidone greater than 12 mg/ day [42]. A recent study [43] of previously drug-naive patients did not find differences between risperidone and haloperidol in the rates of akathisia. Low rates, not dissimilar from placebo, have been reported for ziprasidone [44] and quetiapine [45]. Lower rates are also reported with substituted benzamides (see Sachdev [46] for review). In conclusion, the risk of akathisia is lower (but not absent) with the atypical drugs, with the possible exception of risperidone at higher doses. Akathisia can be caused by dopamine antagonists not generally used as antipsychotics, such as metoclopramide [47]. Serotonin Reuptake Inhibitors Akathisia indistinguishable from that caused by neuroleptics has recently been reported to occur with selective serotonin reuptake inhibitors (SSRIs) [48]. The product insert for fluoxetine [49] describes ‘‘anxiety, nervousness, and insomnia’’ in 10–15% of treated patients, leading to drug discontinuation in 5%. A proportion of these may have typical akathisia, which is probably dose-related. Anecdotal reports of akathisia secondary to other SSRIs—sertraline, paroxetine, fluvoxamine—have appeared in the literature [50]. Akathisia has also been reported with nefazodone and buspirone. The descriptions suggest a similarity with neurolepticinduced akathisia in some of the cases, but there have been no systematic studies to examine the prevalence, manifestations, and determinants of SSRI-induced akathisia. Baldassano et al. [51], in a retrospective chart review, reported a prevalence of 4.5% (3/67) in patients treated with paroxetine. Treatment-emergent anxiety, agitation, and restlessness are more commonly described with SSRIs [48], but whether these are early features of akathisia has not been studied systematically. Other Drugs Akathisia has been reported with a range of other drugs as listed in Table 2. Akathisia has rarely been reported with certain heterocyclic antidepressants and lithium. It is a not uncommon side effect of calcium channel antagonists.

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TABLE 2 Drugs Reported to Cause Acute Akathisisa Antipsychotics Conventional antipsychotics Phenothiazines Butyrophenones Thioxanthenes Dibenzoxazepines Indolic derivatives Rauwolfia alkaloids Newer antipsychotics Benzamides (sulpiride, remoxipride, amisulpride, meloclopramide) Clozapine and related drugs Benisoxazoles (risperidone) Other drugs (savoxepin, sertindole, quetiapine) Antidepressants Selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors Fluoxetine, sertraline Paroxetine, citalopram Fluvoxamine, nefaxodone Heterocyclic antidepressants Amoxapine Mianserin Tryclic antidepressants with/without conjugated estrogen Catecholamine-depleting drugs Tetrabenazine Reserpine 5-HT-receptor ligands Methysergide Buspirone Anticonvulsants Carbamazepine Ethosuximide Calcium antagonists Diltiazem Flunarizine Cinnarizine Other Lithium carbonate Source: Adapted from Sachev [12].

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Predisposing Factors The high rates of akathisia reported in some studies, e.g., the 76% incidence reported by Van Putten et al. [31], suggest that most individuals will develop akathisia under some circumstances, but whether everyone is vulnerable is not known. In a study [14] of a single-dose challenge with droperidol (5 mg) to 20 healthy volunteers, all reported distressing restlessness and 6 were observed to be objectively restless in a cross-sectional assessment. However, not every patient on antipsychotics develops akathisia, however. Drug-related factors are clearly important, with higher drug doses, rapid increment of the dosage, and higher potency of the drug more likely to produce akathisia. As noted above, atypical neuroleptics have a lesser propensity to cause akathisia. The development of parkinsonism also increases the likelihood of akathisia developing, although the latter may occur first, or concurrently, with the parkinsonism. The role of sociodemographic factors and other treatment-related variables is modest. The presence of psychiatric disorder is not necessary for akathisia to develop, but certain organic brain disorders may increase vulnerability. Although some evidence exists that iron deficiency may be a predisposing factor, this is far from established and its role is likely to be minor. The role of genetic factors is poorly understood, but this field is receiving much attention. It has been shown that genetically impaired activity of cytochrome P450 2D6 may increase the risk of akathisia and other extrapyromidal symptoms [51a]. A significant proportion of the susceptibility to akathisia is unexplained. A risk factors model recently proposed by Sachdev and Kruk [16] is presented in Fig. 1. The literature on akathisia in childhood and adolescence is scant, although akathisia has been reported, especially in Tourette disorder patients treated with neuroleptics [52]. The possibility that children may be less vulnerable to akathisia cannot be ruled out, although this may be a function of lower dosages used. Reports of akathisia in the elderly have been too few to make an educated comment on their relative vulnerability. The risk factors for SSRI-induced akathisia have been insufficiently studied, but a tentative list was recently presented by Lane [53] as shown in Table 3. Clinical Characteristics and Diagnosis The most outstanding feature is the subjective distress. In its milder form, it is experienced as a vague feeling of apprehension, irritability, dysphoria, impatience, or general unease [7]. Almost all patients describe a feeling of ‘inner restlessness,’ especially if this description is suggested to them, and this may be referred to the mind or the body or both, but has a characteristic reference to the lower limbs. Patients often describe their feelings as: ‘‘I feel . . . restless; fidgety; unable to keep still; compelled to move; like my legs are jumping; like there are ants in my trousers. . . . My legs want to keep moving. . . . I can’t describe the

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FIGURE 1 Proposed model for the development of acute neuroleptic-induced akathisia, indicating its risk factors. The size of the arrows represents the strength of the association each variable has with akathisia, as determined by the correlation of the variable with the presence or absence of akathisia in the 2 weeks of treatment. The dashed line represents unexplained variance. From Ref. 16.

feeling, it’s so terrible.’’ There is strong urge to move the legs while sitting or standing, and pacing may be one consequence of this. The urge to move may be unrelenting and may preoccupy the person’s thinking. Patients are unable to stay in one position for prolonged periods. Mild cases can often be detected by asking patients if they have difficulty in queuing at supermarkets, cooking a meal while standing, or sitting to watch television. The amount of time a patient is able to stay in a particular position without being compelled to move may be an indication of the severity of akathisia. Lying down provides some relief to the majority of patients, contrasting akathisia from restless leg syndrome. The sensations in the legs are usually localized deep inside, and paraesthesiae are uncommon.

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TABLE 3 Tentative Risk Factors for Akathisia Secondary to Selective Serotonin Reuptake Inhibitors (SSRIs)[53] High dose Rapid increment of dose (?) Past history of drug-induced akathisisa Concomitant use of other medication Neuroleptic drugs Serotonergic drugs ⫾ Discontinuation of MAOI in previous 4 weeks Agitation or restlessness at treatment baseline Idiopathic vulnerability (?)

Akathisia may first become apparent when a patient refuses medication, and it has been recognized as an important cause of noncompliance in schizophrenic patients [54]. Patients, especially if suffering from psychosis, may not always articulate their distress as restlessness. Some may experience their internal distress in the form of apprehension, irritability, impatience, or general unease. Others may exhibit fear, anxiety, terror, anger or rage, or experience vague somatic symptoms. Some authors [7] have reported akathisia manifesting as an exacerbation of psychosis, or as sexual torment. There has been some recent debate on the relationship between akathisia and aggressive, self-destructive, or suicidal behavior, with case reports of violence and suicidal behavior attributed to akathisia being published [55,56]. Our opinion is that this is possibly a reflection of the level of internal distress that akathisia represents, and the inability of some patients to distinguish it from their illness-related distress. Fluoxetine has also been linked with suicidal ideation since the report by Teicher et al. [57], and this has also been attributed to fluoxetine-induced akathisia [58]. Other reports of ego-dystonic suicidal ideation secondary to SSRIs, and possibly linked with akathisia, have been published, but overall it does not appear to be a common occurrence [59]. The objective features of akathisia are both motor and behavioral. Fidgetiness is perhaps the most common sign, manifesting usually as semipurposive or purposeless movements of legs, feet, or toes. These are usually complex and repetitive, but lack the stereotyped quality of a dyskinesia or dystonia. When patients are sitting, they are likely to move their legs, wriggle their toes, pump their legs up and down or cross and uncross them, tap the toes, or invert and evert the feet. In the standing position, the leg movements are typically in the form of shifting one’s weight from foot to foot, marching on the spot, or moving the feet and toes. Restless movements are also seen in the lying position in a

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milder form. The patient may repeatedly shift body position while sitting, but the classical ‘‘inability to sit’’ (from which the disorder gets its name) is present in only 18.5% [15] to 37.2% [16] patients. The patient usually prefers to walk, even though this does not take away the feeling of distress. While the emphasis is on leg and postural movements, semipurposeful or purposeless arm and hand movements may also occur. There is no consensus regarding which movements, if any, are characteristic of akathisia. In our study [16], the features that best discriminated akathisia from nonakathisia were: (1) shifting weight from foot to foot, or walking on the spot, (2) inability to keep legs still (subjectively), (3) feelings of inner restlessness, and (4) shifting of body position in the chair. However, these features are not present in every patient, and in the milder cases, only the subjective report may be present, at least on a brief examination, and only prolonged observation will reveal any motor disorder. Voluntary movements and effortful tasks tend to reduce the movements of AA [12,60]. The majority of the patients report that akathisic movements are voluntary and in response to subjective distress. Except for the most severe cases, patients are able to suppress the movements voluntarily, at least for short periods. A few patients manifest myoclonic jerks of the legs and toes, but these are not prominent features. Tremor of the extremities is not uncommonly associated, and this may be regarded as the co-occurrence of drug-induced parkinsonism. Another feature of the movements is their marked variability over time, and their usual disappearance during sleep. Unlike RLS, periodic movements in sleep are not a feature of akathisia [61]. A list of the important features of akathisia is provided in Table 4. The Longitudinal Course of Akathisia The longitudinal course of akathisia has been inadequately studied. Retrospective inquiry reveals that akathisia is most commonly intermittent, becoming manifest at the time of each escalation of medication and then gradually subsiding. It may persist in some patients for months, perhaps years, becoming chronic in the process. This happened in 4 of 78 patients followed up in our center. The chronicity may manifest itself if a drug used to treat akathisia, e.g., benztropine or propranolol, is withdrawn. It is also not known what happens to the risk of akathisia upon repeated exposure to neuroleptics. This risk may reduce, but this reduction is likely to be small [16]. Differential Diagnosis Since the diagnosis of akathisia is clinical, with no assistance being offered by laboratory tests, the subjective and motor features must be distinguished from those of a number of other disorders. The characteristic features discussed above and the proximity with a drug known to cause akathisia will suggest the diagnosis. In case of doubt, a reduction in the drug dosage will improve AA but worsen

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TABLE 4 Signs and Symptoms of Antipsychotic-Induced Akathisia Symptoms (subjective features) Inner restlessness Inability to remain still (fidgeting)/keep legs still Inability to maintain one posture (e.g., sitting, standing, lying) Feeling of tension in body/mind Apprehension/irritability/general unease/dysphoria Uncomfortable limb sensations Worsening of psychotic symptoms Poor concentration and memory Unwillingness to take medication Signs (objective features) While sitting Crossing/uncrossing or abduction/adduction of legs Pumping legs up and down Lifting foot or part of foot with tapping or bouncing movements Toe movements or sudden jerks of legs/toes Spontaneously rising from chair Crossing/uncrossing or rubbing and shaking of arms/hands Rubbing or massaging of legs Tapping, picking at clothes Nodding, shaking of head Trunk rocking Sitting up/straigtening motions Shifting body or trunk Grunting, shouting, moaning Irregular respirations While standing Marching or walking on one spot Changing stance, shifting body weight, slow treading Flexing/extending knees Arm, hand, trunk, and head movements as while sitting While walking Pacing, repetitive walking, wandering, stomping Sighing/irregular respiration Exaggerated hand swing When lying down Crossing/uncrossing of legs Shifting position of buttocks/torso Other leg, arm, and trunk movements as while sitting Source: Adapted from Sachdev [12].

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agitation and anxiety. An increase in dose will usually lead to a worsening of AA, which is unacceptable as a diagnostic strategy. The response to an anticholinergic drug, such as intravenous biperiden or benztropine [31], has previously been proposed as a diagnostic test, but is likely to result in a number of false negatives, as not all patients with AA respond to these drugs. Further, an intravenous challenge may be inferior to a trial of oral medication, but the latter will be a much slower diagnostic process. A trial of ␤-adrenergic antagonist drugs has similar limitations and is also complicated by the antianxiety effect of these drugs. There are a number of disorders that produce a subjective distress similar to akathisia, with or without the motor features. It is important to distinguish akathisia from psychotic agitation, which is more generalized and is often chaotic, disorganized, and even frenzied. Agitation may also be a feature of affective disorders, both depression and mania. The subjective and objective manifestations of anxiety are different form those of akathisia, but may sometimes be confused. If in doubt, error on the side of akathisia and decrease rather than increase the medication. Some patients may have a dysphoric response to neuroleptics in the absence of akathisia. They may be distressed secondary to bradykinesia, rigidity or tremor produced by the drugs, or may complain of cognitive slowing, lack of concentration, derealization, etc., as side effects with consequent dysphoria. Restlessness can be caused by a other causes, and these are listed in Table 5. A detailed analysis of the clinical features will generally suggest the correct diagnosis. A syndrome resembling akathisia is the ‘‘jitteriness syndrome’’ reported in some panic disorder patients treated with tricyclic antidepressants [62]. RLS can generally be distinguished from drug-induced akathisia, as was discussed above. Restless Legs Syndrome (RLS) or Ekbom’s Syndrome RLS is recognized to be a fairly common disorder [63,64] that may be idiopathic (familial or sporadic) or symptomatic (secondary to other medical conditions). Many causes of RLS are recognized, including: deficiency disorders (iron and folate), pregnancy, metabolic disorders (chronic renal failure), malignancy, some neurological disorders (e.g., neuropathy, myelopathy), peripheral vascular disease, drugs (caffeine, barbiturate withdrawal, etc.), and sleep apnea. Like akathisia, it is characterized by subjective and objective features which are somewhat distinct from those of akathisia, and RLS should not be considered to be a subtype of akathisia except in the very broad sense of the term [12]. The main symptom of RLS is an unpleasant and uncomfortable sensation, frequently localized in the leg, that is aggravated by rest and is worse at nightfall. The motor restlessness is in response to the sensory symptoms. Myoclonic-like jerks may be present during waking hours, and are usually present as periodic leg movements in sleep [65]. Akathisia and RLS are contrasted in Table 6, and detailed accounts are presented elsewhere [63,12].

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TABLE 5 Neuropsychiatric Causes of Restlessness Other than Akathisia Organic disorders Drug-induced restlessnessa Heteroclyclic antidepressants, serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors, serotonin antagonists, central stimulants, aryclcyclohexamines, antimuscarinics Drug withdrawal syndromes Withdrawal from opioids, alcohol (ethanol) and sedative hypnotics, heterocyclic antidepressants, monoamine oxidase inhibitors, nicotine Delirium Dementia Head injury Hypoglycaemia Restless legs syndrome and related syndromes Peripheral neuropathy Peripheral vascular disease Myelopathy Nonorganic psychiatric disorders Affective disorders Psychotic disorder Anxiety disorders Childhood disorder Attention deficit hyperactivity disorder Conduct disorder Autism a

Often, both akathisia and general restlessness have been reported in the literature to be due to the same causes. Source: Adapted from Sachdev [12].

Pathophysiology Since akathisia is caused by psychoactive drugs, is an acute effect, and may occur in otherwise healthy individuals, the focus has been on acute changes in neurotransmitter function. As most (perhaps all) drugs that cause AA directly or indirectly reduce dopamine (DA) function in the brain, dopaminergic mechanisms have been of the greatest interest. That neuroleptics cause akathisia by antagonising DA receptors, especially D2 receptors, is supported by the observations that high-potency D2 antagonists are more likely to cause akathisia, and akathisia is related to drug dose and may occur after the administration of a single dose. Two studies using positron emission tomography (PET) [66,67] demonstrated an association between D2 occupancy in the striatum and the development of akathisia, with the latter authors

Periodic movements in sleep Tremor

Involuntary movements Dyskinesia while awake

Heat or cold

Effect of posture

Exacerbating and relieving factors Diurnal variation

Reason for movement Result of movements

Motor features Characteristic movements

Subjective features Characteristic symptoms Cognitive symptoms Paradoxical behavioral reactions

Featured

Uncommon; if present, of small amplitude and not prominent Rare Often associated (because of neuroleptics)

Worse when sitting or standing in one place for long Little effect

No pattern

Body rocking, fidgetiness, marching in place, crossing/uncrossing of legs, shifting body position in chair, inability to sit To relieve restlessness Some relief while movement occurs

Inner restlessness Present Possibly present

Akathisia

TABLE 6 Contrasting Drug-Induced Akathisia and Idiopathic Restless Legs Syndrome

Common, often prominent and of large amplitude Almost always present No association

May appear only, or worsen markedly, at night Worse when lying or sitting with legs at rest May improve or worsen

To relieve sensory symptoms Movements ameliorate symptoms temporarily

Rubbing and stretching legs, leg flexion, pacing

Paraesthesiae/dysesthesiae in legs Lacking Lacking

Restless legs syndrome

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suggesting a threshold between 74% and 82% D2 receptor occupancy for the production of extrapyramidal effects including akathisia. The D2 antagonism hypothesis has a number of limitations. Typically, D2 antagonism in the striatum leads to reduced rather than increased activity [68], and parkinsonian side effects (rigidity, tremor, and bradykinesia) relate best to this action. The correlation between akathisia and parkinsonism is about 0.3, suggesting that the same mechanism is unlikely to account for both side effects. The D2 antagonism hypothesis also does not explain why acetylcholine and ␤-adrenergic antagonists are effective in some cases of akathisia. An alternative hypothesis was proposed by Marsden and Jenner [69] that the antagonism of the mesocortical and mesolimbic DA projections was responsible for akathisia. This is supported by the observation that lesions of the mesocortical DA neurons leads to increased locomotor activity in rodents [70], and prefrontal lesions in humans have been associated with an akathisia-like syndrome [27]. This model is compatible with the low correlation between akathisia and parkinsonism but lacks empirical support and does not explain some other features of akathisia [12]. In a study of haloperidol-induced Fos expression in the rat brain, Ohashi et al. [71] argued that the effect of propranolol, an antiakathisia drug, could identify the brain regions implicated in the development of akathisia. They found that propranolol attenuated Fos induction in primary somatosensory cortex, cingulate cortex, and pyriform cortex but not the nucleus accumbens or dorsolateral striatum. Since treatment with vehicle also reduced induction in the cingulate and pyriform cortices, the authors argued that the somatosensory cortex, which partially overlaps with the motor cortex in the rat, was involved in akathisia, either directly or through its reciprocal connections with the thalamus. This line of work is promising, but limited by the questionable validity of propranolol attenuation of haloperidol-induced changes as a model of akathisia The association of akathisia with SSRIs has led to speculation on the role of serotonergic mechanisms in akathisia. The majority of the evidence suggests that increased serotonin (5-HT) transmission leads to akathisia-like symptoms and the antagonism of 5-HT, in particular 5-HT2 receptors, leads to reduction or prevention of akathisia. Whether this is a direct effect of serotonin on behavior or an indirect effect through the modulation of DA function is uncertain. It has been demonstrated that SSRIs inhibit the basal firing rate of dopaminergic neurons in the ventral tegmental area in the rat, thereby reducing mesolimbic DA activity [72]. Other mechanisms implicated in the pathogenesis of akathisia include norepinephrine (NE), acetylcholine (ACh), ␥-aminobutyric acid (GABA), glutamate (Glu), and the endogenous opioids. NE and ACh have been implicated mainly because neuroleptics do affect their function, and antiadrenergic and anticholinergic drugs are sometimes effective in treating akathisia. GABA and Glu have a role in the regulation of psychomotor function and are also influenced by neuroleptics.

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In summary, there are many competing hypothesis for the pathogenesis of acute akathisia, but no one is completely satisfactory. The antagonism of mesocortical and mesolimbic DA pathways is still the most attractive hypothesis. A single neurotransmitter hypothesis may, however, be insufficient to account for the complex characteristics of the disorder, and the interaction of many neurotransmitters at various levels in the nervous system must be considered. The development of suitable models, which are currently in their infancy, will assist this understanding. Management Prevention A number of studies have investigated the treatment of AA, but they vary in their methodological rigor. Since akathisia is a drug side effect, optimal management involves its prevention, for which the following measures are applicable. Modification of the Causative Agent. With regard to antipsychotics, the association with drug dosage, rate of increment of dosage, and drug type is well supported. The first principle in prevention would be to use neuroleptic drugs only in which these are clearly indicated. Smaller dosages are generally recommended, especially because recent reviews [73] have suggested that high dosages do not offer any distinct advantage over low dosages in the management of acute psychosis, but produce more toxicity. The use of atypical neuroleptics as first-line treatment of psychosis in many centers has reduced the impact of akathisia. It is advisable to increase the neuroleptic dosage gradually, especially in drug-naive subjects, and to use oral administration wherever feasible. The use of benzodiazepine in combination with neuroleptics for rapid tranquilization will help reduce the total neuroleptic dose administered. If a classical drug is being used, a switch to a lower-potency or an atypical or newer neuroleptic may be appropriate. With regard to non-neuroleptic drugs, lowering the dosage is appropriate if akathisia develops, and if this does not help, an alternative drug should be considered. Modification of Risk Factors. If the patient has a past history of severe akathisia or parkinsonism, it is important to be cautious and vigilant. The evidence with regard to iron deficiency is inconclusive, but it is reasonable to correct such deficiency if it exists, or to administer iron when the patient’s akathisia is resistant to treatment. Prophylactic Use of Antiakathisia Medication. While the routine use of antiakathisia medication in anyone being initiated on neuroleptics is not recommended, there is an argument for their usage in those with a history of troublesome akathisia during a previous episode of exposure to neuroleptics. One may decide to start an anticholinergic drug (e.g., benztropine or benzhexol) or an antiadrenergic drug

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(e.g., propranolol). Since these are only partially effective, akathisia may still emerge. Additionally, the patient is being exposed to the potential of side effects of these drugs. Many clinicians choose not to use these drugs prophylactically but wait for early signs of the development of akathisia. Treatment Although many drugs have been used to treat neuroleptic-induced akathisia, the two classes most commonly used are anticholinergic and antiadrenergic drugs, and there has been a recent examination of 5-HT2 antagonists. There is considerable published literature to support the efficacy of these drugs in at least a proportion of patients, both for treatment and prophylaxis. Anticholinergic Drugs. There are four published open trials, four controlled studies, and one study of prophylaxis that have investigated these drugs (see review by Sachdev [12]). The conclusion to be drawn is that anticholinergic drugs are effective in the treatment of a large number of patients with akathisia. The only negative report [74] was preliminary, and the same authors reported positive results in a subsequent, yet incomplete, study [75]. There is no evidence that any one drug is superior, although claims on behalf of benzhexol and procyclidine have been made. The drug we use most commonly is benztropine (dosage range 0.5–8 mg/day), but benzhexol (1–15 mg), procyclidine (7.5–20 mg), biperiden (2–8 mg), and orphenadrine (100–400 mg) are equally effective. The recent discovery of subclasses of muscarinic receptors makes it possible that patterns of muscarinic selectivity of each of the drugs will emerge, with implications for their use in akathisia or parkinsonism. Pharmacokinetic data on these drugs are meager. For benzhexol, procyclidine, and biperiden, peak plasma concentrations are reached in 1–2 hr, and terminal elimination t1/2’s are 10–12 hr. A twice-daily schedule is therefore appropriate for most patients, although some patients benefit from more frequent administration. The optimal dosage should be titrated, starting with a small initial dose. Prominent peripheral and central anticholinergic side effects should be monitored, especially in the elderly. The measurement of serum anticholinergic activity has been recommended by some authors because of marked individual variations [76], but the facility for such measurements is not readily available. Some of Van Putten’s patients needed high doses (8 mg/day benztropine), and one of our patients responded to 10 mg/day benztropine. The studies of anticholinergic drugs are usually of short duration, and their utility over prolonged periods has not been examined. It is well recognized that akathisia may become apparent in patients on long-term neuroleptics whose anticholinergic drugs are stopped [13]. Whether tolerance to the antiakathisia effect develops is worthy of examination. It is not clear why many patients do not respond to these drugs. A suggestion that was put forward by Braude et al. [15] was that the akathisic patients who

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responded to anticholinergic drugs were the ones who additionally had parkinsonian side effects. This suggestion has not been studied systematically, although some support for it does come from other studies [77,78]. Antiadrenergic Drugs. The two classes of drugs in this group include ␤-adrenergic antagonists (␤A) and ␣1-agonists (clonidine). The first group has been investigated extensively. ␤-ADRENERGIC ANTAGONISTS. Ever since the Lipinski et al. [79] and Wilbur and Kulik [80] reports of the use of propranolol in akathisia, there has been a spate of studies of ␤A drugs. Th initial studies examined propranolol as a lipophilic, nonspecific antagonist, and this has been the most extensively studied treatment. Six open studies and 10 controlled investigations have previously been reviewed [12,81,82]. While the weight of research evidence seems to suggest that propranolol may be a useful drug, its earlier promise is unlikely to be borne out. A balanced viewpoint should be based on the following placebo-controlled studies: Adler et al. [75,83], Kramer et al. [84,85], Irwin et al. [86] and Sachdev and Loneragan [78]. The two former groups reported positive results, and the two latter, negative results. It is significant that in the negative studies, propranolol was a primary treatment, i.e., the patients were not on some antiparkinsonian or other ostensibly antiakathisia medication. Does this mean that propranolol is more likely to work in patients who are resistant to other medication? More research, using wellselected AA patients and properly validated placebo-controlled double-blind studies are necessary. The suggestion from the literature is that relatively small dosages of propranolol are sufficient, with most researchers using dosages of the order of 60 mg/day and rarely above 120 mg/day. The benefit, if likely to occur, is seen within a few days. A trial of 5 days at the higher dose is used by us before we consider the drug to be ineffective. The short half-life would suggest at least twice-a-day schedule, but single daily doses may be effective [87]. A sustainedrelease formulation has been developed to maintain therapeutic concentrations throughout a 24-hr period [88]. Propranolol seems to be well tolerated in this population, and hypotension, bradycardia, sedation, or depression have not generally been reported in appropriately selected individuals. If benefit does occur, how long it will last is not known, but persistence over several months has been reported [87,89]. The efficacy of other ␤A drugs has also been investigated. The rationale has been twofold: to determine if a more selective drug, with fewer sideeffects, would be equally effective, and to investigate whether the antiakathisia effect of propranolol is central or peripheral, and whether ␤1 or ␤2 receptors are primarily involved. These studies have been reviewed elsewhere [12]. The hydrophilic ␤A drugs that have been investigated include nadolol and sotalol, two nonselective ␤-antagonists, and atenolol, a selective ␤1-antagonist. The published evidence

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suggests that these drugs are probably not effective. The evidence is in favor of cardioselective (␤1-antagonists) lipophilic drugs (metoprolol and betaxolol) being as effective as propranolol, and the same is true for an investigational lipophilic selective ␤2-antagonist (ICI 118,551). Pindolol, a nonselective antagonist with intrinsic sympathomimetic activity, was found to be less effective. One must therefore conclude that, to be effective in akathisia, a centrally acting drug is necessary, and there is evidence that both ␤1 and ␤2 selective antagonists may be effective. Our practice, therefore, is to use a nonselective lipophilic antagonist (propranolol), except when there is a medical contraindication, in which case a cardioselective drug may be used. ␣-ADRENERGIC DRUG. Clonidine, an ␣2-agonist that reduces central noradrenergic activity, has been investigated in two small, open-label studies [90,91], which suggest that while the drug may be beneficial, side effects limit its practical use. Further studies are clearly necessary, including those using a transdermal application. Serotonin Antagonists. Miller et al. [92] reported a single-blind open study of ritanserin, a specific 5-HT2 antagonist, with overall improvement. The same authors [93] subsequently reported 3 patients with akathisia resistant to first-line treatment who responded rapidly and substantially to 20 mg/day ritanserin. In an open trial, cyproheptadine, a potent 5-HT2 antagonist with antihistaminic (H1) properties, was effective in improving akathisia in 15/17 patients [94]. In a doubleblind study, cyproheptadine was found to be as effective as propranolol for the treatment of acute akathisia [94a]. A double-blind placebo controlled study of low-dose mianserin (15 mg/day), another 5-HT2 antagonist, found it to be effective in treating akathisia [95]. The same authors found a 5-HT1A partial agonist (buspirone) [96] and a 5-HT3 antagonist (granisetron) [95] to be ineffective in open studies. Serotonin antagonists therefore deserve serious consideration in the treatment of akathisia, especially if anticholinergic and antiadrenergic drugs have failed. Benzodiazepines. The drugs that have been studied include diazepam (5–40 mg/day), lorazepam (1.5–5 mg/day), and clonazepam (0.5–1.5 mg/day), and most studies, which are mainly open-label studies with small subject numbers, have been positive, and suggest the need for better studies. Overall, there has not been a great deal of clinical enthusiasm about the utility of benzodiazepines in treating akathisia. Other Drugs. Amantadine, which has been demonstrated to have antiparkinsonian effects, has had limited investigation in the treatment of akathisia [97–99], with mixed results. Some positive reports of the use of tricyclic antidepressants (amitryptiline) [100], mirtazapine [100a], sodium valproate [101], and piracetam [102] have appeared, but their usefulness remains to be established. A report of

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the beneficial effect of 14-mg nicotine patches in a single-blind study deserves further examination [103]. Treatment of SSRI-Induced Akathisia The risk factors for SSRI-induced akathisia were described in Table 3, and attention to these factors will help reduce the likelihood of akathisia developing. The minimal therapeutic dose of the drug should be given an adequate trial before dose increase is recommended. If a patient on an SSRI drug relapses after initial improvement, the possibility of serotonergic overstimulation should be considered, with the possibility of dose reduction as the appropriate strategy. The concomitant use of neuroleptic and serotonergic drugs should be minimized, and appropriate drug-free intervals instituted when switching from other drugs with potential for interaction, especially MAO’s. If SSRI-induced akathisia develops, one should consider reducing the dose, discontinuing the drug, or changing to another antidepressant. Some patients with mild akathisia will tolerate the distress, with the possibility that some tolerance will develop [104]. Others may improve with the addition of propranolol or shortterm benzodiazepine. Other drugs that have sometimes been found to be effective include mianserin, buspirone, and anticholinergic agents [53]. Conclusion The management of akathisia is difficult, and the research base is limited. A primary effort should be directed at preventing or minimizing akathisia. If it does occur, and the causative drug cannot be ceased, a range of drugs can be used for the treatment of neuroleptic-induced akathisia. A flow chart for the management is presented in Fig. 2.

TARDIVE AKATHISIA As outlined earlier, the prefix ‘‘tardive’’ is strictly to be applied if the onset of akathisia is truly delayed. When patients chronically on neuroleptic medication are assessed, those diagnosed as suffering akathisia may not meet this criterion. The akathisia in chronically medicated patients is therefore heterogeneous, with the onset of akathisia having been acute, tardive, or upon withdrawal. Since studies are often cross-sectional, the chronicity of the akathisia is also difficult to ascertain. The description of tardive akathisia in the literature is therefore to a large extent that of akathisia in patients treated chronically with neuroleptic medication. This caveat applies to most of this chapter, with exceptions being specifically stated. Furthermore, there is no suggestion that drugs that are not dopamine antagonists produce a syndrome of TA, with research again being limited in this context.

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FIGURE 2 Algorithm for the management and treatment of neuroleptic-induced acute akathisia. (Source: Adapted from Sachdev [12].)

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Epidemiology The few cross-sectional studies published suggest that a significant proportion of patients on long-term neuroleptic medication suffer from akathisia, with the figures varying from 0.6% [105] to about 40% [9,106], with a conservative estimate being about 30% [12,107]. The prevalence of so-called pseudo-akathisia was reported as 11% [9] and 5% [108]. In tertiary clinics for movement disorders, TA was reported to comprise 18% [109] and 27% [21] of all patients presenting with tardive syndromes. A longitudinal study to examine the incidence of TA has not, to our knowledge, been published. All conventional neuroleptic drugs have been implicated in the etiology of TA, and it has been documented secondary to metoclopramide [109]. The prevalence of akathisia in a group of patients on stable doses of clozapine was 7.3% in one study [35], but all these patients had previously been treated with conventional neuroleptics. In the same study, the prevalence of akathisia in stably medicated patients on risperidone and classical neuroleptics was 13% and 23.8%, respectively. There are no established risk factors for the development of TA, but this may be because of a lack of systematic research. It is possible that old age, female sex, iron deficiency, negative symptoms in schizophrenic patients, cognitive dysfunction, and affective disorder may increase the risk of TA/CA, but this information is preliminary. That the negative syndrome of schizophrenia may increase the risk for TA is similar to the finding for TD [110]. With regard to withdrawal akathisia, while the evidence with regard to its existence is reasonably convincing [111], its prevalence and risk factors are unknown. Akathisia appears to be common in mentally retarded individuals maintained on long-term neuroleptics [112]. Clinical Manifestations The time of onset of TA is difficult to establish retrospectively. In the study by Burke et al. [21], the duration of neuroleptic treatment prior to the onset of TA ranged form 2 weeks to 22 years, with a mean 4.5 years. The patient with onset after 2 weeks had an acute onset, but her akathisia persisted for 4 months after the cessation of neuroleptics. TA in this clinic population occurred in the first year of exposure in 15/45 patients. In the report by Barnes and Braude [9], 12 of 23 chronic akathisia patients had an acute onset, with akathisia persisting for 7 months to 11 years. The remaining had a withdrawal onset. The range of the symptoms of TA is the same as in AA, but there are differences in the relative prevalence of some features. Table 7 gives a comparison of the prevalence of the various features of akathisia in AA and TA patients in two studies [12,16]. The comparison suggests that the subjective experience of distress may be less in TA, but a longitudinal study to support this is lacking. Behavioral features seen in AA, such as an exacerbation of psychosis, aggressive or suicidal behavior,

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TABLE 7 A Comparison of the Clinical Features in Patients with Acute Akathisia (n ⫽ 32) and Tardive Chronic Akathisia (n ⫽ 31) Feature Subjective Distressing sensations in the limbs Feeling of inner restlessness Inability to remain still when standing or sitting Inability to keep legs still Objective Sitting Inability to remain seated Semipurposeful/purposeless (normal) leg/feet movements Inability to keep toes still Shifting body position in chair Semipurposeful hand/arm movements Standing Shifting weight from foot to foot and/or walking on the spot Other purposeless (normal) foot movements Inability to remain standing on one spot (e.g., walking or pacing) Lying downb Coarse tremor of legs/feet Myoclonic jerks of the feet Semipurposeful or purposeless leg/feet movements Inability to remain lying down

Acutea

Tardive/chronica

44 88 59

36 55 61

56

74

37 66

6 9

44 58 31

39 55 —

66

29

53 31

55 3

18 19 45

0 4 3

26

0

a

Figures are percentages of patients with a particular feature. Some items may not be present in patients with tardive or chronic akathisia. Source: Adapted from Sachdev [12].

b

have not been described with TA. A syndrome of tardive dysbehavior (hyperactivity, aggression, screaming, running, insomnia, etc.) associated with withdrawal from long-term neuroleptic use has been described [113]. Two other syndromes, supersensitivity psychosis and tardive dysmentia, as delayed consequences of chronic neuroleptic medication, remain controversial [12, pp. 162–165]. The motor phenomena of TA are also very similar to those of AA, and I will highlight only the differences. Many patients with TA tend to pump their legs up and down or abduct/adduct them while sitting in a stereotyped manner. Patients

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also commonly exhibit truncal movements (rocking back and forth, or shifting while sitting) and respiratory irregularities (including panting, grunting, moaning, or even shouting). Since many TA patients also have TD, it is often difficult to be certain whether some of the movements described in TA are in fact part of TD. In our opinion, if a movement are preceded by an urge to move, and can be voluntarily suppressed for short periods, it should be regarded as akathisic rather than dyskinetic. Like AA, TA movements are also likely to decrease in the lying position. Preliminary evidence suggests that voluntary movements or concentration tasks tend to reduce TA movements, unlike TD, which is activated by such movements [12]. TA is commonly associated with TD or tardive dystonia. Barnes and Braude [9] reported a moderate to severe orofacial dyskinesia in 39% and choreoathetoid limb movements in 56% of their TA patients. Burke et al. [9] reported that 51 of their 52 TA patients had another tardive syndrome. In our study [12], 58% of the TA subjects also met the criteria for TD, and the association was most robust with limb-truncal dyskinesia. The overlap between TA and TD has been interpreted to mean that TA should be considered to be a subsyndrome of TD. While this argument is difficult to settle, I have argued elsewhere [12] that because there are clinical differences in the nature of the movement disorder in the two, and suggestions that the pathophysiology and pharmacological profiles may be different, it is appropriate to consider TA and TD as separate disorders but with considerable overlap. TA will remit upon discontinuation of the causative drug in only a proportion of the patients, and in the Burke et al. [18] study, the patients took a mean of 1.2 Ⳳ 0.4 years to remit. There is some suggestion that TA is more likely to become persistent in older individuals [12]. Pathophysiology The pathogenesis of TA is unknown, and the discussion that follows is mostly speculative. Dopaminergic mechanisms have received much attention. Tardive or withdrawal onset, persistence after the cessation of neuroleptic drugs, overlap with TD, suppression with neuroleptics, and response to DA-depleting drugs such as tetrabenazine all suggest that the DA receptor supersensitivity hypothesis, which has been proposed for TD [114], may also apply to TA. The report of improvement of the objective manifestations of TA in some patients challenged with low-dose apomorphine lends support to this hypothesis [115]. Whether this supersensitivity in TA is striatal rather than mesolimbic/mesocortical is uncertain. There are many limitations to this hypothesis, which I have discussed elsewhere [12, pp. 247–248]. The persistence of acute akathisia in some patients leading to chronicity while on neuroleptic drugs may be explained on the basis of continuing DA receptor antagonism, especially in the mesolimbic and mesocortical regions. It has been shown that the DA projections to the prefrontal and cingulate

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areas do not seem to develop depolarization deactivation after repeated administration of neuroleptics, unlike the striatal DA receptor [116]. Another possible mechanism is the development of NE receptor supersensitivity which has been demonstrated following chronic neuroleptic treatment at the biochemical [117] and behavioral [118] levels. Bartels et al. [119] suggested that akathisia could be the result of neuroleptic-induced supersensitivity of spinal NE receptors innervated by the ‘‘mesencephalic locomotor region.’’ The roles of cholinergics, GABAergic, and opioid mechanisms have also been suggested in TA [12]. Further, it is possible that brain damage due to free-radical and excitotoxic mechanisms brought about by neuroleptics may play a role in the development of TA, just as it has been suggested for TD [120]. Treatment and Prevention of TA Strategies for Prevention Since there is no effective treatment of TA, the ideal strategy is prevention. The suggestions that follow are best supported for TD, but because of the considerable overlap of TD and TA, they can be argued to be appropriate for TA as well. Neuroleptic drugs continue to remain the mainstay of treatment for a number of psychiatric disorders. Caution is advised in their use for agitation, personality disorders, anxiety, or insomnia, and their prolonged use in affective disorders. When neuroleptics are appropriate, an attempt should be made to minimize the patient’s exposure to the drug by using the smallest dose for the shortest period while taking the risk of psychotic relapse into consideration. The use of atypical antipsychotics as first-line drugs cannot yet be recommended unequivocally, but this strategy is being increasingly adopted by many clinicians. The role of antioxidants (e.g., vitamin E) in the prevention of TA has not been evaluated. When patients are indeed maintained on long-term neuroleptic medication, they should be periodically evaluated (about every 3 months) for early features of TA and TD, which should be adequately documented in the patient’s medical record. Throughout the period of treatment with antipsychotic drugs, informed consent of the patient is necessary. The involvement of a close family member or friend, if appropriate, or a guardian is important if the patient is judged to be incompetent to provide an informed consent. In such cases, consent should be sought as soon as the patient is again considered to be competent. Treatment Once TA is diagnosed, the first step is the evaluation of the neuroleptic drug being administered. While discontinuation of the drug would be ideal, it is not always practicable. Discontinuation may lead to a temporary worsening upon withdrawal, but in the long term should lead to the resolution of a proportion of the disorder. If discontinuation is not possible, the use of lower doses or alternative drugs is recom-

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mended. Preliminary evidence is emerging that an atypical drug may be an alternative worth considering. Of these, clozapine [121–123] has received the most attention. There is a suggestion that the TA may improve while these patients are on clozapine, but whether the latter contributes to this improvement or merely permits natural remission to occur is unclear. If clozapine is inappropriate for a particular patient, olanzapine, quetiapine, or another atypical neuroleptic should be considered. When TA is troublesome, and relief has not been obtained from the changes in the neuroleptic treatment, the following should be considered. Anticholinergic Drugs. Case reports of treatment of TA with anticholinergic drugs have appeared, with mixed results [8,124–126]. There has been an expectation among investigators that TA will behave like TD in showing either no improvement or worsening with anticholinergics [127]. A double-blind controlled acutechallenge study [128] suggested that some TA patients improve with benztropine. Further, the emergence of akathisia in some patients on long-term neuroleptics whose anticholinergic medication was ceased suggests that these drugs may be effective, at least symptomatically, in treating CA. In this instance, the pharmacological profile of TA may be different from that of TD, and since the two syndromes often coexist in the same patient, treatment may be particularly difficult. Antiadrenergic Antagonists. The positive case reports [129,130] of the use of propranolol are counterbalanced by the negative ones [21]. The only double-blind study reported a weakly positive effect, justifying further controlled evaluation. Clonidine and phenoxybenzamine have been tried in a few cases without success. Catecholamine-Depleting Drugs. The utility of drugs such as reserpine, tetrabenazine, and oxypertine in TA has been documented by Burke et al. [21] in an open study. Our own experience with tetrabenazine has been successful in a number of patients with TA, with doses ranging from 50 to 250 mg/day. We tend to start with a dose of 25 mg/day, with gradual increments. Parkinsonian symptoms and depression are common side effects, and the possibility of a worsening of psychosis remains, although it did not occur in any of our cases. Interestingly, tetrabenazine is known to cause acute akathisia in about 10% of cases [131]. Other Drugs. Case reports have been published of the utility of benzodiazepines [21,132] and opiates [21,133]. The suggested steps in the management of TA are presented in Fig. 3. FUTURE DIRECTIONS Akathisia has long been considered a stepchild of movement disorders, and there has been a small but incremental interest in its investigation. The need for ‘‘tight’’ research in this syndrome remains, however, and this has not been obviated by the introduction of atypical neuroleptics. The widespread use of SSRIs has empha-

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FIGURE 3 Algorithm for the management and treatment of neuroleptic-induced acute akathisia. (Source: Adapted from Sachdev [12].)

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sized this need further. Most aspects of akathisia warrant further study, including its clinical manifestations, longitudinal course, predisposing factors, subtypes, treatment strategies, and pathophysiology. Longitudinal studies of patients who have been examined prior to the introduction of medication are likely to be the most informative. The definition and measurement of akathisia should be better standardized for such studies. Neuroimaging studies that examine receptor function in correlation with the clinical state of akathisia may improve our understanding of the pathophysiology. Further attempts at establishing animal models of akathisia, complex as they are likely to be, will lead to a deeper study of the pathomechanisms and rational therapies.

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8 Neuroleptic Malignant Syndrome Joseph H. Friedman Brown University School of Medicine Providence, Rhode Island, U.S.A.

Hubert H. Fernandez University of Florida Gainesville, Florida, U.S.A.

INTRODUCTION The neuroleptic malignant syndrome (NMS) is a variably defined disorder (Table 1) that was first reported in 1960 [1], seven years after the introduction of dopamine-blocking antipsychotic drugs. It did not attract much clinical attention until the English publication of a review paper in 1980 [2]. Since then it has been the subject of a large number of reports. The term ‘‘neuroleptic,’’ meaning ‘‘grips the nerve,’’ refers to the three classes of antipsychotic drugs, phenothiazines, butyrophenones, and thiothixenes, which block dopamine receptors and cause parkinsonism, as well as a variety of other motor side effects. With the release of clozapine, an ‘‘atypical’’ antipsychotic, sometimes referred to as an ‘‘atypical neuroleptic,’’ the definition of the term ‘‘neuroleptic’’ has become unclear. In common use, ‘‘neuroleptic’’ still refers to the antipsychotic drugs of the three classes listed above, while the term ‘‘atypical antipsychotic’’ refers to those with few extrapyramidal effects. Some of the ‘‘atypicals,’’ unfortunately, do have significant extrapyramidal effects [3]. 165

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TABLE 1 Definitions of NMS—All of Which Exclude Other Explanations for the Syndrome and Require the Presence of an Antipsychotic Drug Fever, altered mentation, and “movement disorder” [15] Three major or two major plus four minor criteria [127] Major criteria: temperature ⬎ 99°F; rigidity; elevated CPK Minor criteria: tachycardia, tachypnea, diaphoresis; altered consciousness, leukocytosis, abnormal blood pressure Temperature ⬎ 99.4°F, severe extrapyramidal syndrome, autonomic dysfunction [128] Temperature ⬎ 99°F, severe rigidity or tremor, and three of the following [13]: pulse ⬎ 100 pm; diaphoresis; white blood count ⬎ 10,800 cells/mm3; elevated CPK; hypertension; confusion; incontinence Hyperthermia, rigidity, fluctuating level of consciousness, autonomic instability [129] Severe rigidity and fever plus two of: diaphoresis; dysphagia; tremor; incontinence; altered mentation; mutism; tachycardia; elevated or labile blood pressure, elevated CPK, leukocytosis [130] Temperature ⬎ 100.5 ° F; altered mentation; severe extrapyramidal syndrome; either a response to bromocriptine, L-dopa, or dantrolene, or an autopsy without explanation for fever [131] Temperature ⬎ 38°C; at least two of the following autonomic signs: diastolic blood pressure elevation of 20 points above baseline; pulse greater than 30 above baseline; diaphoresis; incontinence, tachypnea; at least two of the following motor signs: rigidity, tremor, chorea, festinating gait, flexor-extensor posturing, axial extensor dystonia, trismus, sialorhea; encephalopathy, CPK ⬎ 500 and WBC ⬎ 14,000/mm3; fever, severe rigidity, and autonomic changes [73] Use of oral neuroleptics within 7 days on onset (2–4 weeks for depot neuroleptic); temperature ⱖ 38°C; rigidity; five of the following (at the same time): altered mentation; tachycardia; hyper- or hypotension, leukocytosis; metabolic acidiosis; hyercreatinemia or myoglobinuria; diaphoresis or siallorhea, tremor, incontinence, tachycardia or hypoxia; exclusion of alternative explanations [17] Three of the following: (1) oral temperature ⬎ 38°C without other explanation; (2) severe EPS characterized by two of: lead pipe rigidity, pronounced cogwheeling, sialorrhea, oculogyric crisis retrocollis, opisthotonos, trismus, dysphagia, chorea, dyskinesia, festinating gait, flexor-extensor posturing; (3) autonomic dysfunction characterized by two of: 20-point diastolic elevation above baseline, heart rate 30 bpm above baseline, respiratory rate above 25/min, prominent diaphoresis or incontinence. In the absence of one of the above, one of the following: delirium, mutism, stupor or coma, WBC ⬎ 15,000/mm3, CPK ⬎ 1000 U/mL [87,88].

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Whether some of the new ‘‘atypicals,’’ each of which has been reported to cause an NMS-like syndrome, will eventually be considered ‘‘neuroleptics’’ remains to be seen. NMS may also be induced by nonantipsychotic drugs, including the dopamine depletors such as reserpine [4], and tetrabenazine [5] and the drugs used to treat nausea and gastroparesis, such as prochlorperazine (Compazine) [6], and metoclopramide (Reglan) [7]. The situation is further complicated by the occurrence of an NMS-like syndrome that occurs as the result of abrupt discontinuation of L-dopa or amantadine in patients with idiopathic Parkinson’s disease [8,9]. This has led to the suggestion of a new umbrella term, ‘‘acute dopamine deficiency syndrome’’ [10], However, the development of NMS in patients who have been on stable doses of neuroleptics and are without apparent explanations for a dopaminergic ‘‘plunge’’ makes the term seem overly specific, assigning a pathophysiology with a degree of certainty that is somewhat excessive. Finally, the rare reports of an NMS-like syndrome induced by a variety of non-neuroleptic compounds raises questions related to the specificity of this syndrome (see Table 2). CLINICAL ASPECTS: SIGNS AND COURSE Although NMS may develop at any time after starting a neuroleptic, it usually develops soon after initiation or a dose increase [11–13]. Addonizio et al. [12] reported that two-thirds of cases begin within 2 weeks, supporting another observation that 89% of cases occurred within 10 days, although they noted that 33% occurred fulminantly, within hours. Caroff and Mann [11] reported onset within the first day in 16%, that two-thirds developed NMS within the first week and 96% by 1 month. Since onset time can be variably defined, especially with regard to mental status changes, these numbers are relatively consistent, the important

TABLE 2 Drugs Reported to Induce NMS-like Syndrome Alphamethyltyrosine and tetrabenazine (in patients with Huntington’s disease) [4] Withdrawal of amantadine in Parkinson’s disease [19,42] Withdrawal of L-dopa in PD Withdrawal of dopamine agonists in PD [131] Tricyclic depressants plus monoamine oxidase inhibitors [132,133] Carbamazepine [134] L-dopa “off” phenomenon in PD [21] Fluoxetine [135] Zopiclone (a cyclopyrilone similar to benzodiazepines) [136] Diphenhydramine plus diprophylin [137] Tricyclic antidepressants [138]

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points being that NMS usually begins in the first 2 weeks but may begin within 1 day, or as long as months or perhaps years after significant dose changes. Of 115 patients in one review [12], two-thirds developed the full-blown syndrome within hours to 3 days, while some patients progressed slowly over 3 weeks. The signs of NMS generally include hyperthermia, rigidity, mental status changes, and autonomic dysfunction. The fever can be as high as 107⬚F, with 14% of those with fever having maximal temperatures ⱖ 105.8⬚F [12] and 43% over 104⬚F. Temperatures may fluctuate, as with infection, so that one should not expect to see a flat or unidirectional fever curve. Rigidity is the most common of the extrapyramidal syndromes described, occurring in over 90% of patients [12]. Dystonia occurred in 29% of patients and tremor in 48% [14]. The distinction between generalized dystonia and severe parkinsonian rigidity may not be possible, so that severe rigidity may, in fact, be closer to 100% in frequency. The mental state changes may be hard to interpret, since most cases occurred after neuroleptic increase or initiation, presumably due to exacerbation, recurrence, or new-onset psychosis. Stupor or coma are the most commonly described mental changes, followed by lethargy and confusion [15]. Aside from fever, other autonomic signs include tachycardia, tachypnea, diaphoresis, labile blood pressure, incontinence, pallor or flushing, and cardiac arrhythmias. These disorders, however, are closely linked and can be signs of other, medically related problems. Diaphoresis, tachycardia, tachypnea, and flushing are common concomitants of hyperpyrexia. Pallor is associated with hypotension, hence with labile blood pressure. Pulmonary emboli, associated with NMS and also confused with NMS, also may cause tachypnea, tachycardia, and mental changes from hypoxia and fever. In general, the paradigmatic NMS case is a previously medically healthy person who develops an otherwise unexplained fever with stupor or confusion and extreme rigidity within hours to days of either starting a neuroleptic or having a dose increased. In most cases a change in mental state was the first sign, followed by rigidity, hyperthermia, and autonomic dysfunction [16]. Of 222 published cases [17] meeting strict criteria for NMS requiring fever, rigidity and onset within 1 week, 71% had this progression of symptoms. Hyperthermia followed mental state changes in 76% of cases and rigidity in 71%, whereas hyperthermia generally preceded autonomic dysfunction. The laboratory abnormalities present in NMS include elevated creatine phosphokinase (CPK) and leukocytosis. The CPK ranges from normal to massive elevations above the values most laboratories routinely report. Most NMS patients have CPK elevation, 97% in one review [12], but this is undoubtedly biased by the requirement for CPK elevation in some NMS criteria. The general belief among many physicians that CPK elevation is required for diagnosis, and the observation that CPK may be elevated in psychosis or with neuroleptic treatment

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in general (see below), increases the association of an elevated CPK with the NMS. The white count elevation occurs in 40% [15] to 72% [12]. Whether this represents a stress reaction, concomitant infection, or is actually intrinsic to the NMS is unknown. Electroencephalograms and imaging studies of the brain are normal or abnormal in nonspecific ways. One review reports the mean duration of NMS as 13 days after discontinuation of a standard neuroleptic and 26 days for a depot neuroleptic. Mean values, and mortality rates with and without interventions, are discussed below under ‘‘Treatment.’’

SPECIAL CONSIDERATIONS NMS in Children Only recently has the question of whether NMS is different in adults and children been addressed [18]. From a worldwide literature search, 77 cases meeting stringent a-priori criteria were identified, composed of 49 boys, 27 girls, and one unidentified. Eight were mentally retarded and 39% had preexistent medical problems. Nine were also taking lithium, 72% were on a high-potency neuroleptic, and 60% were on two or more low-potency neuroleptics. Mean time interval to onset of NMS was 16 days (range 2.5 hr to 16.8 days). Mean time from initial symptoms to maximum symptoms was 3 days. Resolution occurred over a mean of 12 days (range up to 61 days). Outcome was available in 65 patients (84%). Seven died and 15 had residual deficits including rigidity, nerve palsies, and abnormal movements. The only identifiable risk factor for death was the date of the case report publication, the mortality being higher in the earlier reports. This suggests that over time greater familiarity led to earlier diagnosis, better treatment, and improved outcome. It was unclear if an active intervention (anticholinergics, amantadine, bromocriptine, dantrolene, ECT, levodopa) made a difference, although the authors of the review thought their data supported bromocriptine as the first choice for treatment [18]. Overall there were no noticeable differences between adult NMS and childhood NMS. The 2:1 ratio of males over females may be due to a similar gender ratio of antipsychotic drug use among children. NMS-like Syndrome in Parkinson’s Disease An NMS-like syndrome has been well described in Parkinson’s disease (PD) patients who had never received drugs that interfere with dopamine. Most cases occurred in patients who were suddenly taken off their anti-PD medications [8,19,20]. Rarely it occurred during the ‘‘off’’ state in patients experiencing severe ‘‘on–off’’ phenomena [21]. Fluctuating rigidity and diaphoresis are not uncom-

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mon problems in the PD patients, but fever, fluctuating confusional states, and elevated CPK are uncommon. Ueda et al. [9] prospectively followed 116 consecutive non-neuroleptictreated PD patients admitted to a hospital and found that 11 met strict NMS criteria. All improved after rehydration and resumption of the anti-PD medications. Two also received dantrolene. Atypical Antipsychotics and NMS There have been several cases of NMS induced by the atypical antipsychotics [22–25]. Some difficulty with diagnosis concerns the relatively uncommon side effect (3%) of clozapine inducing elevated temperatures and the relatively common (25%) side effect of patients developing autonomic problems on either clozapine or risperidone [26]. Furthermore, clozapine has been associated with very high CPK levels without evidence of NMS [27,28] or evidence of muscle damage by history, examination, and EMG (personal observation and Ref. 29). It appears clear from the literature that NMS induced by atypical antipsychotics is clinically identical to that induced by neuroleptics. The few reports published compared with the relatively widespread use of these drugs suggest that NMS probably occurs less often with atypicals than with neuroleptics. Only 1 of 8858 patients on Olanzapine developed NMS in a postmarketing surveillance study [15]. PATHOGENESIS OF NMS Receptor Alterations The pathogenesis of NMS is not clear. Reduced dopamine stimulation presumably disrupts the thermoregulatory centers of the hypothalamus, and the striato-nigral and meso-limbic/meso-cortical connections, causing hyperthermia, movement disorder, and an altered sensorium. Blockade of dopaminergic receptors in the spinal cord is thought to be responsible for dysautonomia. The findings of decreased homovanillic acid (HVA) levels (dopamine’s main metabolite) during the active phase of the illness [30–33] support this ‘‘acute dopamine deficiency’’ theory in NMS. The recent development of dopamine receptor tracers also supports the central dopamine hypothesis in NMS. A single-photon emission-computed tomography (SPECT) using 123I-iodobenzamide (a tracer for D2 receptor availability) showed a lack of binding to D2 receptors in the basal ganglia during the acute phase of NMS, which returned to normal values with resolution of extrapyramidal signs in one patient [34]. However, dopaminergic blockade cannot completely explain all manifestations of NMS. In addition, similar clinical syndromes have been observed in association with drugs that lack direct effects on the dopaminergic system. A

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syndrome resembling NMS has been described in patients receiving selective serotonin reuptake inhibitors (SSRIs). This has caused some experts to question whether these two entities represent different aspects of a generalized hyperthermic spectrum [35,36]. Reduction of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA), serotonin’s main metabolite, have also been noted in NMS [37]. Similarly, cases of NMS-like syndromes precipitated by tricyclic antidepressants have led to the hypothesis that NMS may reflect a relative norepinephrine/dopamine excess [38]. This could lead to sympathoadrenal hyperactivity that may potentially explain most, if not all, of the clinical features of NMS [39]. In consonance with this, elevated plasma and urine catecholamines have been reported in patients with NMS [40,41]. A hyperglutaminergic hypothesis stemmed from observations of NMS response to N-methyl-d-aspartate (NMDA) antagonists such as amantadine and memantine [42], and NMS precipitation with amantadine withdrawal [43]. The blockade of dopaminergic systems leads to a state of relatively increased glutamatergic transmission. Glutamate receptor antagonists reduce body temperature [44,45], decrease rigidity [46,47], and have marked influences on respiration and blood pressure [48,49]. Other studies on NMS pathogenesis have explored the possibility of opioidreceptor dysfunction [50–52] and the role of prostaglandins [53]. Pathohysiology of Individual Signs and Symptoms Hyperthermia Both ‘‘central’’ (i.e., hypothalamic) and ‘‘peripheral’’ (i.e., myotoxic) mechanisms are implicated in hyperthermia in NMS. The dopaminergic system in the preoptic area and anterior hypothalamus has been identified as the principal site of thermoregulation [54]. Intrahypothalamic injection of dopamine into the preoptic region of rats resulted in a drop in core temperature that was blocked by haloperidol [54]. Studies also indicate a diencephalo-spinal dopaminergic projection system that appears to inhibit the thoracolumbar sympathetic outflow [55]. Blockade of these spinal dopaminergic receptors by neuroleptic drugs activates the peripheral sympathetic nervous system, leading to increased ‘‘nonshivering’’ thermogenesis due to an increase in metabolism, possibly resulting in excess heat production. On the contrary, Addonizio et al.’s [12] report of 115 cases of NMS noted that in most patients, marked rigidity occurred before temperature rise, suggesting that hyperthermia may be secondary to excessive peripheral heat production from myotoxicity or muscle contractions. This is supported by the success of dantrolene, a peripherally acting muscle relaxant, in reducing fever in some NMS cases. However, in a single case reported by Harris et al. [56], dantrolene controlled

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rigidity in an NMS case induced by haloperido, but L-dopa was required to reduce the hyperthermia. Movement Disorders Parkinsonism (mainly, rigidity and tremor) is presumably caused by the blockade of striatal dopaminergic receptors. This is supported by the relief of rigidity in NMS with dopamine agonists such as bromocriptine. However, why the severity should evolve so quickly is unexplained. Neuroleptics may also have a direct affect on skeletal muscle. Phenothiazines have been shown experimentally to increase contractility in isolated muscle preparations. Prolonged muscle rigidity could contribute to dyspnea, dysphagia, and myoglobinemia. Altered Level of Consciousness Consequences of hyperthermia, muscle rigidity, and autonomic instability in NMS, plus intercurrent infections and metabolic derangements, contribute to mental status changes. However, changes in mental status or rigidity can be the initial manifestation in NMS in up to 82% of patients [57]. This supports the central hypothesis of dopaminergic blockade causing downregulation of meso-limbic and meso-cortical connections, resulting in an altered sensorium. Autonomic Instability Disruption of the inhibitory pathways from dopaminergic hypothalamo-spinal tracts produces hyperactivity of preganglionic sympathetic neurons [39]. All manifestations of dysautonomia may be a consequence of this dysregulation: pallor caused by vasoconstriction that impedes heat dissipation and worsens hyperthermia, intense diaphoresis, mydriasis, urinary retention, and tachycardia. This peripheral hyperadrenergic state may also contribute to increased rigidity and tremor. Epinephrine, for example, increases contraction strength by increasing the amount of calcium released from the sarcoplasmic reticulum [58]. Pulmonary abnormalities, such as tachypnea, dyspnea, and stridor [15], may be due to rigidity, autonomic dysfunction, or a response to lactic acidosis from muscle contraction. Tachypnea may also result from blockade of carotid body, oxygen-sensing glomus cells, which are dopaminergic. Mechanisms of Laboratory Alterations Elevations in CPK may reflect myonecrosis developing during intense, sustained muscle contractions, but the level of CPK rise is not always related to the degree of clinical rigidity [59]. Heightened sympathetic innervation of skeletal muscles

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increases vasoconstrictor activity of myocytes simulating atherosclerotic-ischemic pathology [60]. This observation suggests that catecholamine-induced ischemia from vasoconstriction resulting in muscle damage could be a contributor to CPK elevation in NMS. Elevations of other enzymes such as aldolase, lactate dehydrogenase, and aspartate aminotransferase may be due to injured muscle, as they are significantly correlated with the CPK rise [61]. Alternatively, hepatic injury such as acute fatty changes in the liver induced by hyperpyrexia could cause these enzyme elevations [62]. Leukocytosis in the range 12,000–30,000/mm3, with or without a left shift, may be an acute-phase reaction or secondary to hemoconcentration from diaphoresis and dehydration. Intercurrent infection and pulmonary complications could give rise to persistent leukocytosis. Electrolyte imbalance may result from hemoconcentration.

DIFFERENTIAL DIAGNOSIS OF NMS Elevated CPK in Psychiatric Patients Since elevated CPK has often been considered a hallmark feature of NMS, it is important first to consider the topic of CPK in psychotic and neuroleptic-treated patients. Elevated CPK (MB) has been reported in cases of psychosis due to manic depression, and schizophrenia [63] without apparent trauma [64]. The incidence of elevated CPK for patients newly admitted to psychiatry wards runs as high as 70% [65] and may reach as high as 20,000 IU. The usual duration of this elevation is less than 1 week [65]. In a retrospective study from Israel [66], one-third of newly admitted psychotic patients had CPK levels above 500 IU (below 220 IU is normal), with a male-to-female ratio of 23:7. In patients readmitted to the hospital with another psychotic episode, the CPK levels were relatively similar at the second admission as the first. All patients had been drugfree for at least 3 days prior to admission, and none had neurological disorders such as myopathy. No correlation was found between CPK and psychiatric diagnosis. Elevated CPK has also been reported in patients who were no longer psychotic, but taking antipsychotic medications [29,67]. In 11 patients cited in one report of ‘‘massive’’ CPK elevations, the median value was 9,610 IU with a range of 1,591–177,000 the upper limit of normal being 225 IU. Drugs implicated were clozapine, olanzapine, risperidone, melperope, loxapine, and haloperidol, all low-potency, atypical or ‘‘borderline’’ atypicals (due to 5-H2A receptor antagonism), except for haloperidol. None of the patients had an NMS-like syndrome and none developed renal failure.

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CNS or Systemic Infection The first major confounding diagnosis is infection. Any infection in a patient taking neuroleptics may simulate NMS. Of course, without some objective criterion present, such as an extremely high CPK, one cannot be certain whether one is dealing with infection alone or infection and NMS (one triggering the other). It is a common experience for systemic infections with superimposed bacterial infections to cause significant nonfocal encephalopathies [68], but evidence suggests that this phenomenon is not limited to bacteria alone [69]. In addition, it is common clinical experience for patients with a variety of neurological disorders, particularly multiple sclerosis and many movement disorders, to worsen dramatically with systemic infection and fever (personal observation). Thus a careful evaluation for infection must be undertaken, keeping in mind that systemic infections may cause cerebral compromise even without involving the cerebrospinal fluid or meninges. Aside from the CPK, which might be helpful in making a diagnosis, the percentage of white blood cells made up of polymorphonuclear cells is probably the only other laboratory test possibly helpful in supporting one diagnosis over another, a shift toward immature polymorphonuclear cells suggesting infection. Chest X-rays are usually suboptimal, as patients may be stiff and uncooperative. Occult infections such as abscesses or cholangitis may be missed due to the patient’s inability to report localizing symptoms. On rare occasions a nonlocalizing viral syndrome, such as influenza, could also produce an NMS-like syndrome. In immunocompromised patients on neuroleptics there may be no agreement on the diagnosis of NMS [70]. Finally, it should be noted that meningoencephalitis of almost any etiology can cause an NMS-like syndrome, so that the presence of a neuroleptic is merely coincidental. Other Drug Interactions or Adverse Events Elevated core temperature in the absence of infection will occur with dehydration and extreme heat exposure. Since phenothiazines may impair autonomic function, causing hypotension and impaired sweating, neuroleptic-treated patients with simple heat prostration might be confused with NMS [71]. Typically, severe rigidity should be absent. In an important, albeit small, study Sewell and Jeste [72] reviewed records on every case they could cull from psychiatric admissions in San Diego (CA) County. Over a 21-month period, 41 cases thought to be NMS were found. Many cases were missed, but presumably in a somewhat random fashion. Of the 41 cases, seven charts were unobtainable. Of the 34 charts reviewed, 10 were thought to have medical explanations for the syndrome. All the medical cases but one were on neuroleptics, and this other was on lithium. Three medical patients died, 2 from pneumonia and 1 from lethal catatonia. The confounding diagnosis of the non-NMS patients were ‘‘CPK rise of undetermined etiology,’’ three cases of

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‘‘extrapyramidal side effects,’’ and three cases of infection. Interestingly, in trying to distinguish traits of the two syndromes there were no differences in neuroleptic potency, neuroleptic doses, use of lithium, fever, CPK, or leukocytosis. In a prospective study of 8 patients thought to have NMS at a psychiatric hospital, 6 had NMS, 1 was catatonic without fever, and the last had been on lithium carbonate without neuroleptics [73]. All met NMS diagnostic criteria. Many signs of NMS may have explanations other than NMS, with confusion caused by anticholinergics, akathisia causing paradoxical worsening of psychosis, rigidity being a parkinsonian effect of the neuroleptic, dehydration caused by inability to eat, and muscle contractions leading to elevations of CPK. Serotonin Syndrome The ‘‘serotonin syndrome’’ (SS) is an NMS-like illness, caused, presumably, by an excess of 5-hydroxytryptamine [74]. Some believe that several of the cases reported as NMS were, in fact, cases of the serotonin syndrome [75]. (See also Chapter 11.) Like NMS, the SS consists of a spectrum of clinical abnormalities. Gillman asserts that unlike NMS, the SS is not an idiosyncratic reaction but rather a response to increasing levels of serotonin in the synaptic cleft [74]. This concept is based on animal [76,77] and human responses to increasing serotonin [78] showing a dose–response relationship. In humans the most frequent abnormality is the rapid onset of agitation or hyperactivity, with confusion being less common. Myoclonus, clonus, hyperreflexia, diaphoresis, shivering, tremor, and extraocular movement abnormalities [74] are common. Occurring less often, but still frequently present, are fever, diaphoresis, and other changes commonly seen with fever (e.g., tachycardia and tachypnea). Elevated CPK is occasionally described. The major distinguishing features between SS and NMS are the different drug exposures, and the presence of obtundation and extreme rigidity, which favor NMS, versus the presence of myoclonus and agitated behavior, which point to the SS. SS develops over minutes to hours, whereas NMS typically develops over days. However, NMS may be abrupt in onset as well. The main causes of SS are drug combinations involving monoamine oxidase inhibitors, (MAOIs). The offending second agents include L-tryptophan, tricyclic antidepressants with serotonin reuptake-inhibiting properties, meperidine and some other analgesics, and more recently, the serotonin reuptake-inhibiting antidepressants [79]. Lethal Catatonia In 1934 Stauder described 27 cases of a catatonic syndrome he called lethal catatonia. Patients first became agitated, then developed a fixed posture with cramped muscles which persisted until death within 14 days. Autopsies were

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unrevealing. In 1992 the syndrome was renamed ‘‘malignant catatonia’’ (MC) [80], to reflect the fact that the syndrome did not always lead to death. The new definition also required autonomic dysfunction or fever. It is not clear that a distinction can be made between NMS and MC other than by history. Castillo et al. [81] suggested that MC is characterized by agitation, whereas NMS is characterized by progressive rigidity. However, some NMS criteria do not require rigidity. Anderson [82] and others [83] speculated that NMS is a neurolepticinduced form of catatonia. In addition, many reports have suggested an association between catatonia and NMS [84], whence the use of a neuroleptic to treat catatonic excitement raises the issue of NMS or MC, and the vexing question arises whether to decrease or increase the neuroleptic dose. Core temperature and CPK may be elevated in catatonia in the absence of neuroleptic [80,85]. Therefore, we believe there are no clear distinctions between malignant catatonia and NMS except for the absence of neuroleptic exposure. The differential diagnosis list for NMS is contained in Table 3. Obviously, the differential varies with the criteria used for diagnosis. The major distinctions among the definitions are the requirements for hyperthermia and rigidity.

TABLE 3

Differential Diagnosis for NMS

1. Infection in patient taking a neuroleptic 2. Infectiona in patient with Parkinson’s disease and other akinetic rigid syndromes (including catatonia) 3. Infectiona in patient with Huntington’s disease 4. Serotonin syndrome 5. Other drug interactions or adverse effects: a. Zopiclone [136] b. Phenelzine [132] c. Fluoxetine [135] d. Meperidine plus MAO inhibitor e. Phenelzine [133] 6. Satoyashi’s syndrome [139] 7. Malignant catatonia 8. Tonic seizures 9. Nonconvulsive status epilepticus [100] 10. Malignant hyperthermia 11. Central anticholinergic drug syndrome [140] 12. Heat stroke [97] a

Infection could be CNS or systemic.

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EPIDEMIOLOGY A complete review of NMS epidemiology was published by Adityanjee et al. [86]. A total of 21 reports on incidence were reviewed, 13 non-U.S. and 9 U.S. (see Table 4). The non-U.S. reviews surveyed over 13,000 patients and reported incidences varying between 0 and 3.2%. The larger studies, based on 1000 or more subjects, reported an incidence between 0.02% and 1%, with a median frequency of 0.3%. The U.S. studies surveyed close to 9000 patients and reported a frequency of 0.07% to 12.2%, with a median of 0.2%. (The 12.2% was an exception, the next highest incidence being 3.2%. Both were retrospective studies.) Retrospective reports described incidence varying between 0.02% and 12.2% but surveyed much larger populations than the prospective studies. The prospectively studied frequency described a range from 0% to 1.8%. One interesting observation was the decline in NMS incidence in prospective studies reported by the same group at the same hospital [73,87,88], with the later-reported rate falling by 83%, from 0.9% to 0.15%, despite loosened criteria for diagnosis. This result was ascribed to heightened awareness and earlier intervention to prevent NMS. A major problem with the reports on NMS frequency is the different sets of criteria used for diagnosis. Some studies allowed cases of NMS without fever, whereas others did not. The retrospective studies were limited by the lack of ability to confidently exclude all potential explanations for the NMS-like syndrome, since investigations were chart reviews. If NMS is related, as some reports suggest, to the type of drug used, such as high-potency versus low-potency or depot versus oral, psychiatric diagnosis, dehydration, concurrent use of lithium, and gender, then frequency will vary significantly with the population and the treatment ‘‘style’’ of the institution. There are other significant problems in interpreting data on NMS ‘‘frequency.’’ ‘‘Incidence’’ describes the new onset of a trait during a specified period of time. In describing a drug reaction that tends to occur early after exposure, restricting the study population to newly exposed patients would presumably provide a higher incidence than a report that describes the incidence in a hospital that cares primarily for chronic patients in whom neuroleptic treatment would rarely be intiated. An acute-care psychiatric unit should therefore see the highest incidence and a chronic-care state psychiatric institution the lowest. If some of the suggested risk factors, such as depot form of delivery [89], gender, brain injury, etc., are, in fact, real, then different populations (private versus public clinics) should show different incidences of the syndrome. One can conclude that NMS occurs often enough, whatever criteria are used, that all internists, neurologists, and psychiatrists who treat psychotic patients or use dopamine-blocking or -depleting drugs must be familiar with it, since they will all see occasional cases.

Source: Modified from Ref. 86.

Delay [1] Delay & Deniker [141] Singh [142] Neppe [143] Mohan et al. [144] Sukanova [145] Shalev & Munitz [13] Pope et al. [128] Addonizio et al. [13] Addonizio et al. [12] Keck et al. [87] Gelenberg et al. [146] Friedman et al. [131] Keck et al. [73] Deng et al. [89] Warner et al. [147] Keck et al. [81] Modestin et al. [148] Naganuma & Fujii [149] Spivak et al. [150]

Author France France India South Africa India Czechoslovakia Israel United States United States United States United States United States United States United States China United States United States Switzerland Japan Russia

Country

TABLE 4 Studies of incidence of NMS

Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Prospective Prospective Retrospective Prospective Retrospective Prospective Prospective Prospective Prospective

Nature

Duration Unspecified 6 years 6 years Unspecified 3 years 6 years 14 years 1 year Unspecified Unspecified 18 months 1 year 6 months 2 years 7 years 31 months 47 months Unspecified 8 years Unspecified

Size

n ⫽ 62 n ⫽ several thousand n ⫽ 1,500 n ⫽ 6,000 n ⫽ 6,663 n ⫽ 4,000 n ⫽ 1,250 n ⫽ 483 n ⫽ 82 n ⫽ 82 n ⫽ 679 n ⫽ 1,470 n ⫽ 495 n ⫽ 551 n ⫽ 9,792 n ⫽ 2,680 n ⫽ 2,995 n ⫽ 335 n ⫽ 564 n ⫽ 78,708

3.2% 0.5–1.0% 0.2% 0.02% 0.1% 0.15% 0.4% 1.4% 2.4% 12% 0.9% 0.07% 0.2% 0.9% 0.12% 0.1% 0.15% 0% 1.8% 0.02%

Frequency

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RISK FACTORS The only known risk factor for NMS is previous NMS [13], particularly with the same drug, and male gender. Although malignant hyperthermia (MH) has a strong clinical resemblance to NMS in terms of phenomenology, one is not a risk factor for the other. It is difficult to determine whether a particular drug or a class of drugs increases the risk. This is due to the fact that the number of patients treated with particular drugs varies from place to place, and the rationale for choosing a particular drug for a particular patient is also not known. Shalev and Munitz report that a rapid increase in neuroleptic dose is associated with NMS but also point out that this titration schedule represented standard treatment at that time [13]. Young age has been hypothesized as a risk factor [2,150], as well as affective disorder (versus other psychotic conditions such as schizophrenia) [13,90]. Lithium use in combination with a neuroleptic has been suggested as a risk factor [91], but not supported [13]. Intramuscular (IM) injections [90,92], psychotic agitation, confusion, disorientation, catatonia, higher-than-usual doses of neuroleptics, and dehydration have all been proposed [13,59,87,92]. The presence of medical problems as risk factors is hard to confirm, since some studies looked at patients admitted to psychiatric wards that excluded medically ill patients. It is difficult to identify particular risk factors or sets of risk factors in a disorder as complex as NMS. If catatonia or agitation are risk factors, then higher neuroleptic doses or parenteral administration of neuroleptics would be implicated secondarily, as these patients would be more likely than others to get high doses of IM drugs. Similarly, agitated men, especially young ones, are more likely to receive IM neuroleptics than are other psychotic patients. Catatonia itself may be misdiagnosed, as it may be confused with neuroleptic-induced parkinsonism. Dehydration, another potential risk factor, is rarely defined strictly. Elevated ambient temperature was suggested in one study but not supported in others [88], or by increased rates of NMS in tropical climates [92]. Low serum iron in MC was found to be potential risk factor for NMS [93] after an earlier report identified low serum iron in some NMS patients [94]. One report has suggested a genetic predisposition [95] after identifying a mother and two daughters who suffered NMS. The ryonodine receptor (RYR1) gene mutation associated with MH was not detected. in NMS patients [96]. Only one case has been reported in which a single patient developed both NMS and MH.

COMPLICATIONS OF NMS The major complication of NMS is renal failure due to acute tubular necrosis (ATN) from myoglobinemia. Modest elevations of CPK may occur without frank

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muscle damage, but major elevations of serum CPK are strongly indicative of muscle damage and thus myoglobinemia. Elevated core body temperature can cause damage on its own. Heat tetany due to hyperventilation-induced respiratory alkalosis, with carpopedal spasm, may occur but reverses [97]. ‘‘Heat stroke’’ occurs at extremely high temperatures. At 40.6⬚C (105.1⬚F), obtundation, delirium, seizures, and even focal abnormalities may occur [97]. At 42⬚C (107.6⬚F), oxidative phosphorylation reactions cease, proteins denature, and organs necrose. Parkinsonism, chorea, dementia [98], and ataxia [98,99] have been reported as permanent sequelae of NMS in patients whose temperatures varied between 40.4⬚C and 42.5⬚C. Liver and muscle enzymes are generally elevated with extreme hyperpyrexia. Disseminated intravascular coagulation and other clotting problems may also occur. Nonconvulsive status epilepticus was described in 2 patients with NMS who had never had a seizure [100]. Permanent neuropsychological impairments have been rarely reported as well [101,102]. A case of NMS-induced sinus arrest lasting up to 50 sec, with bradycardia, apnea, and tracheal spasm, has been reported [103]. Autopsy studies of NMS have been rare. The first case reported in detail was published in 1988. The 48-year-old patient died within 2 days of onset, the cause of death not being described. The morphological changes in the brain were similar to those found in heat stroke, which are similar to those of hypoxicischemia except that the NMS case also revealed necrosis of the anterior hypothalamus involving the hypothalamus and the tuberal nucleii [104]. Since the anterior hypothalamic nucleii are important in temperature regulation, the possibility of this being a specific site for NMS pathology was raised, especially since this area had not been affected in reports of heat stroke. The next reported case did not bear out the hypothalamic involvement [105] and showed, like the previous cases, only nonspecific tiny foci of acute ischemic change scattered throughout subcortical structures, but no areas of necrosis. These findings were similar to those previously described [106–108] and revealed no abnormalities that could be deemed specific for NMS. Obvious complications such as aspiration pneumonia, pressure sores, and contractures may occur as in any profoundly debilitated patient. A subacute demyelinating neuropathy has been described in 2 patients with NMS under the age of 50, one of whom received dantrolene, the other supportive care only [109]. These were generalized neuropathies, not pressure palsies. This may be a variant of critical-care neuropathy. NMS RECURRENCE NMS may recur [110], but the frequency of recurrence is uncertain. Since most NMS patients have a primary psychosis, this issue is extremely important. Leven-

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son and Fisher followed 4 NMS cases for from 2 to 11 years [111]. Three were restarted on neuroleptics. One of these, who received the precipitating drug a second time, had a recurrent episode. The other 2 had no further problems. In a retrospective Finnish study [101] of 12 patients identified with NMS, 7 were treated successfully with neuroleptics, all with a lower-potency drug, and in all cases but 1, of a different chemical class. Rosebush et al. prospectively studied 15 NMS patients who were rechallenged with neuroleptics. They noted that out of the 7 rechallenges given within 2 weeks of the NMS, NMS recurred in 6 patients. However, 2 of these tolerated another challenge after an additional 2 weeks [112]. All unsuccessful rechallenges used either the same drug that precipitated the syndrome or carbamazepine. They noted that of the 5 initially unsuccessful attempts, they were able to successfully restart neuroleptics subsequently. In their review, these authors noted the most unsuccessful (69%) rechallenges occurred within 2 weeks of NMS onset, and most (84%) successes occurred when the rechallenge occurred more than 2 weeks later.

TREATMENT Review of Literature No controlled trials for treating NMS have been published. Given the rarity of the diagnosis and the variable criteria used for diagnosis, it is highly unlikely that such a study will ever be performed. We are left sifting through case reports and predominantly retrospective series. The main principles for supportive care are straightforward: hydration (specifically to avoid acute tubular necrosis), cooling, pulmonary toilette, attention to electrolyte balance and to renal and liver function. Also important is the prevention of decubital sores, passive range of motion to prevent contractures, and monitoring of autonomic function. However, the treatment of the actual NMS is uncertain. Dopamine agonists, levodopa, dantrolene, electroconvulsive therapy (ECT), anticholinergics, carbamazepine, amantadine, plasmapharesis, or supportive care alone have all been advocated. Most authors recommend treatment with a dopamine agonist, with bromocriptine being the most commonly cited. This may reflect the fact that this drug was the first dopamine agonist available. Support for the use of agonist is largely theoretical but is also based on several clinical reports of efficacy. There are no data to prefer one dopamine agonist over the other. While there are pharmacological differences distinguishing the different agonists, the clinical implications of these distinctions remains unclear. Three separate reviews address the efficacy of bromocriptine (BCP). Rosenburg and Green reviewed 67 NMS cases published by others and found an 85% benefit in time to improvement over supportive care, with a mean response time of 1 day on BCP versus almost 7 days in the supportive care-only group

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[113]. In 1991, Sakkas et al. reviewed all published cases of NMS and noted that bromocriptine reduced mortality by 60%, from 21% in the supportive care-only group to 7.8% in the treated group [114,115]. A review of the bromocriptine treatment experience limited to Japan concluded that 81.8% of the NMS patients treated with bromocriptine improved. Dantrolene has been used to treat NMS based on its action in uncoupling skeletal muscle by blocking release of Ca2Ⳮ from the sarcoplasmic reticulum. It is the primary treatment of malignant hyperthermia. By reducing muscle contraction, less heat is generated and fever is reduced [116]. Clearly dantrolene should be of greater value in patients with extreme rigidity than in those without. Sakkas et al. [114] reported in a 1991 review of published cases that dantrolene reduced the death rate to 10% and as monotherapy it reduced it to 8.6%, which was a statistically significant reduction from historical data. However, in a single patient, dantrolene reduced stiffness but not fever, whereas levodopa resolved the fever [56]. Amantadine reduced the death rate to only 3% when used with other drugs and to 6% when used alone. Carbamazepine has been reported to both ameliorate [117] and precipitate [118] NMS. Two cases responded within 8 hr to carbamazepine in a dose of 600 mg. Carbamazepine was inadvertently discontinued and the NMS recurred in both cases [117]. NMS developed in another case with carbamazepine withdrawal [119]. The rationale for using carbamazepine is unclear. Two cases were reportedly alleviated by intravenous diazepam, but only for a few minutes [120]. Oral diazepam in one of these patients did not maintain the benefit induced by the intravenous administration. Rosebush et al. [121] reported a prospective nonrandomized series in which ‘‘treating’’ NMS slowed rather than hastened recovery. This article stands in contrast to most others, which reflect published reports showing a marked benefit of various treatments on both mortality and recovery time [11,114,115]. Rosebush et al. studied 20 consecutive patients with NMS, of whom 2 received dantrolene, 2 bromocriptine, and 4 received both drugs, versus 12 who received supportive care only [121]. All patients had temperatures above 39⬚C and elevated CPK levels (mean 7683 IU and range 587–37,000 IU). All had their neuroleptic stopped, and all were treated within 72 hr of diagnosis. Their results favored supportive care alone, with all patients surviving but drug-treated patients taking 9.9 days to resolve (normal mental state and vital signs) versus 6.8 in the supportive care group. No obvious differences at baseline were found to explain this difference, but treatment was not randomized. ECT has been reported to be effective in treating NMS and is recommended by certain authorities in cases where lethal catatonia or NMS recurrence are difficult to differentiate [122]. ECT is also advised in refractory cases of NMS [123,124]. This is based on the premise that NMS and catatonia are related, with

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NMS being on a continuum between catatonia and MC [123]. As with all reports of treatment outcome of NMS, the use of any particular intervention is heavily biased by the choice of patient, and of the treating physician. Moreover, most journals are more likely to publish positive rather than negative outcomes. Mann et al. reviewed published cases of NMS treated with ECT and found successful outcomes in 23 of 27 cases, but cardiac arrhythmias developed in 4 patients [124]. Another review of published reports concluded that ECT reduced mortality compared to historical ‘‘controls’’ receiving supportive care only, and that bad outcomes attended only those who had remained on the neuroleptic drug [125]. A single case of NMS that failed to respond to 6 days of bromocriptine, dantrolene, and amantadine improved with plasmapharesis [126]. These treatments were undertaken with the rationale that protein-bound fluphenazine, which had been given 3 days before in the depot decanoate form, would be more quickly cleared. Since the depot forms of antipsychotics are highly lipophilic and slowly absorbed, it is not clear how long plasmapharesis needs to be continued. Treatment Recommendations for NMS We believe that little data exist to strongly recommend any single approach to therapy, especially in a syndrome that may be difficult to diagnose with confidence. Any recommended approach must take into account the heterogeneity of the syndrome and of the clinical situation, for example, the severity of psychosis. Supportive care must be instituted immediately, with particular attention to hydration and assessment of renal function. Equally important is to consider an infection that is either masquerading as NMS or complicating the NMS. After diagnostic tests have been obtained, the bladder should be emptied, by catheter if necessary, so that proper fluid intake and output can be followed. Hydration is next instituted, the rate and choice of fluid determined by the clinical state of the patient. The offending drug is stopped unless the patient has PD and has an NMS-like illness from drug withdrawal. Up to this point there is uniformity of opinion. The next steps are controversial. If the NMS is mild, the patients may be observed and receive supportive care only. For patients with high fevers or marked rigidity we recommend bromocriptine 10–15 mg T.I.D. depending on the patient’s age, with the lower dose given to older patients. A cooling blanket should be employed, and in cases of severe rigidity, especially in the face of CPK levels exceeding 10,000 IU, dantrolene should be given intravenously. If a response does not occur within a few hours, intubation and paralysis should be instituted. Alternatively, if rigidity is severe, both dantrolene and a paralyzing agent can be given, as the latter works immediately. After a few hours the paralysis should be allowed to wear off to see if the dantrolene was successful. Since paralysis is a frightening experience, patients will also require sedation. Paralysis should be stopped every 6 hr or so

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for assessment. If extreme rigidity persists, intravenous dantrolene sodium should be adminstered again. Patients thought possibly to have malignant catatonia, which is based on a history of catatonic excitement, should be treated with intravenous lorazepam and then ECT if they are unresponsive to the lorazepam. In most cases patients will require an antipsychotic on recovery. We recommend a non-depot preparation of a drug from a different chemical family than the offending drug. Given the general feeling that the atypical antipsychotics are less likely to cause NMS than neuroleptics, they represent the first choice. When these are not available, a switch from phenothiazine to a butyrophenone or a thixene (or vice versa) makes sense. Patients with PD who suffer an NMS-like syndrome due to withdrawal of anti-PD medication are probably the easiest to treat, although they are often very frail. The anti-PD medications must be reinstituted as soon as possible. Since all anti-PD medications, with the exception of benztropine, are oral, this may require use of a nasogastric tube. If this is insufficient, then additional anti-PD medication should be used, specifically L-dopa, a dopamine agonist, or amantadine. If druginduced psychosis was the complication that precipitated the decrease in PD medication that initiated the NMS-like syndrome, then we recommend resuming the offending drug and then dealing with the psychosis, using either clozapine or quetiapine [3]. The psychosis is not life-threatening, whereas the NMS may be. In cases in which extreme rigidity poses the threat of myoglobinuria and extreme hyperpyrexia, we recommend intravenous dantrolene or a paralyzing agent. When using a paralyzing agent it is always important to recognize that consciousness is unimpaired, so these patients also require sedation. REFERENCES 1. Delay J, Pichot P, Lemperiere T. Un neuroleptique majeur non phenothiazine et non reserpinique l’haloperidol dans le traitment des psychoses. Ann Med Psychol (Paris) 1960; 118:145–152. 2. Caroff S. The neuroleptic malignant syndrome. J Clin Psychiatry 1980; 41:79–83. 3. Fernandez HH, Friedman JH. The role of atypical antipsychotics in the treatment of movement disorders. CNS Drugs 1999; 11(6):467–483. 4. Burke RE, Fahn S, Mayeux R, Weinberg H, Louis K, Willner JH. Neuroleptic malignant syndrome caused by dopamine-depleting drugs in a patient with Huntington’s disease. Neurology 1981; 31:1022–1026. 5. Petzinger GM, Bressman SB. A case of tetrabenazine-induced neuroleptic malignant syndrome after prolonged treatment. Move Disord 1997; 12:246–248. 6. Pesola GR, Quinto C. Prochlorperazine induced neuroleptic malignant syndrome. J Emerg Med 1996; 14:727–729. 7. Nonimo F, Camponori A. Neuroleptic malignant syndrome associated with metoclopramide. Ann Pharmacother 1999; 33:644–645.

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8. Friedman JH, Feinberg SS, Feldman RG. A neuroleptic malignant-like syndrome due to levodopa therapy withdrawal. JAMA 1985; 254:2792–2795. 9. Ueda M, Hamamoto M, Nagayama H, et al. Susceptibility to neuroleptic malignant syndrome in Parkinson’s disease. Neurology 1999; 52:777–781. 10. Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in Parkinson’s disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991; 151: 794–796. 11. Caroff SN, Mann SC, Keck PE. Specific treatment of the neuroleptic malignant syndrome. Biol Psychiatry 1998; 44:378–381. 12. Addonizio G, Susman VL, Roth SD. Neuroleptic malignant syndrome: review and analysis of 115 cases. Biol Psychiatry 1987; 22:1004–1020. 13. Shalev A, Munitz H. The neuroleptic malignant syndrome: Agent and host interaction. Acta Psychiatr Scand 1986; 73:337–347. 14. Addonizio G, Susman VL, Roth SD. Symptoms of neuroleptic malignant syndrome in 82 consecutive patients. Am J Psychiatry 1986; 143:1587–1590. 15. Kurlan R, Hamill R, Shoulson I. Neuroleptic malignant syndrome: Review. Clin Neuropharmacol 1984; 7:109–120. 16. Velamoor VR, Morman RMG, Caroff SN, et al. Progression of symptoms in neuroleptic malignant syndrome. J Nerv Ment Dis 1994; 182:168–73. 17. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin N Am 1993; 77: 185–202. 18. Silva RR, Munoz DM, Alpert M, et al. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38:187–194. 19. Henderson VW, Wooten GF. Neuroleptic malignant syndrome: A pathogenic role for dopamine receptor blockade. Neurology 1981; 131:132–137. 20. Toru M, Matsuda O, Makigucki K, Sugano K. Neuroleptic malignant syndromelike state following a withdrawal of antiparkinsonian drugs. J Nerv Ment Dis 1981; 169:324–327. 21. Pfeiffer RF, Sucha El. ‘‘On-off’’ induced malignant hyperthermia. Move Disord 1989; 4:338–341. 22. Buckley PF, Hasan S. Atypical neuroleptic malignant syndrome and atypical antipsychotics. Am J Psychiatry 1998; 155:1633. 23. Newman M, Adityanjee M, Jampala C. Atypical neuroleptic malignant syndrome associated with risperidone treatment. Am J Psychiatry 1997; 154:1475. 24. Hasan S, Buckley P. Novel antipsychotics and the neuroleptic malignant syndrome: A review and critque. Am J Psychiatry 1998; 155:1113–1116. 25. Burkhard PR, Vingerhoets FJ, Alberque C, Landis T. Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry 1999; 56:101–102. 26. Buckley PF, Meltzer HY. Treatment of schizophrenia. In: Schatzberg A, Nemeroff CD, Eds. Textbook Pharmacology. Washington. DC: American Psychiatric Press, 1995:615–639. 27. Parsa MA, Rohr T, Ramirez LF, Meltzer HY. Neuroleptic malignant syndrome without neuroleptics. J Clin Psychopharmacol 1990; 10:437–438. 28. Scelsa SN, Simpson DM, McQuistion HL, et al. Clozapine induced myotoxicity in patients with chronic psychotic disorders. Neurology 1996; 47:1518–1523.

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9 New Approaches to the Treatment of Dopamine Blocking Agent-Induced Movement Disorders Sanjay Gupta Olean General Hospital, Olean University of Buffalo School of Medicine and Biomedical Sciences Buffalo, New York, U.S.A.

INTRODUCTION Movement disorders are commonly seen in both neurological and psychiatric practice. Dopamine receptor blocking agents (DRBA) are the most common cause of drug-induced movement disorders. These agents are commonly referred to as neuroleptics, a term coined by Deniker which means ‘‘that which takes on the neuron’’ [1]. In addition to antipsychotic drugs, other agents such as antiemetic drugs and metoclopramide are also included in this category due to their blockade of dopamine receptors. For the assessment of DRBA-induced movement disorders a good knowledge of the classification of these disorders is essential. The movement disorders can be classified into hypokinetic or hyperkinetic type [2]. Hypokinetic disorders are characterized by impairment in the initiation of movement (akinesia) and reduction in the speed and amplitude of movement (bradykinesia). Additionally, there may be increased muscle tone or rigidity. A 193

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common disorder of this kind is neuroleptic-induced parkinsonism [3]. The hyperkinetic disorders are characterized by increased motor activity and are called dyskinesias. These include disorders such as dystonia, akathisia, chorea, tics, tremor, and myoclonus [3]. DRUG-INDUCED PARKINSONISM Drug-induced parkinsonism (DIP) is similar to Parkinson’s disease (PD) with respect to the presenting neurological signs, such as tremor, rigidity, akinesia, and postural instability [4–8]. DIP occurs in 10–15% of patients treated with neuroleptics, and there is considerable variability in susceptibility to this side effect [9]. The onset of DIP is usually associated within a short time (usually within 3 months) of exposure to DRBAs, while the onset of idiopathic PD is insidious. PD usually occurs in patients over the age of 50 years, while DIP can occur at any age [8,10]. DIP commonly occurs in psychiatric patients, but the use of drugs such as metoclopramide (Reglan), prochlorperazine (Compazine), and droperidol (Inapsine) result in this disorder being recognized in nonpsychiatric patients as well [8]. Signs of parkinsonism may occur in older adults on a stable dosage of a neuroleptic. The question arises whether this is idiopathic Parkinson’s disease (IPD) or DIP with IPD being unmasked prematurely. The patient may also have increased sensitivity to the neuroleptic, associated with aging. In such situations it is prudent to discontinue the neuroleptic if possible, as this should help resolve the symptoms. This could take an extended period of time. Once the neuroleptic is discontinued the DIP improves, whereas IPD will worsen progressively over time after the initial improvement due to stopping the neuroleptic [7]. The conventional strategies for treatment of DIP include a change in dosage or type of antipsychotic or introduction of another medication to counteract this side effect. Anticholinergic Agents Anticholinergic agents have been the mainstay of treatment of confirmed DIP in psychiatric practice. Single boluses of anticholinergics were no different than placebo in relieving severe DIP [11]. Benztropine, trihexyphenydyl, and biperidin are used extensively for treating DIP. The literature describing the use of anticholinergic agents is summarized in several reviews [12,13]. Amantidine Amantidine, an N-Methyl-D-Aspartate (NMDA) receptor antagonist, has been used to treat DIP, especially in patients sensitive to the side effects of anticholinergic agents. Amantidine is used because it is well tolerated, has lower propensity

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to cause memory impairment, and is thought to enhance dopaminergic activity. The action is thought to occur through dopamine release by some, while others think it is due to blockage of dopamine reuptake or NMDA receptor blocking activite. Despite its demonstrated efficacy, there remains a persistent concern that it may not be as efficacious as anticholinergic drugs [14]. However, amantidine has been compared to benztropine in a double-blind study and found to be equally effective and better tolerated [15]. Levodopa Several published reports have suggested the efficacy of levodopa in the treatment of DIP. The results are still contradictory with regard to the use of levodopa in treating DIP. In an open study, single intravenous boluses of levodopa were given at 2 mg/kg over 5 min and compared to placebo. All 40 patients showed improvement with regard to akinesia and rigidity, while tremor was found to be the least responsive symptom. Milder cases of DIP seemed to have a better response [16]. The study indicated that patients on chlorpromazine appeared to have a better response than those on haloperidol. Angrist has reported worsening of psychosis in all 10 schizophrenic patients given 3–6 g of levodopa [17]. This may have resulted due to discontinuation of neuroleptic therapy. However, levodopa can also precipitate psychosis. In another study, 16 of 20 patients worsened psychiatrically after their antiparkinsonian drug was discontinued and they were placed on levodopa [18]. Several other levodopa studies have produced conflicting results [7]. There is insufficient clinical evidence for the efficacy of levodopa in treating DIP. In addition, there is a risk of precipitation of psychosis and abnormal involuntary movements. Hence it is not a preferred treatment for DIP. Electroconvulsive Therapy Electroconvulsive therapy (ECT) has been used for the treatment of Parkinson’s disease [19,20]. Isolated case reports have documented its effectiveness in DIP, but there are no well-conducted controlled trials. In a single study, bilateral ECT given at three treatments a week was found to have efficacy beginning the first week, but the DIP began to worsen again [21]. In addition, anticholinergic agents were used concurrently, which confounds the findings. The mechanism of action of ECT in the treatment of DIP is unclear. ECT has been shown to enhance dopaminergic transmission. ECT is clearly not an established first-line treatment for DIP. Well-designed controlled studies are needed. In patients who have tardive dyskinesia (TD), antiparkinsonian agents have been shown to worsen the abnormal involuntary movements [22]. In patients with coexisting DIP and TD, neuroleptic withdrawal will help ameliorate both conditions over time. This strategy, however, is not feasible, as relapse of psychotic symptoms will result. DIP is one of the major causes of medication non-

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compliance. The issue of chronic prophylaxis with anticholinergic in patients trested with conventional neuroleptics remains unresolved [7,23]. Atypical Antipsychotics Atypical antipsychotics such as clozaril-challenged the notion that antipsychotic effcacy and extrapyramidal side effects are tightly linked. Clozapine risperidone, olanzapine, and quetiapine, and ziprasidone are agents of first choice in the treatment of psychosis [24–30]. These agents have a highly favorable DIP profile. However, in in many clinical situations conventional agents may need to be used. Rarely, some patients, especially young adults and children treated with risperidone, have been reported to have DIP. Atypical agents should be used in patients with DIP where the offending agent can not be withdrawn one to recurrence of psychosis. TARDIVE DYSKINESIA—NOVEL APPROACHES TO TREATMENT Antioxidants Antioxidants, such as ␣-tocopherol (vitamin E), appear to be promising as treatments and prophylactic measures against TD. Their action is based on the theory of free-radical toxicity in the basal ganglia [31,32]. If their production increases and they cannot be destroyed rapidly enough, damage to the neurotransmitter terminals is believed to result. In addition, it is thought that chronic neuroleptic exposure leads to increased free-radical production [33] which in turn damages catecholaminergic as well as other neurotransmitter terminals by destabilizing neuronal membranes through lipid peroxidation [34]. The body depends on freeradical scavengers, or antioxidants, to protect against oxidative damage. ␣-tocopherol, an antioxidant scavenger, may help to decrease or prevent this damage by destroying excess free radicals. The efficacy of vitamin E in the treatment of TD has been evaluated in several studies [31,35–39]. Five studies have followed a double-blind, placebocontrolled, crossover design; the studies by Adler et al. employed a double-blind parallel design [38,40]. Vitamin E was found beneficial in all but one study [37]. Patients who improved in these studies tended to have a duration of TD of less than 5 years. In two of the studies [35,36], it was noted that patients with dystonia or buccolingual movements showed greater improvement (33–50%). Shriqui et al. found vitamin E (1200 IU/day) to be no better than placebo, speculating that their patients did not improve because of neuroleptic exposure greater than 10 years [37] This study had 80% power to detect a true difference of 22.5% in Abnormal Involuntary Movements Scale (AIMS) scores between the treatment and placebo group. Egan et al. [36] have significantly improved study design by conducting videotaped

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interviews and reporting on interrater reliability, an important factor that can influence results. They found significant improvement following vitamin E treatment in patients with TD of less than 5 years’ duration. These findings suggest that membrane destabilization effects might be partially reversible early in the course of tardive dyskinesia and hence improvement occurs. Longer duration of TD leads to permanent structural changes which are not amenable to treatment. This is consistent with the free radical hypothesis. Adler et al. [38] took this research a step further in their 1993 prospective study of vitamin E in the prophylaxis and treatment of TD. Twelve of the 29 patients had TD for at least 5 years. They reported positive results at 36-week follow-up. In a 1998 study [40], Adler et al. found that 1600 IU of vitamin E produced a significant improvement (3 points in mean AIMS scores) starting at 10 weeks and continuing for up to 36 weeks. The results of the 1998 Adler study were in direct contrast to a larger, multicenter Veterans Affairs Cooperative Study (CS 394) which included 158 VA patients [41]. Although the study has not been published yet, two of the investigators indicate that there were reductions of TD in both the study and control groups without a significant difference between the two. Several differences between the Adler study and CS 394 could account for the discrepancies in results, including sample size, sampling error, bias, and changes in prescribing practices (i.e., in CS 394, enrollment began when atypical antipsychotics were prescribed more often). In a large, uncontrolled study administering a high-dose multivitamin treatment (with vitamin E) along with neuroleptic medications, Hawkings reported a remarkably low incidence of TD [42]. This finding suggests the need for additional research on the use of vitamin E as a prophylactic agent in TD. In the studies, vitamin E dosages ranging from 1200 to 1600 IU were used, beginning with 400 IU bid with upward titration at weekly intervals. Adverse effects reported include-nausea, vomiting, abdominal cramps, diarrhea, headache, and fatigue, though most patients tolerate it well [36]. Vitamin E remains a promising agent for the treatment and prophylaxis of TD. Additional studies examining larger samples, including patients with schizophrenia as well as affective disorders, longer treatment periods, and longitudinal designs would be beneficial. Future research should address the combination of other antioxidants, such as ␤carotene [43] and ascorbic acid [44], with vitamin E in the treatment of TD. Ascorbic acid in particular may be a promising adjunct to vitamin E therapy since it recycles the tocopheroxyl radical of vitamin E [44]. Atypical Antipsychotics in the Treatment of Tardive Dyskinesia and Its Variants Clozapine Clozapine, a dibenzodiazepine derivative, has proven to be efficacious in patients refractory to standard antipsychotic agents. It has been reported to have an affinity

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for multiple dopaminergic receptor subtypes (including D1, D2, D3, and D4) [45]. In addition, it has been reported to act on ␣-adrenergic, histaminergic, muscarinic, and serotonergic receptors. Clozapine is known to have minimal extrapyramidal side effects, possibly due to its affinity for the mesolimbic dopaminergic receptors, and hence has been studied as a treating agent for tardive dyskinesia [46,47]. The use of clozapine in the treatment of TD has raised several issues concerning its mechanism of action. The first possibility is that clozapine itself actively treats or reverses TD. Second, clozapine may simply suppress or ‘‘mask’’ the dyskinetic movements in the same way that other antipsychotics do; or third, as it does not cause TD or worsen its manifestations, the dyskinesia may remit spontaneously. Simpson et al. [46] studied seven schizophrenic patients in a placebo–clozapine–placebo design. Clozapine was given for 18 weeks, though patients were not at a therapeutic level for the entire duration. Simpson et al. noted that TD began to decrease after midtrial, returning to original severity upon drug discontinuation. No patients remitted completely. In two studies [48,49] it was reported that a portion of their subjects remitted completely; however, both studies were open, uncontrolled trials. Gerbino et al. [48] treated 24 patients (average daily dose 650 mg) for a minimum of 4 weeks. All patients demonstrated at least a 50% reduction in TD, with 7 achieving 100% reduction by the end of the treatment trial. An average of 90% improvement was maintained even after a 50% dose reduction. In addition, 17 of the 24 patients were followed for up to 7 year with maintenance of efficacy, even upon withdrawal of clozapine. Lieberman et al. [50] reported on 30 psychiatric patients with TD followed on clozapine for a minimum of 12 weeks, indicating statistically and clinically significant improvement in severity (43% of patients had 50% improvement). Whether clozapine when used alone results in TD is debatable. There have only been a few cases of TD associated with the initiation of clozapine therapy [51], and one study found that higher levels of TD were associated with higher levels of plasma clozapine and a higher ratio of plasma/dose [52]. In the Kane study, two of 28 patients treated with clozapine for at least 1 year developed mild TD as measured by the Simpson Dyskinesia Scale on at least two consecutive ratings 3 months apart [51]. This study was unable to conclude definitively whether TD was caused by clozapine in these two patients. Only studies in neuroleptic-naive patients will be able to determine whether clozapine causes TD. In summary, clozapine appears to reduce dyskinetic movements, although the question of its therapeutic mechanism remains unanswered. The majority of relevant studies suggest suppression of TD [46,50,53], although Gerbino et al. [48] demonstrated complete and lasting remission in their patient sample. While results with clozapine look promising, well-designed placebo-controlled studies using adequate doses and duration of treatment, follow-up, assessments at drug-

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free baseline, and blood level monitoring are needed to fully evaluate its effectiveness. The use of clozapine is limited by its potential to cause agranulocytosis, which requires weekly monitoring of the blood count for the first 6 months biweekly thereafter. Risperidone The efficacy of risperidone in treating TD needs further investigation, since there is evidence both for [54] and against [55] its use. It is nearly impossible to determine if risperidone induces TD, since most patients receiving risperidone have already been exposed to standard antipsychotics known to cause TD. Since DIP is dose-dependent with risperidone, it can be hypothesized that TD is also dose-dependent. Few studies have specifically addressed the relationship of risperidone to TD, but one recent follow-up study reported no cases of TD in a sample of 625 patients with dementia. Improvement was reported on measures of dyskinetic movements, hyperkinesia, buccolinguomasticatory factor, choreoathetoid movements, and clinical global impression of dyskinesia [56]. There are a few case reports of TD associated with the initiation of risperidone therapy [57,59]. One of these reports described rapid-onset TD in a neuroleptic-naive patient [58], but the others included patients who had been previously exposed to conventional neuroleptics known to cause TD. In addition, we have obserred a neuroleptic-naive patient who developed dyskinetic movements with risperidone. Prospective, double-blind, placebo-controlled, long-term studies of risperidone and other atypical antipsychotics in neuroleptic-naive patients are needed to determine whether these agents cause TD. Olanzapine The development of acute extrapyramidal symptoms (EPS) is associated with increased risk of TD [60]. Several studies have found that olanzapine is comparable to placebo and superior to haloperidol for incidence of EPS [28,61,62]. In a large double-blind, placebo-controlled study [62], significantly fewer patients receiving olanzapine (2.8%) exhibited new-onset TD than haloperidol-treated patients (8.0%). Although there have been no controlled trials of the use of olanzapine as a treatment for TD, olanzapine has been anecdotally reported to improve tardive dyskinesia [63–65]. Since all three patients were elderly and had received previous conventional antipsychotic trials, it is unclear whether the improvement of TD was due to the discontinuation of the conventional neuroleptic or a result of the introduction of olanzapine. An advantage of olanzapine, which is pharmacologically similar to clozapine, is that it has no associated risk of potentially fatal agranulocytosis [66,67]. Other Atypical Antipsychotics Other atypical antipsychotics, including quetiapine and ziprasidone, have recently been introduced and have not been studied for treatment periods long enough to

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assess treatment-emergent TD. Quetiapine has a greater affinity for 5-HT2 receptors than for D2 receptors [48], indicating a low likelihood of producing extrapyramidal symptoms, and thus of dyskinesias. In a large, multicenter study, quetiapine produced EPS rates similar to placebo [68]. Ziprasidone is a partial 5-HT1A agonist and a 5-HT2C antagonist, properties it shares with clozapine. Ziprasidone has demonstrated EPS rates similar to placebo [69]. Long-term, placebo-controlled trials are needed to determine the liability of quetiapine and ziprasidone to produce TD. Substituted Benzamides Substituted benzamides are antipsychotic agents that include sulpiride, tiapride, and remoxipride. These agents have been approved internationally but have not yet been approved by the U.S. Food and Drug Administration. These drugs are selective dopamine D2 receptor blockers which may preferentially act on the mesolimbic DA pathways [70], and have been studied in the treatment of TD. Tiapride has been the most extensively investigated of these agents. Several studies [71–74] have employed placebo controls and blood levels, with videotaped ratings of TD, dosages ranging from 300 to 1200 mg/day. In addition, no significant side effects were reported with doses up to 1200 mg/day. All but one study [74] demonstrated significant improvement with tiapride compared to placebo treatment. Sulpiride was also investigated in a double-blind, placebo-controlled, crossover trial at doses of 400 to 2100 mg/day, with a significant reduction of severity of abnormal involuntary movements [75]. During the final placebo phase the TD scores returned to their baseline, presulpiride treatment level. Similarly, 8 psychiatric patients in a single-blind controlled study were administered remoxipride (150–600 mg/day), resulting in a partial reduction of TD scores without increasing parkinsonism [76,77]. In summary, the studies using substituted benzamides have uniformly used small sample sizes ranging from 8 to 21 patients with varying diagnoses and without prospective follow-up. Though the studies have found a beneficial effect, it is unclear whether these agents simply suppress TD, like traditional neuroleptics in higher doses, or actually treat the disorder. Some Issues Regarding Atypical Antipsychotic Drugs The atypical antipsychotics, while having a low propensity to cause TD, are associated with weight gain, which has become a focal point of research interest [77–81]. Clozapine and olanzapine are associated with excessive weight gain compared to risperidone, quetiapine, and ziprasidone [77]. In the case of clozapine a 5-year naturalistic study confirmed the propensity of clozapine to cause weight increase occurring until month 46 after the initiation of treatment [82]. Clozapineand olanzapine-related weight gain is reported to occur in those with a low body

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mass index and those responding to the drug [83–85], a finding that has not been associated with haloperidol or risperidone. The weight gain with olanzapine has been reported to plateau by week 39 [83]. Clozapine and olanzapine cause weight gain toward the higher end of the spectrum compared with ziprasidone, which causes the least if any weight gain [77]. Risperidone causes weight gain in midrange compared with ziprasidone (low) and clozapine (highest) [77]. Molindone, a conventional antipsychotic, has the least weight gain among all the antipsychotics, both conventional and atypicals [77]. The exact mechanism of weight gain is unknown, though speculations involve multiple causes including drug effects, the effects of monoamine and histamine, hormonal effects including prolactin, sedentary life style of chronically mentally ill patients, poor eating habits, and lack of exercise [86,91]. One study conducted in China revealed that first-episode patients with schizophrenia with a 5-HT2C receptor genotype variant had a greater propensity to gain more than 7% of their body weight [92]. Several antipsychotics including clozapine are antagonists of the 5-HT2C receptor, which may be one of the mechanisms involved in antipsychotic-induced weight gain. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved in mechanisms leading to pathological overeating and obesity. A positron emission tomography (PET) study of obese individuals without psychiatric illness compared to controls using the radiotracer C11 raclopride revealed a reduction in the D2 receptor availability in the striatum of the obese group compared to normal controls [93]. Schizophrenia is a risk factor for diabetes mellitus II, with prevalence 2–4 times higher than the general population [94–96]. In the recent past a significant body of literature has consisted of case studies of patients on clozapine, risperidone, olanzapine, and quetiapine developing type 2 diabetes mellitus [77]. There are more cases of diabetes including diabetic ketoacidosis reported with clozapine and olanzapine compared with risperidone, quetiapine or ziprasidone. [78]. It is not clearly known yet if the occurrence of diabetes is a molecule effect of the medication, or a function of the illness, or a combination of multiple factors such as drug molecule, schizophrenia spectrum illness, lifestyle, and increasing prevalence of diabetes and obesity. To date, retrospective studies have been done to address this issue, including the investigation of large databases, which suggest that patients on antipsychotics as a group may have a higher prevalence of diabetes [97–99]. To assess pancreatic ␤-cell function, a study was done using a hyperglycemic clamp in normal subjects given risperidone, olanzapine, or placebo under controlled conditions. The researches found weight increase in the risperidone and olanzapine groups comapred with placebo but found no direct evidence to suggest impairment of pancreatic ␤-cell function with either drug. Topiramate, an antiepileptic agent, and nizatidine been studied and could result in weight loss in patients gaining weight on the atypical antipsychotic agents [100–103]. There

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is no clear understanding as to which group of patients would lose weight with these agents. The prolongation of the QTc interval on EKG and the subsequent risk of causing a malignant ventricular arrhthymia called ‘‘torsades de pointes’’ has been an issue with some of the conventional antipsychotics and the new atypical antipsychotic ziprasidone as revealed by Pfizer Study 054 [104]. The conventional agents thioridazine and the mesoridazine have both been given ‘‘black’’ boxes because of a significant propensity to cause prolongation of the QTc interval on EKG [105]. In the case of ziprasidone, limited information is available from Study 054 with relatively healthy, predominantly male subjects. The ziprasidone package insert suggests that the drug not be prescribed if the QTc reaches 500 msec or greater [106]. There is a paucity of data on the use of this drug in patients with multiple medical problems, the elderly, alcoholics, and those on multiple medications [107]. The occurrence of prolonged QTc leading to torsades de pointes and sudden death is an important issue that physicians should be educated about in weighing the risks against the benefits of using these agents on a caseby-case basis [107]. Based on our current knowledge of TD, we believe that the standard of care should involve the following: (1) informed consent prior to beginning antipsychotic treatment; (2) periodic assessment for TD every 3 months; (3) minimization of risk factors by using antipsychotics with the low incidences of TD, such as atypical antipsychotics; (4) use of minimal effective doses of antipsychotics; (5) if abnormal involuntary movements develop, other causes of dyskinesia should first be investigated; (6) the risk versus benefit of antipsychotic use must be evaluated on an individual basis; (7) a medication change to clozapine should be considered; and (8) clinicians may consider the routine use of vitamin E for prophylaxis or treatment in patients after obtaining informed consent, indicating that it is a new treatment that is still in the process of investigation. To date, vitamin E shows the most promise as an effective and safe treatment for TD. Future studies should assess combinations of antioxidants, such as ␤-carotene and ascorbic acid, with vitamin E in the treatment of TD. The atypical antipsychotics appear to be well tolerated and have low liabilities to cause treatment-emergent TD. These agents also hold the possibility of treatments for preexistent TD, although further prospective, double-blind, placebo-controlled trials are warranted to determine their efficacy in the prophylaxis of TD. Several other new antipsychotics are in various phases of premarketing trials and a new range of agents should be available whose efficacy can be evaluated both in the treatment and prevention of TD. The standard of care in patients needing neuroleptic medications has become the atypical antipsychotics. These newer agents such as olanzapine, risperidone, quetiapine, and ziprasidone are patient-friendly, and hence compliance is enhanced. Clozapine is also a highly efficacious atypical antipsychotic whose

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use is limited by side effects such as agrnulocytosis, seizures, and the need for weekly blood work. The atypical agents have a lower incidence of drug-induced parkinsonism and tardive dyskinesia. The use of these agents reduces the need for anticholinergic agents and propranalol to counteract neuroleptic-induced side effects. The limitations of the currently available atypical antipsychotics include the lack of an available parenteral formulation, nonavailability of the decanoate form for noncompliant patients, and cost. REFERENCES 1. Deniker K. Introduction to neuroleptic chemotherapy into psychiatry. In: Ayd FJJ, Blackwell B, Eds. Discoveries in Biological Psychiatry. Philadelphia: Lippincott, 1970:155–164. 2. Weiner WJ, Lang E. Movement Disorders: A Comprehensive Survey. Mt. Kisco. NY: Futura, 1989. 3. Wojcieszek JM, Lang AE. Hyperkinetic movement disorders. In: Coffey CE, Cummings JL, Eds. Textbook of Geriatric Neuropsychiatry. Washington. DC: American Psychiatric Press, 1994:406–431. 4. Hall RA, Jackson RB, Swain JM. Neurotoxic reactions resulting from chlorpromazine administration. JAMA 1956; 161:214–218. 5. Goetz CG, Klawans HL. Drug-induced extrapyramidal disorders—A neuropsychiatric interface. J Clin Psychopharmacol 1981; 1:297–303. 6. Casey DE. Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 1991; 4:109–120. 7. Freidman JH. Drug-induced Parkinsonism. In: Lang AE, Weiner WJ, Eds. DrugInduced Movement Disorders. Mt. Kisco. NY: Futura, 1992:41–83. 8. Miller LG, Jankovic J. Drug-induced dyskinesias. In Joseph AB, Young RR, Eds. Movement Disorders in Neurology and Neuropsychiatry. Malden. MA: Blackwell, 1999. 9. Tarsy D. Neuroleptic-induced extrapyramidal reactions: Classification, description, and diagnosis. Clin Neuropharmacol 1983; 6(suppl 1):S9–S26. 10. Hausner RS. Neuroleptic-induced Parkinsonism and Parkinson’s disease: Differential diagnosis and treatment. J Clin Psychiatry 1983; 44:13–16. 11. Simpson GM. Controlled studies of antiparkinsonian agents in the treatment of extrapyramidal syndromes. Acta Psychiatr Scand 1970; 212:44–51. 12. McEvoy JP. The clinical use of anticholinergic drugs as treatment for extrapyramidal side effects of neuroleptic drugs. J Clin Psychopharmacol 1983; 3:288–302. 13. Keepers GA, Casey DE. Clinical management of acute neuroleptic-induced extrapyramidal syndromes. In: Masserman JH, Ed. Current Psychiatric Therapies. New York: Grune & Stratton, 1986. 14. McEvoy JP, McCue M, Freter S. Replacement of chronically administered anticholinergic drugs by amantadine in outpatient management of schizophrenia. Clin Ther 1987; 9:429–433. 15. DiMascio A, et al. A controlled trial of amantidine in drug-induced extrapyramidal disorders. Arch Gen Psychiatry 1976; 33:599–602.

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38. Adler LA, et al. Vitamin E treatment of tardive dyskinesia. Am J Psychiatry 1993; 150:1405–1407. 39. Sajjad SH. Vitamin E in the treatment of tardive dyskinesia: A preliminary study over 7 months at different doses. Int Clin Psychopharmacol 1998; 13:861–862. 40. Adler LA, et al. Long-treatment effects of vitamin E for tardive dyskinesia. Biol Psychiatry 1998; 43:868–872. 41. Lohr JB, Lavori P. Whither vitamin E and tardive dyskinesia. Biol Psychiatry 1998; 43:861–862. 42. Hawkings DR. Successful prevention of tardive dyskinesia. J Orthomolec Med 1989; 41:35–36. 43. Palozza P, Krinsky NI. Beta-carotene and alphatocopherol are synergistic antioxidants. Arch Biochem Biophys 1992; 297:184–187. 44. Schriqui CL, Annable L. Tardive dyskinesia. In: Schriqui CL, Nasrallah HA, Eds. Contemporary Issues in the Treatment of Schizophrenia. Washinton. DC: American Psychiatric Press, 1965:611. 45. Coward DM. General pharmacology of clozapine. Br J Psychiatry 1992; 160(suppl 17):5–11. 46. Simpson GM, Lee JH, Shrivastava RK. Clozapine in tardive dyskinesia. Psychopharmacology 1978; 56:75–80. 47. Meltzer HY. Clozapine: Mechanism of action in relation to its clinical advantages. In: Kales A, Stefanos GN, Talbott HA, Eds. Recent Advances in Schizophrenia. New York: Springer-Verlag, 1990:237–246. 48. Gerbino L, Shopsin B, Collara M. Clozapine in the treatment of tardive dyskinesia: An interim report. In: Fann WE, Smith RC, Davis JM, Eds. Tardive Dyskinesia, Research and Treatment. New York: SP Medical and Scientific Books, 1980: 475–489. 49. Cole JO, Gardos G, Tarsy D. Drug trials in persistent dyskinesia. In: Fann WE, Smith RC, Davis JM, Eds. Tardive Dyskinesia, Research and Treatment. New York: SP Medical and Scientific Books, 1980:419–427. 50. Lieberman JA, et al. The effects of clozapine on tardive dyskinesia. Br J Psychiatry 1991; 158:503–510. 51. Kane JM, et al. Does clozapine cause tardive dyskinesia. J Clin Psychiatry 1993; 54:327–330. 52. Pollack S, et al. High plasma clozapine levels in tardive dyskinesia. Psychopharmacol Bull 1993; 29:257–262. 53. Small JG, et al. Treatment outcome with clozapine in tardive dyskinesia, neuroleptic sensitivity, and treatment-resistent psychosis. J Clin Psychiatry 1987; 54:327–330. 54. Chouinard G, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chornic schizophrenia. J Clin Psychopharmacol 1993; 13:25–40. 55. Meco G, et al. Risperidone in the treatment of chronic schizophrenia with tardive dyskinesia. Curr Therapeut Res 1989; 46(5):876–883. 56. Brecher MB. Follow-up study of risperidone in the treatment of patients with dementia. Interim results on tardive dyskinesia and dyskinesia severity. Proceedings of the 11th European College of Neuropsychopharmacology Congress; 1998, Paris, Abstract P.4.005.

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57. Silberbauer C. Risperidone-induced tardive dyskinesia. Pharmacopsychiatry 1998; 31:68–69. 58. Freidman JH. Rapid onset tardive dyskinesia (‘‘fly catcher tongue’’) induced by risperidone in a neuroleptically naive patient induced by risperidone. Med Health R I 1998; 81:271–272. 59. Fischer P, Tauscher J, Kufferle B. Risperidone and tardive dyskinesia in organic psychosis. Pharmacopsychiatry 1998; 31:70–71. 60. Kane JM, et al. Intergrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 1986; 22:254–258. 61. Beasley CM. Olanzepine versus placebo and haloperidol: Acute phase results of the North-American double-blind olanzepine trial. Neuropsychopharmacology 1996; 14:111–123. 62. Tollefson GD, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizophreniform disorders: Results of an international collaborative trial. Am J Psychiatry 1997; 154:457–465. 63. Littrell KH, et al. Marked reduction in tardive dyskinesia following treatment with olanzapine. Arch Gen Psychiatry 1998; 55:279–280. 64. Almeida OP. Olanzapine for the treatment of tardive dyskinesia. J Clin Psychiatry 1998; 59:380–381. 65. O’Brien J, Barber R. Marked improvement in tardive dyskinesia following treatment with olanzapine in an elderly subject. Br J Psychiatry 1998; 172:186. 66. Pilowsky LS, Busatto GF, Taylor M. Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine: A 1231 IBZM single photon emission tomography (SPET) study. Psychopharmacol (Berl) 1996; 124:148–153. 67. Fulton B, Goa KL. Olanzapine: A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychosis. Drugs 1997; 53:281–298. 68. Arvantis LA, Miller BG. Multiple fixed doses of seroquel (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo. Biol Psychiatry 1997; 42(4):233–246. 69. Arato M, O’Conner RO, Meltzer HY. Results of a placebo-controlled long-term study with ziprasidone. Vienna. Austria: Annual European Congress of Neuropsychopharmacology, 1997. 70. Ogren SO, et al. Remoxipride, a new potential antipsychotic compound with selective antidopaminergic actions in the rat brain. Eur J pharmacology 1984; 102: 459–474. 71. Greil W, et al. Tiapride: Effects on tardive dyskinesia and on prolactin plasma concentrations. Neuropsychobiology 1985; 14:17–22. 72. Pollak P, et al. Effects of tiapride in tardive dyskinesia. Psychopharmacology 1985; 85:236–239. 73. Roos RAC, et al. Assessment of the therapeutic range of tiapride in patients with tardive dyskinesia. J Neurol Neurosurg Psychiatry 1986; 49:1055–1058. 74. Murphy DJ, Hughes G, Shaw GK. Tiapride in tardive dyskinesia. Psychopharmacol Bull 1982; 18(4):13–16. 75. Casey DE, Gerlach J, Simmelsgaard H. Sulpiride in tardive dyskinesia. Psychopharmacology 1979; 66:73–77.

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76. Andersson U, et al. Remoxipride, a selective dopamine D2 receptor antagonist, in tardive dyskinesia. Psychopharmacology 1988; 94:167–171. 77. Allison DB, Meentore JL, Heo M, et al. Antipsychotic-induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999; 156:1686–1696. 78. Masand PS, Gupta S. Long-term side-effects of novel antipsychotics. J Psychiatr Pract 2000; 6:299–309. 79. Wirshing DA, Wirshing WC, Kysar L, et al. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry 1999; 60:356–363. 80. Gupta S, Droney T, Al-Samarrai T, Keller P, Frank B. Olanzapine-induced weight gain. Ann Clin Psychiatry 1998; 10:39. 81. Ganguli R. Weight gain associated with antipsychotic drugs. J Clin Psychiatry 1999; 60(suppl 21):20–24. 82. Henderson DC, Cagliero E, Gray C, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry 2000; 157:975–981. 83. Kinon BJ, Basson BR, Gilmore JA, et al. Long-term olanzapine treatment: Weight change and weight related health factors in schizophrenia. J Clin Psychiatry 2002; 62:92–100. 84. Gupta S, Droney T, Al-Samarrai S, Keller P, Frank B. Olanzapine: Weight gain and therapeutic efficacy. J Clin Psychopharmacology 1999; 19:273–275. 85. Czobor P, Volavka J, Sheitman B. Antipsychotic-induced weight gain and therapeutic response: A differential association. J Clin Psychopharmacol 2002; 22:244–251. 86. DeVry J, Schreiber R. Effects of selected serotonin 5HT (1) and 5HT (2) receptor agonists on feeding behavior: Possible mechanisims of action. Neurosci Biobehav Rev 2000; 24:341–353. 87. Meguid MM, Fetissov SO, Varma M, et al. Hypothalmic dopamine, and serotonin in the regulation of food intake. Nuitrition 2000; 16:11–181. 88. Kraly FS, Katz JB, Burchard JB, Case C, Gabriel VA, Lanz TA, Mikkelsen ME, Sokol MB. H2. histaminergic control of inhibition of eating induced by intragastric NaCl in rats. Physiol Behav 1998; 65:105–113. 89. Leibowitz SF. Neurochemical systems of the hypothalamus: Control of feeding and drinking behavior and water electrolyte excretion. In: Morgan P, Panksepp J, Eds. Handbook of the Hypothalamus. Vol. 3. New York: Marcel Dekker, 1980:299–438. 90. Baptista T. Body weight gain induced by antipsychotic drugs: Mechanisms and management. Acta Psychiatr Scand 1999; 100:3–16. 91. McIntyre RS, Mancini DA, Basile VS. Mechanisms of antipsychotic-induced weight gain. J Clin Psychiatry 2001; 62(supp l23):23–29. 92. Reynolds GP, Zhang Z, Zhang X. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359:2086–2087. 93. Wang G, Volkow N, Logan J, et al. Brain dopamine and obesity. Lancet 2001; 357:354–357. 94. Keskiner A, El-Joumi A, Bausquet T. Psychotrpic drugs diabetes and chronic mental illness. Psychosomatics 1973; 14:176–181. 95. McKee HA, D’Arcy PF, Wilson PJ. Diabetes and schizophrenia: A preliminary study. J Clin Hosp Pharm 1986; 11:297–299.

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10 Lithium-Induced Movement Disorders

Stewart A. Factor Albany Medical Center Albany, New York, U.S.A.

INTRODUCTION Lithium has a long history as a therapeutic agent and currently enjoys frequent use, primarily in psychiatric disease. However, toxicity has been a concern with this drug for over 50 years. In fact, it is this risk of toxicity which significantly delayed its approval by the U.S. Food and Drug Administration (FDA). Lithium toxicity may occur as an acute intoxication or may result in a chronic irreversible syndrome. Among the features of toxicity are a variety of movement disorders. Tremor is the most common and well known. Others, such as chorea and parkinsonism, are controversial due to their frequent occurrence in patients who are treated concomitantly with neuroleptics. In this chapter the history of lithium use will be reviewed along with its current indications. Discussion will also include the pharmacology, particularly in relation to toxicity, mechanism of action, followed by a review of acute and irreversible manifestations of lithium toxicity. Finally, a review of the movement disorders which are seen in relation to lithium therapy will be provided. HISTORY Lithium (Li), the element, was discovered in 1818 by Johan August Arfwedson, a Swedish scientist [1,2]. He named it lithion from the Greek term for stone, to 209

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signify its mineral origin. Humphrey Davy isolated lithium metal. The element has an atomic number of 3 on the Periodic Table and an atomic weight of 6.94 [3]. It has 3 protons, 4 neutrons, and 3 orbiting electrons. It is in the Group 1A alkaline metals and is the lightest of all metals. Li does not occur freely in nature but is always combined and is most commonly found in igneous rocks. The medicinal use of Li has a long and interesting history. Its approval by the FDA in 1970 for the treatment of mania associated with bipolar disorder was the culmination of centuries of use in various forms for various ailments. While the first modern-day use was recommended by Alexander Ure in 1843 [1], its availability may go back to approximately 100 A.D. among the Greeks and Romans [2,4]. At that time, use of alkaline mineral waters, presumably containing large quantities of Li, were recommended to treat mania, arthritis, and other ailments [4]. The first recorded recommendation for therapeutic Li use was by Soranus of Ephesus (89–139 A.D.) for these purposes [2]. In 1843 Ure proposed that lithium carbonate solution injected directly into the bladder would dissolve urinary calculi [1]. Over the next two decades, oral formulations became available for the treatment of gout and rheumatism [1,3,5]. S. Weir Mitchell recommended Li bromide as an antiepileptic [2]. In 1873 William Hammond treated mania with Li, and this was followed in 1886 by Carl Lang’s recommendation that a mixture containing lithium carbonate would prevent depression. Fritz Lang suggested its use in acute depression [1]. At the turn of the century, Li spas with mineral spring water were opened, touting the curative nature of the element. It turned out that these springs actually had no Li in the waters, and many ultimately closed down. In addition, Li appeared in numerous beverages, including soft drinks and beer, at around that time. Because of the sham offerings and associated controversy that surrounded them, Li vanished from sight until the 1940s. At that time lithium chloride was made available as a salt substitute for patients with heart disease and hypertension. It was this use that led to numerous cases of toxicity, resulting in some deaths [5] and a variety of other unusual side effects including movement disorders [6]. It once again disappeared from the scene, and these phenomena ultimately led to a delay in its marketing as a prescription drug. In 1949, John F. J. Cade rediscovered its antimania effects and reported them in the Medical Journal of Australia [7]. He found that lithium carbonate injected into guinea pigs made them lethargic and unresponsive, although they remained conscious. However, it has been suggested that he mistook intoxication for a calming effect [8]. Nevertheless, based on his findings, he treated patients with psychotic excitement and had favorable results with no hypnotic effects. In 1954, Shou and colleagues [9] followed suit with a double-blind study that also demonstrated antimania effects. In addition, they were the first to utilize therapeutic plasma levels as a guide [10]. Further studies found that Li could be useful in the prevention of the manifestations of bipolar illness as well. A number of

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physicians, including Gershon, reintroduced Li in the United States in 1960 [11]. The work of these investigators ultimately led to FDA approval for treatment of mania in 1970 and for prophylaxis of bipolar illness in 1974. Li has been widely utilized since that time. The primary use of Li today is as prophylactic treatment for episodes of depression and mania in bipolar illness. While it can be useful in the treatment of acute mania, this indication is usually as an adjunct to neuroleptic therapy, because of the delay in effectiveness of Li by 6–10 days [12]. While it is not considered first-line therapy, it has been shown to help prevent depression in unipolar illness and aggression as well. In this way, it is generally not considered for primary therapy but more in combination therapy with standard antidepressant medications (so-called Li augmentation). Li is also utilized as an adjunct to neuroleptic therapy in the treatment of drug-resistant schizophrenia and has well-established antiaggressive properties [12]. Baldessarini [5] has suggested that this drug is useful only in those with psychiatric illness and that there is no psychotropic effect in normal patients, such as sedative, depressant, or euphoric effects. Toxicity is still a large issue and patients require frequent plasma-level vigilance to avoid toxic side effects. PHARMACOLOGY The therapeutic window of Li is narrow, and the monitoring of plasma levels to prevent toxicity is important. It also has a number of very unusual and interesting pharmacological characteristics which need to be reviewed, since toxicity is a major issue related to the subject of this chapter. In the United States it is available as lithium carbonate capsules or tablets or as lithium liquid. Other forms are utilized around the world, including acetate, glutamate and gluconate. There are also immediate-release and sustained-release formulations. Li is absorbed rapidly and completely by the gastrointestinal tract, and levels peak in 11⁄2 –4 hr for standard forms, but it takes longer with the controlled-release forms. There are no metabolites, there is no protein binding, and it is excreted almost exclusively by the kidney (95%). The rest is excreted through saliva and sweat. Elimination half-life of Li is 18–24 hr [3,5]. A substantial amount of Li filtered through the glomeruli is absorbed in the proximal tubule (80%). Factors which alter this characteristic include age, which causes a decrease in the filtration rate and an increase in plasma levels, and sodium depletion. In addition, there are a number of drugs which can affect the reabsorption of Li and alter drug levels. Thiazide diuretics, nonsteroidal anti-inflammatory agents (particularly indomethacin), and ACE inhibitors can all increase reabsorption and therefore lead to higher plasma levels and toxicity. Passage of Li through the blood–brain barrier is slow, and levels in the cerebrospinal fluid reach about half that seen in the plasma at steady state. Once

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it is in extracellular fluid, it gradually accumulates in tissue—this is particularly slow in brain tissue. The concentration gradient across membranes is smaller than sodium and potassium, leading to this slower accumulation. Cellular uptake is through passive diffusion and ion-gated channels. In general, Li is taken up more slowly in the brain, accumulates intracellularly, and then persists at higher levels than in the plasma even when the drug is stopped. This often leads to a delay in onset and a delay in improvement of neurotoxic effects [13,14]. MECHANISM OF ACTION The mechanism through which Li exerts its mood-altering effects or causes movement disorders remains unknown. It appears that Li acts at multiple sites involving various neurotransmitters and at varied levels of transmission (pre- and postsynaptic) [14a]. One hypothesis suggests that Li changes behavior by acting on the noradrenergic system. This is based on animal studies which have shown that Li blocks stimulus-induced release and enhances the reuptake of norepinephrine [5,14a,15]. It may also have postsynaptic effects, enhancing subsensitivity of receptors following treatment with antidepressant agents. In the 1980s, reports of Li’s ability to inhibit norepinephrine-induced inositol phospholipid hydrolysis in rat cortex, hippocampus, and striatum (overactive receptor-mediated neuronal pathways) became the focus of its possible mechanism of action in treating affective disorders [5,16]. This receptor-activated hydrolysis of phosphoinositides is referred to as the phosphatidyl inositol effect and represents a second-messenger producing system. It was suggested that a decrease in second-messenger production by Li leads to altered cellular function which mediates the ultimate behavioral change. The inositol effect is stimulated not only by norepinephrine, but by other neurotransmitters [15]. Casebolt and Jope [16] proposed a list of possible sites of action of Li. They include (1) decrease in receptor number or function; (2) inositol-1-phosphatase inhibition; (3) alteration of G protein coupled to phospholipase C, or (4) depletion of inositol phospholipid substrates. One other site later considered was the depletion of myo-inositol in selected brain regions [14a]. The decrease in inositol phospholipid hydrolysis observed in animal models seemed to occur only after chronic pretreatment with Li. In most cases, rats were pretreated with Li for 14–30 days prior to evaluation of the tissue samples for inositol phospholipid hydrolysis. Adenylyl cyclase is another second-messenger system in which the activity is attenuated, yet the drug has different effects on the formation of cyclic AMP depending on the state of activation of adenylyl cyclase [14a]. It has been suggested that, further downstream, Li may alter the activity of protein kinases. Protein kinase A activity is enhanced and this increased activity increases cAMP binding. Protein kinase C is also affected by this drug, but in this case it is downregulation [14a]. Whether Li has a direct effect on these enzymes or the alterations occur through second-messenger systems remains to be clarified. It

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is possible that an inhibition of second-messenger function or function farther downstream related to the noradrenergic or other neurotransmitter systems may lead to Li-induced movement disorders. Alterations in dopaminergic systems have also been considered to play a role in the action of Li. Unfortunately, contradictory information concerning Li’s effect on the nigrostriatal dopamine system from animal studies and clinical observations has left this possibility unclear. Matsis et al. [17] suggested that chronic Li administration results in dopamine receptor hypersensitivity in the neostriatum. They also speculated that Li might enhance calcium-dependent dopamine release, based on the observation that calcium levels are elevated in patients receiving chronic Li therapy. However, rats given Li for 14 days were found to have a slight reduction in dopamine synthesis in the striatum. Single large doses of Li also did not appear to have a significant effect on dopamine synthesis or release in the rat striatum [18]. Although Walevski and Radwan [19] also suggest that Li causes dopamine receptor hypersensitivity, there are no animal or human data to support this theory. To the contrary, Klawans et al. [20] studied guinea pigs that were treated with Li and then haloperidol. The guinea pigs did not develop a reduced threshold for apomorphine or amphetamine-induced stereotyped behaviors as compared to that typically observed in groups of animals treated with haloperidol alone. Li has also been shown to alter the serotonin system [21]. Longterm treatment with Li exerts region-specific (hippocampal) effects on serotonin receptor binding and endogenous serotonin release. The binding is decreased and release is increased [14a]. Li also increases transport of the serotonin precursor tryptophan into hippocampus and striatum but not into cortex. There is, in turn, an increase in serotonin synthesis acutely, which goes back to baseline with chronic administration. The changes described by Treiser et al. [21] were considered to be a ‘‘stabilization of serotonergic transmission’’ and perhaps related to the effect of Li on bipolar illness. The drug has also affected other systems. For instance, Li can enhance the effects of cholinergic agents and prevent receptor supersensitivity. Low GABA levels may be increased by Li to normal levels, and chronic administration may lead to a decreased receptor binding in specific areas [14a]. Acute Li use may lead to enhanced glutamate release, but chronic use actually leads to increased uptake. Finally, several neuropeptides may be affected by Li. Levels of dynorphin, substance P, tachykinin, and others are increased after Li therapy. OVERVIEW OF ACUTE TOXICITY The initial features of acute Li intoxication include vomiting, diarrhea, and shakiness, and then this would be followed by signs of neurotoxicity, which basically appears in the form of an acute encephalopathy or delirium. Patients can become disoriented and confused. They are easily distractible and have a fluctuating level

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of consciousness, usually with more lethargy and incoherence. There may be delusions and hallucinations which are auditory, visual, or tactile. Focal neurological findings, including muscle weakness, spasticity, increased reflexes, and extensor plantar responses, have been described. In addition, seizures have been reported in association with EEG changes. The primary EEG changes are widespread slowing the bilateral synchronous paroxysmal bursts of delta activity. In addition, there have been cases reported with runs of periodic sharp waves similar to those seen in Creutzfeldt-Jakob disease [22,23]. The combination of subacuteonset encephalopathy with myoclonus and these EEG changes could lead to that misdiagnosis. Cerebellar signs including dysarthria, oculomotor signs, truncal and gait ataxia, and nystagmus have also been reported, and cases of neuropathy with paraesthesias have been described. A number of movement disorders have been associated with this acute syndrome, including tremor, parkinsonism, myoclonus, and chorea. This mixture of signs and symptoms make it important for this intoxication to be differentiated from neuroleptic malignant syndrome and the serotonin syndrome, especially in patients on polytherapy [5,10,12,14,22–25]. Like these other drug-induced disorders, acute Li intoxication can lead to coma and death. The recommended treatment for acute intoxication includes withholding Li, supportive therapy, and hemodialysis [5,10]. There is uncertainty about whether hemodialysis will effect the long-term outcome. While this syndrome generally occurs with serum Li levels in the toxic range (above 1.2 mEq/L), occasionally it occurs within the therapeutic range but at a higher level than the patient may be used to. This may relate to CNS accumulation of Li. It appears that patients in the throes of an acute manic episode may be more vulnerable for the occurrence of acute toxicity [26]. OVERVIEW OF THE IRREVERSIBLE NEUROTOXICITY It has become well known that Li therapy can lead to a syndrome associated with chronic and possibly permanent neurological signs and symptoms. It was first reported in the early 1970s [27,28], but those patients were usually treated with a combination of Li and haloperidol. Since then, however, numerous cases have been described with Li monotherapy. The phenomenon has been referred to since 1989 as the ‘‘syndrome of irreversible lithium-effectuated neuro toxicity (SILENT)’’ [29]. The irreversible neurotoxicity has also been referred to in the literature as ‘‘long lasting, persisting, or permanent neurologic deficits’’ [30–32]. It has recently been reviewed in detail by Kores and Lader in 1997 [10]. As a definition of the irreversible syndrome, it has been recommended that neurological signs and symptoms be present for more than 2 months after stopping the drug; however, this time period is arbitrary. It is unclear how long this phenomenon actually lasts, but in some cases it was longer than a year [32]. The irreversible neurological deficits may occur in the wake of acute Li toxicity or may occur

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without that prodromal experience. In these latter cases there will be a gradual progression of neurological signs and symptoms. While more than half of the cases had onset while the serum drug levels were in toxic ranges, many did not, as Li levels were ranged quite widely. The dosages used varied anywhere from 750 mg/day to 3000 mg/day [10]. The prevalence of irreversible sequelae is unknown, but Nagaraja et al. found that it occurred in 6 of 488 patients (1.2%) treated chronically with Li [33]. The clinical syndrome that makes up SILENT is primarily cerebellar in nature. Cerebellar symptoms include truncal ataxia, clumsiness, limb ataxia, gait ataxia, and dysarthria with scanning speech. Of 43 cases reviewed by Kores and Lader, 37 were ataxic [10]. In addition, some patients developed a cerebellar intention tremor. Movement disorders were also noted to occur in these cases. In particular, Parkinsonism and choreoathetosis have been described. What appears to be true for both cases is that most of the patients who develop these phenomena were also treated with dopamine-blocking agents. However, isolated cases of parkinsonism and choreoathetosis have been described in patients receiving Li alone [10,31,32]. The actual frequency of movement disorders remains unclear, however, because of the frequent concomitant use of Li with dopamine receptor antagonists. There have been a few cases in which both Parkinsonism and chorea occurred at the same time. There are a number of other neurological sequelae which may occur in patients secondary to Li therapy. They include corticospinal tract signs, such as spasticity and increased reflexes. In addition, patients may have cognitive changes including memory loss, disorientation, and even frank dementia. Peripheral neuropathy, sensory, motor, or mixed, which is axonal in nature, and myopathy have been described. Finally, rare cases of pseudotumor cerebri with headache, papilledema, and increased intracranial pressure have been reported [10,30]. There have been few pathological evaluations of patients with permanent neurological sequelae from Li. In one case [13] of a patient with persistent cerebellar dysfunction along with hyperreflexia and Babinski signs, an autopsy was performed 11 weeks after the acute intoxication. It demonstrated prominent spongiform change and astrogliosis in the white matter of the cerebellum. There was Purkinje cell loss with concomitant Bergman gliosis noted in the cerebellar cortex, and the dentate nuclei exhibited moderate gliosis and neuronal loss. This case demonstrates clear irreversible pathological changes secondary to Li intoxication. While the mechanism by which this occurs is unknown it is possible that Li may have direct neurotoxic effects. There has been one histological evaluation of peripheral nerve in patients with persistent neurological complications to Li therapy, and it demonstrated axonal neuropathy [34]. Why this irreversible neurological syndrome occurs in some patients treated with Li and not others is unclear. There are, however, some apparent risk factors which do exist that might increase patient susceptibility. One interesting risk

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factor, which continuously arises in the literature, is female gender. In literature reviews it is obvious that there is a significant overrepresentation of women who suffer from this SILENT syndrome [10,30]. The ratio is approximately 4 or 5:1 female to male. It is unclear if this is a reflection of a predominance of women treated with Li or if it is a true risk factor. In addition, as is seen with neuroleptic malignant syndrome, dehydration and concomitant infection may be important risk factors. Finally, renal disease may lead to accumulation of Li and secondary Li toxicity. As noted previously, there are a variety of drugs which can increase the serum Li level and lead to Li toxicity. The relationship between blood levels and toxicity is inconsistent. Patients with therapeutic levels and small doses of Li can develop this irreversible neurological syndrome. It is likely that brain levels play a more direct role, although at this time it is not possible to make appropriate measures. In addition, some other individual susceptibility characteristics may be responsible for the occurrence of this syndrome. The acute toxicity which occurs in a large percentage of these patients prior to the onset of the more prolonged phenomenon does not seem different in any way from that which occurs in patients with a complete recovery [10]. Finally, concomitant use of other medications, including neuroleptics, anticholinergics, and possibly phenytoin, may increase the risk of the occurrence of this disorder, although it is well known that Li alone may result in significant irreversible neurological symptoms [10]. MOVEMENT DISORDERS A variety of movement disorders have been reported to occur in association with Li therapy. With the exception of tremor, these have been controversial because of the frequent concomitant use of neuroleptics and other drugs. However, they remain an important concern when treating patients. The movement disorders can occur in patients who are in therapeutic range of Li therapy or in the toxic range. They can occur as a manifestation of the acute toxicity and may also be present as a manifestation of the irreversible syndrome. Those movement disorders which will be discussed include tremor, chorea, parkinsonism, and others. In addition, there will be some discussion with regard to the possible interaction between Li and dopamine receptor-blocking agents and the resulting syndrome. Tremor Tremor is the most common neurological side effect associated with Li therapy. It was well recognized in the early period of using Li to treat bipolar disorder. A Medline search uncovered well over 100 references regarding Li tremor since 1966. Despite this widely known occurrence, the prevalence has varied widely but remains unknown. It is unclear why the frequencies vary so much, but there

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are a number of possible reasons. First, in some studies the presence of tremor was not elucidated prior to therapy. In addition, the estimate of tremor was made in some studies through subjective complaint, while in others, it was made through objective evaluation. Also, the diagnosis of those patients being treated and the use of concomitant medications varied from study to study. These studies often did not indicate whether they included troublesome or nontroublesome tremor or both. A recent review of the literature by Gelenberg and Jefferson [35] combined several studies totaling over 1000 patients and examined the prevalence. The prevalence rate varied from 4% to 65%, with the pooled percentage being approximately 27%. In one study [36], 32% of patients felt that the tremor was severe enough to result in noncompliance and some disability. If one took into account the milder tremors which are not troublesome, the percentage may actually be on the higher end of that range. Gelenberg and Jefferson [35] point out, however, that there is not a clear quantitation of the number of patients who actually are noncompliant because of this side effect. The tremor is primarily a postural and action tremor. Some descriptions indicate that it may actually be less rhythmic than one would see in essential tremor, being described as variable in intensity and frequency and irregular in nature [37]. This type of tremor is commonly observed with other drug therapies, particularly valproate and tricyclic antidepressants. The tremor is thought to have a frequency of 8–12 Hz and thus would fall into the realm of exaggerated physiological tremor, although it can be exceedingly difficult to differentiate from essential tremor as well. It generally affects mainly the hands and it is unusual to see head, voice, or leg tremors caused by this drug. The tremor is generally quite benign and nontroublesome to patients. That is usually the case when the tremor occurs while Li is in the therapeutic range. While most literature indicates that there does not appear to be a relationship with serum levels of Li [38], in actuality there may be a relationship within individual patients. Tremor can occur at almost any dose or blood level. However, within individuals the tremor does worsen with increasing doses and increasing plasma concentrations. When the Li levels go into the toxic range, it is quite typical for the tremor to become much more severe and disabling and to spread to other body parts. In fact, an increase in tremor to that level should suggest that the patient is becoming toxic. Thus, the tremor occurs at therapeutic levels and worsens with acute toxicity. It rarely occurs as a manifestation of the persistent neurological syndrome. When tremor is present in this situation it is usually of the cerebellar type. The tremor associated with Li therapy may also worsen secondary to the concomitant use of antidepressants or valproate. It has been shown [35] that antidepressants potentiate the tremorogenic features of Li, and combined therapy can cause a disabling tremor. Tremor severity and frequency can also vary depending on the psychiatric state of the patient [39], euthymic patients having a significantly lower frequency than noneuthymic patients. It should also be noted that patients with essential tremor

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will experience an increase in the severity of the their tremor if Li is added to their medication regimen. Even when the tremor is mild and appears inconsequential, it is a frequent source of social embarrassment for patients. When it is embarrassing or disabling, the Li regimen requires either adjustment or the addition of medication specific for treating tremor. There are a number of other factors that may increase the risk for tremor when Li therapy is initiated, other than those noted above. Execessive caffeine intake can cause an increase in tremor. However, caffeine, at high doses, can actually increase the clearance of Li. Patients who drink large quantities of caffeinated beverages during the day may actually find that the tremor increases when they stop drinking them, because of an increased serum level of Li as a result [40]. In those patients the Li dose needs to be lowered together with the change in caffeine ingestion. A family history of tremor, a history of alcoholism, and associated anxiety all increase the risks for tremor in patients treated with Li. One other possible risk factor is male gender. In one study [41], tremor was significantly more common in men than in women. Also, the prevalence of tremor seems to increase with age [42]. In patients treated chronically with Li therapy, the tremor which occurs can actually have a decrease in frequency over time [42], and in some patients the tremor can actually disappear altogether without alterations in doses. The mechanism that leads to tremor is unknown. If it is indeed an enhanced physiological tremor, then it may relate to any of the mechanisms causing physiological tremor, including properties of motor neuron firing, oscillations in stretch reflex causing synchronization of motor neuron discharges, or a superspinal rhythmic input to the motor neurons [43]. There has been much discussion about whether physiological tremor is a central or peripheral phenomenon, and those same arguments have been addressed in relation to Li as well [37,44]. Some of the arguments relate to effectiveness of ␤-adrenergic blockers of various types. In one study, it was suggested that tremor may relate to Li effects in the basal ganglia, since patients with the tremor tended to have greater extrapyramidal symptoms [45], but this remains a matter of debate, particularly in relation to the apparent occurrence of rigidity (to be discussed under parkinsonism). As previously indicated, the tremor induced by Li is usually mild and not disabling [46] However, in some patients it can be very embarrassing and in others it may become disabling. It is in those patients that action needs to be taken with regard to treatment. The following steps can be taken in an attempt to improve the tremor in patients. Of course, the first consideration is lowering the dose of Li or stopping it completely, if that is possible, and utilizing other medications to treat the underlying psychiatric disorder. Sometimes the serum Li levels can be diminished by changing the number of doses per day or even the preparation, and that should be considered. Reducing or eliminating other

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drugs that cause tremor may also be helpful, and eliminating any drugs that enhance reabsorption of Li, leading to higher serum levels, such as nonsteroidals or loop diuretics, will lead to decreased blood levels and perhaps less tremor. If patients need to stay on Li and are unable to tolerate lower doses, then use of antitremor medications becomes necessary. The medications most frequently utilized are ␤-adrenergic receptor blockers. The ones utilized in the treatment of Li-induced tremor include propranolol, metoprolol, oxprenolol, and nadolol. [37,47–52]. Unfortunately, most of the publications relating to the use of these drugs are individual cases or a small series of cases, and larger double-blind trials have not been performed. Propranolol is the most commonly utilized drug and seems to be more effective than the more selective agents [51]. It should be used with caution in patients with depression. As with essential tremor, the doses need to be adjusted individually. Doses as low as 30 mg/day can be quite effective, but in some cases higher doses are necessary. Using similar guidelines as those for essential tremor [43] can be beneficial to patients. In some cases, PRN use of ␤-blockers is recommended because continuous propranolol use might actually alter the glomerular filtration rate [52]. It would make perfect sense that primidone might be helpful in the treatment of Li-induced tremor in the same way that ␤blockers would. However, there has been only a single report of its use [53]. In this paper a single patient with tremor due to combined treatment of Li and amitriptyline showed definite benefit. The patient was taken off, with notable worsening of tremor, and then restarted, with the same tremorolytic effect. Personal experience has found similar results in several patients. Thus, primidone is a reasonable treatment option for disabling or embarrassing Li-induced tremor. Chorea Chorea was reported as a complication of Li use before it was approved by the FDA. The first case was described by Peters in 1949 in a nonpsychiatric patient using Li-containing salt substitute for hypertension [6]. The movements described by Peters were ‘‘facial grimacing, lip smacking, writhing movements as in Huntington’s disease.’’ Since then several cases have been described, but these reports met with some controversy. The descriptions in some of the cases were, poor, and a number of the patients were receiving neuroleptics [19,28,54], carbamazepine [55] or phenytoin [56]. The occurrence of chorea is exceedingly rare and perhaps even more so than suggested by the literature because of the abovedescribed problems. The actual prevalence is unknown. Unlike tremor, chorea occurs predominantly in patients with acute toxicity, with only a single case reported as a persistent phenomenon [32]. While a literature review may uncover as many as 17 cases of Li-induced chorea, only 7 of those were in patients receiving Li as their only psychotropic

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medication [6,14,28,32,57–59]. In some of those cases patients had orofacial dyskinesia and the authors referred to it as tardive dyskinesia induced by Li [19,57], but I believe this choice of terminology is misleading. Tardive dyskinesia implies the onset of the movement disorder in relation to neuroleptic therapy. These were cases without neuroleptic therapy that should simply be referred to as Li-induced orofacial dyskinesia or chorea. In the 7 cases noted to have a choreiform disorder the descriptions were fairly detailed, including descriptions such as ‘‘choreoathetotic movements of Huntington’s chorea’’ and ‘‘writhing, repetitious movements of extremities.’’ In the case which I reported with a colleague, our patient had nearly constant head, neck, trunk, and extremity movements which were spontaneous, irregular, purposeless, writhing, twisting, flowing, and rocking in nature. The upper extremities were affected more than the lower extremities. Voluntary movement or sustained posture increased the severity of these movements, which we thought fulfilled the definition of chorea [14] (see published video segments). The Li levels in these patients ranged from 1.25 to 5.7 mEq/L. The one persistent case of chorea from Li intoxication was described by Apte and Langston [32]. The patient had ingested twenty-seven 300mg tablets of Li in a suicide attempt. He developed the usual manifestations of acute intoxication, with nausea and vomiting. He became dehydrated and oliguric, and a serum level was 5.7 mEq/L. He was encephalopathic and required hemodialysis. Neurologically, he developed a speech disorder so that he was unintelligible, and he developed a resting tremor. On the 7th day chorea occurred, with the description of ‘‘writhing, repetitious movements of the extremities,’’ and he had asterixis. After 3 weeks his mental status improved as did his renal function; however, the chorea continued. He also developed some of the usual manifestations of the persistent neurological sequelae, primarily cerebellar ataxia. He was followed for 1.5 years and at that time continued to have ataxia and ‘‘continuous low amplitude choreiform and athetoid movements affecting the extremities, mostly hands and arms.’’ This patient had no prior exposure to neuroleptics. One of the characteristics of chorea in Li-intoxicated patients is that it does not occur initially as manifestation of the intoxication. Onset is delayed hours to perhaps days. For example, in our case [14] the patient was perhaps beginning to show signs of intoxication a few days prior to her arriving in the emergency room. She was seen by a friend who thought she had slurred speech and was somewhat unsteady on her feet. It was not until 18 hr after arriving in the emergency department in a stuporous state that she become somewhat more alert and the involuntary movements began. This phenomenon actually characterized chorea in several other cases in the literature. In addition, with cessation of therapy the chorea does not dissipate quickly, but the improvement lags behind a change in serum levels. For example, in our case the chorea did not begin to improve until levels dropped substantially and didn’t go away until levels reached 0. This feature of the chorea probably reflects the delayed uptake in neural tissue and

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persistently high levels within neural tissue when serum levels drop. It would seem that more chronic exposure to high levels is required to develop chorea. Treatment of acute toxicity with fluids, cessation of Li therapy, and possibly hemodialysis would be the treatment for this problem. For the most part, chorea is fully reversible with treatment of acute intoxication of course with the exception of a single case. Parkinsonism The occurrence of parkinsonism as a complication of Li therapy has engendered more controversy than chorea. The reasons include (1) that many of the reported patients had been recently treated or were concomitantly treated with neuroleptic agents; and (2) that the descriptions of some cases were lacking in the detail needed to confirm the presence of parkinsonism. For example, some patients were described as having tremor and difficulty with walking. This could represent the presence of Li-induced tremor and ataxia, common toxic side effects of Li, and therefore the diagnosis was unclear [60]. [3] Many of the main papers examining the occurrence of parkinsonism (otherwise called extrapyramidal syndrome) examined a single clinical sign, that being cogwheel rigidity. Cogwheeling is a well-known sign associated with postural or kinetic tremor [44]. It is found in many disorders of postural tremor, including essential tremor, and thus its occurrence, especially in isolation, would not necessarily indicate the presence of parkinsonism. The first paper examining cogwheel rigidity with Li therapy was reported by Shopsin and Gershon in 1975 [61]. They examined 27 patients who had been randomly selected and exposed to Li for 3 months to 5 years. They indicate that no concomitant neuroleptics were utilized but provided no information on whether the patients were ever on them and when. They were looking only at ‘‘cogwheel rigidity’’, and no mention is made in the paper with regard to tremor. They found that 16 of 27 patients manifested cogwheel rigidity. All were treated with Li for more than a year, indicating that the length of therapy was the most important risk factor and not age or Li levels. They also noted that the longer the duration of exposure to Li, the more severe the symptoms were although few cases were considered moderate or severe. They referred to the presence of this as an indication that extrapyramidal syndromes do occur with Li and fairly commonly. However, they indicate that cogwheel rigidity ‘‘occurred in the documented absence of other extrapyramidal or neurological symptoms.’’ This would certainly be contrary to a diagnosis of parkinsonism. In addition, benztropine had no effect on these clinical features in 9 treated patients. A year later, Branchey et al. [62] reexamined the question of cogwheeling in Li-treated patients. They examined 36 patients treated for 6 months to 7 years, none of whom had received neuroleptics for the previous 6 months. Li levels

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were therapeutic in all of their patients. Shopsin and Gershon made no mention of Li levels in their paper [61]. This time parkinsonism was measured with the Simpson-Angus scale, which was modified to include a measure for cogwheeling. They found only 3 of 36 patients manifested cogwheeling and in all cases it was extremely mild and tremor was present in all 3. They do indicate that some patients had increase in muscle tone or rigidity but say little else about it. However, they conclude that the cogwheeling was so mild and of such little consequence that they believe that extrapyramidal features did not occur with Li therapy. Two other studies followed, this time utilizing blinded investigators to examine the patients [63,64]. In the work by Kane et al. [63], 38 patients were examined. They had a mean dose of 1300 mg of Li per day, and levels were therapeutic. The mean duration of treatment was 15.6 months, and they utilized the same modified Simpson-Angus scale to measure parkinsonism. Two of the patients reportedly had cogwheel rigidity, and in both cases ‘‘additional signs of extrapyramidal disorder’’ were present. The latter features were considered of minor significance. They describe one patient who ended up being diagnosed with normal–pressure hydrocephalus and it is unclear if that patient was 1 of the 2 who manifested symptomatology or a separate individual. The 2 patients who exhibited parkinsonian features had been exposed to a neuroleptic 8 months and 5 months prior to this neurological evaluation. The patient who had received it 5 months earlier received a depot form of fluphenazine. It is possible that their symptoms related to that prior neuroleptic exposure. Benztropine was utilized in both patients to no effect. The authors conclude that extrapyramidal side effects with Li therapy are rare. Finally, Asnis et al. [64] examined the largest cohort of patients and addressed the question of whether this cogwheeling actually related to the presence of parkinsonism. Ninety-seven patients were examined, 79 with only Li and 12 with Li and neuroleptics, and they compared the two groups. They found that 28% of the 79 Li-treated patients had slight cogwheeling, 7.6% or 6 patients had moderate cogwheeling, as compared to 33% with moderate cogwheeling in the combined Li-and-neuroleptic group. The authors felt that age, duration of Li treatment, and serum Li level were risk factors for the occurrence of cogwheeling. Interestingly, 4 of the 6 patients with cogwheeling had no increase in muscle tone that the investigators could detect. They also found that ‘‘other extrapyramidal symptoms associated with cogwheeling were rare in this study’’ but gave little detail of that. These authors ultimately concluded that ‘‘Li-induced cogwheel rigidity may not be at the extrapyramidal level but at whatever neuroanatomic level is responsible for the tremor.’’ And this was based on the finding that the moderate group had significantly higher frequency of tremor than those who did not have cogwheeling. We can conclude very little from the results of these studies with regard to Li-induced parkinsonism. These studies provide no information with regard to the frequency of drug-induced parkinsonism or even the

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existence of drug-induced parkinsonism from Li. In fact, the confusion associated with these papers had led some authors to conclude that Li does not, in fact, cause drug-induced parkinsonism [44]. Whether Li can induce parkinsonism in the absence of neuroleptics remains an unanswered question. Although the actual frequency is unclear, based on what I could find in the literature, it appears to be even more rare than Li-induced chorea. There have been several case reports in the literature [32,65–67]. In each of these cases patients were clearly described as having not only cogwheel rigidity but features such as resting tremor, increased tone in all limbs, bradykinesia, flexed posture, parkinsonian gait, masked face, postural instability. In one case the parkinsonism occurred as a manifestation of acute Li toxicity [67]. In that case other manifestations of Li intoxication were present. Finelli [23], in reviewing cases of Li-induced Creutzfeldt-Jakob-type syndrome, found that 3 of 6 patients manifested parkinsonian symptoms among other features, and they developed symptoms with therapeutic and toxic levels. In two other cases parkinsonism occurred in isolation in association with Li levels slightly above the therapeutic range [65,66], and finally, one patient developed the parkinsonism from acute intoxication in association with chorea and while the chorea continued to be a permanent neurological sequelae along with ataxia, the parkinsonism dissipated [32]. I have seen a single case of Li-induced parkinsonism in a patient who never received neuroleptics. He was a 59-year-old man with a history of bipolar disorder for several decades and treatment with Li for 15 years. His dose was 600 mg bid and his level was 1.0 mEq/L. He was also on gabapentin 2100 mg day, bupropion hydrochloride 150 mg bid. He was seen because of a question of jaw movements which he described as a habit due to the fact that his upper denture did not fit well and he said he tended to play with it with his tongue. He also had tremor which he said was present for 2 months. His examination demonstrated a to-andfro jaw movement which he could stop on request. He had no tongue movements. He demonstrated the poor fitting of his dentures. He had upper-extremity tremor which was greater on the left than the right and mainly postural,low-amplitude, and fast. It was also present with action. He did have muscle rigidity in all four limbs. He was bradykinetic; this was demonstrated with low amplitude and slow movements with finger tapping, hand grips, and foot tapping, and grips, and foot tapping. He had a stooped posture with flexion of the limbs and hands in a typical parkinsonian fashion. The gait was slow and stiff, with decreased arm swing and no ataxia. This patient was thought to have drug-induced parkinsonism and Liinduced tremor at the same time, while the jaw movements were thought to be denture-related. Unfortunately, because of the bipolar disorder, he was unable to stop the Li and we could not confirm if that drug was indeed the cause of his parkinsonism. However, with an absence of a history of antipsychotics, I believe that this was a Li-induced parkinsonian symptome. In conclusion, it does appear

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that Li can rarely cause parkinsonian symptoms in patients who are treated chronically. It can occur in therapeutic levels or as a manifestation of toxicity. Other Movement Disorders Li therapy may also be associated with myoclonus [68,69]. The prevalence is unknown. It is generally associated with Li toxicity although, as previously noted, some patients become toxic even when the levels are in the therapeutic range. [69]. Myoclonus may be spontaneous or action-induced. It is generalized. In one report [70] the myoclonus followed a similar pattern, regard to delayed latency of onset and delayed recovery, as seen with Li-induced chorea. That was in a patient who attempted an overdose Li. Li either alone or in combination with other psychotropic medications has reportedly caused a syndrome similar to Creutzfeldt-Jakob syndrome [22,23]. Six cases have been reported, and 5 of those were associated with myoclonus. Generally the patients develop a progressive dementia or confusional state associated with myoclonus, sometimes parkinsonism, and EEG changes including periodic sharp wave complexes similar to those seen in Creutzfeldt-Jakob disease. This syndrome is fully reversible after withdrawal of the medication, as is myoclonus associated with toxicity. There have been no cases of myoclonus associated with a persistent neurological syndrome. The Creutzfeldt-Jakob-like syndrome occurred in patients with toxic and therapeutic levels. Akathisia has been reported in a few single case reports in association with Li therapy [71,72]. In one case the akathisia occurred in a patient treated with Li and haloperidol [71]. When the haloperidol was discontinued it persisted, and then finally cleared within 24 hr of stopping Li. The patient was rechallenged with Li alone, and within hours the akathisia returned. This occurred at therapeutic levels with short-term therapy. In another case [72] the patient was treated with Li for her manic behavior and had never received Li previously or any neuroleptics. Akathisia developed at a therapeutic level and after 10 days. It was reversed with trihexiphenidyl therapy. No other movement disorders have been clearly associated with Li treatment. There have been no cases of dystonia reported to occur in association with this therapy. LITHIUM–NEUROLEPTIC INTERACTION In 1974, Cohen and Cohen [27] described a rare ‘‘severe encephalopathic syndrome’’ in 4 patients treated with Li and haloperidol. All patients were treated with high doses of both drugs and, in fact, Li levels were above the therapeutic range with potential for toxicity. All patients had elevated WBC and were febrile. The first 2 patients had substantially elevated creatine kinase levels. From a

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clinical standpoint all of them developed confusion, 2 of them had parkinsonism, and 2 were ataxic. Persistent syndromes were the result. In the first 2, that sequelae included parkinsonism, ataxia, and dementia; and in the second 2, primarily orofacial dyskinesias. The discussion in that paper did not mention neuroleptic malignant syndrome, and the irreversible sequelae of Li therapy was not yet known. They suggested that the two drugs may have interacted to produce a ‘‘summative or synergistic effect.’’ There was some discussion in the literature after this publication that such an interaction probably did not exist and there were concerns about any possible prohibition of the use of neuroleptics combined with Li since they were so commonly utilized, especially in acutely manic individuals. Baastrup et al [73] reviewed the hospital records of 425 patients who had been treated with that combination and found that none had developed a syndrome resembling what Cohen and Cohen had described. Others have also argued against such an interaction [31,74,75]. In fact, Donaldson et al. [31] indicate that all the cases described by Cohen and Cohen were simply cases of severe Li intoxication with persistent neurological sequelae. My own interpretation of these cases was that at least 2 of them experienced neuroleptic malignant syndrome and all 4 cases had sequelae of Li-induced toxicity so that in at least 2 of them the syndrome represented a combination of side effects of both drugs. The issue was revisited in 1981 by Spring and Frankel [26]. They presented a patient with features similar to those described by Cohen and Cohen. He was treated with high-dose Li and haloperidol, with his Li level being slightly above therapeutic range. He developed a parkinsonian syndrome so severe that he was barely able to move. He became febrile and eventually became completely immobile. His temperature peaked at 104⬚F. After drug doses were diminished there was a gradual improvement for a brief period and then a more substantive improvement after that. The patient did not have a creatine kinase level or a WBC count measured. The patient was not left with permanent sequeale. These authors went on to separate the Li-neuroleptic interaction into two types of syndromes. Which syndrome evolved depended on which neuroleptic drug was utilized. When phenothiazines were utilized in addition to the Li, the patient developed a neurotoxic syndrome identical to that seen with Li alone. The authors discussed work which showed that phenothiazines enhanced intracellular Li levels through changes in Li transport through cell membranes. It was found that thioridazine had the greatest effect. However, haloperidol did not have this effect on Li. The other syndrome was seen with potent dopamine-blocking agents, such as haloperidol, and Li whereby a neuroleptic malignant syndrome developed and Li enhanced that effect. The enhancement was suggested to be due to Li’s ability to inhibit striatal dopamine synthesis, which, in turn, increased the effect of the dopamine-blocking agents [18]. They concluded that the combined use of Li and neuroleptics was potentially more dangerous than using either drug alone. They felt that the combination should not be utilized.

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It has been suggested that Li induces the reappearance of tardive dyskinesia in patients who had previously had neuroleptic-induced tardive dyskinesia [76,77]. Some investigators feel that that Li might enhance the parkinsonism resulting from neuroleptic therapy [78–80]. This enhancement of extrapyramidal features and tardive dyskinesia could occur in the therapeutic range for Li. Toxic levels were not considered necessary. In addition, these recurrences or enhancements of syndromes can occur either acutely or after chronic therapy. The study, which provides the strongest evidence that an interaction does occur, was presented by Addonizio et al. [78]. In this study, 10 subjects on neuroleptics had Li added and 9 subjects remained on neuroleptic monotherapy. The patients were evaluated by blinded raters to examine for change in extrapyramidal symptoms when Li was added. The two groups were not matched. The study was singleblind in nature and the patients were evaluated 3 times in 3 weeks using the Simpson-Angus scale. In the group which received Li the neuroleptics were either kept the same or diminished in dose. Anticholinergics were also utilized but in all but 2 of the patients, and the dose remained the same. Subjects receiving Li showed a statistically significant increase in parkinsonian score on all visits. The mean Li level was in the therapeutic range. The patients who remained on neuroleptic monotherapy showed no change in parkinsonism. Because of the effect tremor might have on the impact of the measure of these symptoms, there was also an analysis excluding tremor as a symptom. The results of this study strongly suggested that Li might indeed worsen drug-induced parkinsonism. Still, the authors felt that a double-blind, placebo-controlled trial was needed to provide a definitive answer. There are some concerns about the study also. They gave an example of one particular patient who developed a severe increase in SimpsonAngus score. They described that patient as ‘‘she developed severe rigidity and tremor.’’ This represents a similar problem that was seen when trying to examine the possibility of Li-induced parkinsonism. This patient could simply have developed Li-induced tremor with cogwheel phenomenon. They also argued against the two subtypes of toxicity described previously by Spring and Frankel because they did not see it. Despite this last study, it is quite clear that Li and neuroleptics as monotherapy can cause many of the syndromes that have been described in these papers. In addition, the interaction between Li and neuroleptics has not been examined on a large-scale basis in controlled studies. These facts make it difficult to be sure that an interaction actually does exist. In addition, the effect of Li, on dopamine systems is also unclear, as described above under mechanism of action. Also, the effects of neuroleptics on Li pharmacology remains unclear. So an interaction between Li and neuroleptics is unproven at this time, but it is reasonable to maintain vigilance of the possibility that it may exist. Utilizing the lowest possible doses of both drugs in those situations requiring them is reasonable.

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CONCLUSION Lithium is a commonly used agent for acute mania, for prevention of recurrence of bipolar disorder, and occasionally for depression. Toxicity has been a concern for decades, so its use should be limited to those physicians understanding the intricacies of its pharmacology. Movement disorders are part of that concern. They can occur at therapeutic levels, and at toxic levels, and some neurological signs and symptoms may be permanent. A low-amplitude, fast postural and action tremor is the most common of neurological side effects, occurring in about onethird of treated patients. While it is usually mild and not troublesome, it can be embarrassing and, with increasing blood levels, disabling. Various factors enhance its occurrence. Chorea, parkinsonism, myoclonus, and akathisia can occur as a manifestation of lithium intoxication. All are rare and usually occur in association with other signs of toxicity. Chorea is the only movement disorder to be permanent, and that occurred in a single case. It is important for the treating physicians to be aware of the potential of Li to cause such problems. There are questions about whether the concomitant use of Li and neuroleptics causes more profound neurological syndromes (particularly parkinsonism, neuroleptic malignant syndrome, and irreversible Li-related sequelae). While they remain unanswered, patients receiving the combination should probably be observed very carefully. ACKNOWLEDGMENTS This work was supported by the Albany Medical College Parkinson’s Research Fund and the Riley Family Chair in Parkinson’s Disease. Special thanks to Robin Tassinari, MD, and Eric Molho, MD, for their assistance. REFERENCES 1. Jefferson JW, Griest JH. Lithium. In: Kaplan HI, Sadock BJ, Eds. Comprehensive Textbook on Psychiatry. 6th edn.. Baltimore. MD: Williams, & Wilkins, 1995: 2022–2023. 2. Incredible, Elemental Lithium. Mountainview. CA: Scios, 1998. 3. Kalinowsky LB. Somatic Treatments in Psychiatry: Pharmacology, Convulsive, Insulin, Surgical, Other Methods. New York: Grune & Stratton, 1961. 4. Beck AT, Brady JP. The history of depression. Psychiatric Ann 1977. 5. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Goodman AG, Rawl TW, Nies AS, Taylor P, Eds. The Pharmacological Basis of Therapeutics. Elmsford. NY: Pergamon, 1990:383–435. 6. Peters HA. Lithium intoxication producing chorea athetosis with recovery. Wisc Med J 1949; 48:1075–1076. 7. Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Austral 1949; 2:349–352.

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8. Janicak PG, Davis JM, Preskorn SH, Ayd FJ. Principles and Practice of Psychopharmacotherapy. 2nd edn., Williams & Wilkins. 1997:403–404. 9. Shou M, Juel-Nielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by administration of lithium salts. J Neurol Neurosurg Psychiatry 1954; 17:250–260. 10. Kores B, Lader MH. Irreversible lithium neurotoxicity: An overview. Clin Neuropharmacol 1997; 20:283–299. 11. Gershon S, Yuwiler A. Lithium ion: A specific psychopharmacological approach to the treatment of mania. J Neuropsychiatsy 1960; 1:229–241. 12. Peet M, Pratt JP. Lithium: Current status in psychiatric disorders. Drugs 1993; 46: 7–17. 13. Schneider JA, Mirra SS. Neuropathologic correlates of persistent neurologic deficit in lithium intoxication. Ann Neurol 1994; 36:928–931. 14. Podskalney GD, Factor SA. Chorea caused by lithium intoxication: A case report and literature review. Move Disord 1996; 11:733–737. 14a. Lenox RH, Hahn C-G. Overview of the mechanism of action of Lithium in the brain: Fifty-year update. J Clin Psychiatry 2000; 61(supply 9):5–15. 15. Cooper JR, Bloom FE, Roth RH. Epinephrine and norepinephrine. In: The Biochemical Basis of Neuropharmacology. 6th ed., Oxford University Press. 1991:220–284. 16. Casebolt TL, Jope RS. Long-term lithium treatment selectively reduces receptorcoupled inositol phospholipid hydrolysis in rat brain. Biol Psychiatry 1989; 25: 329–340. 17. Matsis PP, Fisher RA, Tasman-Jones C. Acute lithium toxicity—chorea, hypercalcemia and hyperamylasemia. Austral N Z Med 1989; 19:718–720. 18. Friedman E, Gershon S. Effect of lithium on brain dopamine. Nature 1973; 243: 520–521. 19. Walevski A, Radwan M. Choreoathetosis as toxic effect of lithium treatment. Eur Neurol 1986; 25:412–415. 20. Klawans HL, Weiner WJ, Nausieda PA. The effect of lithium on an animal model of tardive dyskinesia. Progr Neuropsychol Pharmacol 1977; 1:53–60. 21. Treiser SL, Casio CS, O’Donohue TL, Thoa NB, Jacobowitz DM, Kellar KJ. Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 1981; 213:1529–1531. 22. Smith SJM, Kocen RS. A Creutzfeld-Jakob like syndrome due to lithium toxicity. J Neurol Neurosurg Psychiatry 1988; 51:120–123. 23. Finelli PF. Drug-induced Creutzfeld Jakob like syndrome. Psychiatr Neurosci 1992; 17:103–105. 24. Factor SA, Singer C. Neuroleptic malignant syndrome. In: Lang AE, Weiner WJ, Eds. Drug-Induced Movement Disorders. Mount Kisco. NY: Futura, 1992:199–230. 25. Sternbach H. The serotonin syndrome. Am J Psychiatry 1991; 148:705–713. 26. Spring G, Frankel M. New data on lithium and haloperidol incompatibility. Am J Psychiatry 1981; 138:818–821. 27. Cohen WJ, Cohen NH. Lithium carbonate, haloperidol, and irreversible brain damage. JAMA 1974; 230:1283–1287. 28. Von Hartitzsch B, Hoenich NA, Leigh RJ, et al. Permanent neurological despite hemodialysis for lithium intoxication. Br Med J 1972; 4:757–759.

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29. Adityanjee RJ, et al. The syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). Pharmacopsychiatry 1989; 22:81–83. 30. Schou M. Long-lasting neurological sequelae after lithium intoxication. Acta Psychiatr Scand 1984; 70:594–602. 31. Donaldson IM, Cunningham J. Persisting neurologic sequelae of lithium carbonate therapy. Arch Neurol 1983; 40:747–751. 32. Apte SN, Langston JW. Permanent neurological deficits due to lithium toxicity. Ann Neurol 1983; 13:453–455. 33. Nagaraja D, Taly AB, Sahu RN, et al. Permanent neurological sequelae due to lithium toxicity. Clin Neurol Neurosurg 1987; 89:31–34. 34. Pamphlett RS, MacKenzie RA. Severe peripheral neuropathy due to lithium intoxication. J Neurol Neurosurg Psychiatry 1982; 45:656. 35. Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry 1995; 56:283–287. 36. Goodwin FK, Jamison KR. Medication compliance. In: Goodwin FK, Jamison KR, Eds. Manic-Depressive Illness. New York: Oxford University Press, 1990:746–762. 37. Lapierre YD. Control of lithium tremor with propranolol. Can Med Assoc J 1976; 114:619–620. 38. Bech P, Thomsen J, Prytz S, et al. The profile and severity of lithium-induced side effects in mentally healthy subjects. Neuropsychobiology 1979; 5:160–166. 39. Bone S, Roose SP, Dunner DL, et al. Incidence of side effects in patients on longterm lithium therapy. Am J Psychiatry 1980; 137:103–104. 40. Jefferson JW. Lithium tremor and caffeine intake: Two cases of drinking less and shaking more. J Clin Psychiatry 1988; 49:72–73. 41. Vestergaard P, Amdisen A, Shou M. Clinically significant side effects of lithium treatment. A survey of 237 patients in long-term treatment. Acta Psychiatr Scand 1980; 62:193–200. 42. Vestergaard P, Poulstrup I, Shou M. Prospective studies on a lithium cohort. 3. Tremor, weight gain, diarrhea, psychological complaints. Acta Psychiatr Scand 1988; 78:434–441. 43. Elble RJ, Koller WC. Tremor. Baltimore. MD: Johns Hopkins Press, 1990. 44. Riley DE. Antidepressant therapy and movement disorders. In: Lang AE, Weiner WJ, Eds. Drug-Induced Movement Disorders. Mount Kisco. NY: Futura, 1992:231–255. 45. Tyrer P, Lee I, Trotter C. Physiological characteristics of tremor after chronic lithium therapy. Br J Psychiatry 1981; 139:59–61. 46. Chacko RC, Marsh BJ, Marmion J, Dworkin RJ, Telschow R. Lithium side effects in elderly bipolar outpatients. Hillside J Clin Psychiatry 1987; 9:79–88. 47. Gaby NS, Lefkowitz DS, Israel JR. Treatment of lithium tremor with Metoprolol. Am J Psychiatry 1983; 140:593–595. 48. Poldinger W. Therapy of extrapyramidal side effects, with particular reference to persistent dyskinesia and lithium tremor. Int Pharmacopsychiatry 1978; 13:230–233. 49. Dave M, Langbart MM. Nadolol for lithium tremor in the presence of liver damage. Ann Clin Psychiatry 1994; 6:51–52. 50. Kruse JM, Ereshefsky L, Scavone M. Treatment of lithium-induced tremor with nadolol. Clin Pharm 1984; 3:299–301. 51. Zubenko GS, Cohen BM, Lipinski JF. Comparison of metoprolol and propranolol in the treatment of lithium tremor. Psychiatry Res 1984; 11:163–164.

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77. Beitman BD. Tardive dyskinesia reinduced by lithium carbonate. Am J Psychiatry 1978; 135:1229–1230. 78. Addonizio G, Roth SD, Stokes PE, Stoll PM. Increased extrapyramidal symptoms with addition of lithium to neuroleptics. J Nerv Ment Dis 1988; 176:682–685. 79. Yassa R. A case of lithium-chlorpromazine interaction. J Clin Psychiatry 1986; 47: 90–91. 80. Sachev PS. Lithium potentiation of neuroleptic-related extrapyramidal side effects. Am J Psychiatry 1986; 143:942.

11 Movement Disorders Induced by Selective Serotonin Reuptake Inhibitors and Other Antidepressants Kersi J. Bharucha University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma, U.S.A.

Kapil D. Sethi Medical College of Georgia Augusta, Georgia, U.S.A.

INTRODUCTION The emphasis of antidepressant therapy has shifted away from the traditional tricyclic antidepressants (TCAs) such as amitriptyline to the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, and sertraline. Because of their potential side effects, the older monoamine oxidase inhibitors (MAOIs) are now rarely used for the treatment of depression. SSRIs are the most widely prescribed class of antidepressant drugs at present. Hence this chapter will focus primarily on the movement disorders induced by the SSRIs. Other drugs, such as the benzodiazepines and buspirone that are primarily anxiolytics, will not be dealt with in this chapter. Lithium, which is used primarily to treat bipolar disorders, is discussed elsewhere in this volume. 233

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It is important to emphasize that movement disorders induced primarily by the antidepressants are much less common than those induced by the ‘‘neuroleptic’’ or antipsychotic drugs such as haloperidol. In the majority of patients, the commonly prescribed antidepressants do not induce movement disorders and can be safely taken for indefinite periods. Often, the movement disorders following these drugs result from drug interactions or occur in patients who have previously been ‘‘primed’’ with neuroleptic medications. It is also important to remember that patients with depression have abnormalities of neurotransmitter function. Hence adverse effect profiles encountered in depressed patients cannot always be extrapolated to normal individuals. Finally, unlike the antipsychotic drugs, which induce tardive dyskinesia, antidepressants do not commonly induce persistent movement disorders. Several other issues are relevant to the literature on movement disorders and antidepressants. Certain drugs, classed as antidepressants, also have antidopaminergic properties and hence have side effects similar to the antipsychotics. An example is amoxapine. Amoxapine has been reported to cause tardive dyskinesia [1], but this drug is not a pure antidepressant and also has antidopaminergic activity. This is attributed to its active metabolite, 7-hydroxyamoxapine, which has affinity for postsynaptic dopamine receptors. Certain other commercial formulations may contain a combination of an antidepressant and an antipsychotic, an example being amitriptyline and perphenazine (commercially marketed as Triavil in the United States). The incidence of movement disorders caused by antidepressants is unknown, as there have been few systematic epidemiological studies and most of the information is derived from anecdotal case reports. Moreover, in most instances the patients have not been examined by a neurologist with expertise in movement disorders. For this reason, descriptions of some clinical phenomena such as dystonia, chorea, and myoclonus may be inaccurate, or may have been loosely lumped together under the terms ‘‘dyskinesia’’ or ‘‘extrapyramidal syndrome.’’ It is also important to keep in mind that some patients may be on concomitant antipsychotic medications and the movement disorder may be incorrectly attributed to the antidepressant. Finally, depression is a common symptom of certain movement disorders such as Parkinson’s and Huntington’s diseases. The effects of the newer antidepressants on some of these disorders will be discussed in the latter part of the chapter. PHARMACOLOGY OF THE ANTIDEPRESSANTS It is important to review briefly the mode of action and metabolism of the various antidepressants, as most of the movement disorders induced by these drugs result from excessive levels of the drugs or their metabolites. The older tricyclic and tetracyclic antidepressants act by blocking the reuptake of norepinephrine (NE)

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and serotonin (5-HT), and also block muscarinic acetylcholine and H1 and H2 histamine receptors in varying degrees. The SSRIs block the reuptake of 5-HT more effectively than NE and include the drugs fluoxetine, sertraline, paroxetine, and fluvoxamine. The serotonin-norepinephrine reuptake inhibitor (SNRI) class includes the drug venlafaxine, which blocks the reuptake of both NE and 5HT. The SSRIs and the SNRIs lack significant effect on muscarinic cholinergic, histaminergic, and adrenergic receptors and hence lead to fewer pharmacokinetic interactions than the older TCAs. Other newer antidepressants include nefazodone, a postsynaptic 5-HT antagonist and presynaptic 5-HT reuptake inhibitor, and mirtazapine, a presynaptic and postsynaptic receptor antagonist of NE and 5-HT. Most of the adverse effects of the newer SSRIs and older tricyclics are related to drug interactions. These may be pharmacodynamic, in which one drug influences the action of another, or pharmacokinetic, in which one drug influences the metabolism of the other. The metabolism of the antidepressants is dependent on the cytochrome P-450 enzyme system in the liver (also termed the CYPs). CYP enzymes are hemoproteins which mediate oxidation and reduction reactions on substrates that may be endogenous (bile acids, prostaglandins and steroids) or exogenous (drugs) [2]. The latter are located mainly in the smooth endoplasmic reticulum of the liver. Numerous CYP enzymes have been identified by molecular cloning experiments, and are identified by standard nomenclature [3] identifying the CYP family, the subfamily, and a number for the individual gene. For example, CYP2A6 is the abbreviation for the CYP in family 2, subfamily A, and gene product 6. Perhaps the most familiar of all the CYP enzymes is CYP2D6. Several years ago there were reports that fluoxetine inhibits the metabolism of tricyclic antidepressants (TCAs). Both fluoxetine and the TCAs compete for CYP2D6, which appears to be the rate-limiting enzyme in their metabolism. Thus TCAs appear to potentiate the adverse effects of fluoxetine if the two classes of drugs are used simultaneously. However, adverse effects are not commonly observed in patients taking fluoxetine and TCAs, but may occur in the 3–10 % of white persons and 0–2% of Asians and black persons who show decreased or no activity of CYP2D6 [4]. Other drugs may also inhibit the CYP enzymes and lead to adverse effects from SSRIs. For example, quinidine is a potent and selective inhibitor of CYP2D6 [5], and this property has been utilized in clinical studies to suppress this enzyme in humans. On a comparative scale rating the inhibition of CYP2D6, by various new antidepressants, paroxetine appears to be the most potent, followed by norfluoxetine, fluoxetine, sertraline, fluvoxamine, venlafaxine, nefazodone, and mirtazapine in that order [6]. Fluoxetine and its active metabolite norfluoxetine also inhibit CYP1A2 and CYP3A4 [6], CYP3A4 does not display genetic polymorphism. Of the SSRIs, fluvoxamine is the most potent inhibitor of CYP1A2, with mirtazapine and venlafaxine having the least inhibitory

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effect. CYP3A4 is the most abundant class of the CYP enzymes, and nefazodone is a potent inhibitor whereas venlafaxine has no inhibitory effect [6]. On the basis of in-vitro data on the cytochrome P-450 enzyme system, the SSRIs mirtazapine and venlafaxine are least likely to cause pharmacokinetic drug interactions. Fluvoxamine, fluoxetine, paroxetine, and nefazodone are most likely to do so, with sertraline falling in the middle [6]. However, these predictions are made based on in-vitro studies and may not apply to patients. There are also important differences in the half-lives of the SSRIs, which is probably why some adverse effects such as the serotonin syndrome are more commonly encountered with the longer-acting SSRIs such as fluoxetine. The half-life of fluoxetine is about 72–144 hr, whereas it is about 21 hr for paroxetine, about 26 hr for sertraline, and about 35 hr for citalopram [6]. The half-life of norfluoxetine, the active metabolite of fluoxetine, is much longer than that of its parent drug. Hence any adverse effects resulting from fluoxetine are likely to be more prolonged than those seen with the other SSRIs. THE SEROTONIN SYNDROME The serotonin syndrome is a potentially serious adverse effect associated with the use of SSRIs and will be discussed in more detail in this chapter. The more severe forms of this syndrome present with disorientation and a movement disorder. It has been extensively described in the older literature in the context of drug interactions with the nonselective MAOIs. With the decline in the use of these antidepressants, the syndrome was reported only infrequently. However, there has been a resurgence of cases in the last few years, following the increased use of the newer SSRIs. Other cases have also been reported in the context of drug interaction with the MAO-B inhibitor selegiline, which is prescribed in Parkinson’s disease. (See Table 1 for a list of drugs and compounds that may potentiate the actions of serotonin.) Oates and Sjoerdsma first described the serotonin syndrome in depressed patients in 1960 [7], and attributed the condition to excessive levels of serotonin in the brain. An earlier report in 1955 by Mitchell [8] of a patient with muscle twitching, ankle clonus, and Babinski’s sign, who was given iproniazid and meperidine, is possibly also a case of this syndrome. Myoclonic jerking appears to be a key clinical feature in this syndrome. Bodner and colleagues [9] reviewed the clinical features in 81 cases. These were variable but included changes in mental status with agitation, confusion, disorientation, and restlessness, and even coma. Accompanying these were motor symptoms such as myoclonus, rigidity, hyperreflexia, ankle clonus, and ataxia, and autonomic symptoms (low-grade fever, nausea, diarrhea, headache, shivering, flushing, diaphoresis, tachycardia, tachypnea, fluctuations in blood pressure, and pupillary dilatation). Usually, routine laboratory studies including serum electrolytes, spinal fluid, and imaging

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TABLE 1 Drugs and Substances Potentiating Serotonin in the Brain Serotonin reuptake inhibitors (selective and nonselective) Antidepressants Fluoxetine Sertraline Paroxetine Fluvoxamine Venlafaxine Citalopram Nefazodone Trazodone Amitriptyline Imipramine Trazodone Opiate derivatives Meperidine Dextromethorphan Stimulants Cocaine Amphetamine Serotonin metabolism inhibitors Monoamine oxidase inhibitors Phenelzine Tranylcypromine Isocarboxazid Selegiline Moclobemide Serotonin precursors (increase synthesis) L-tryptophan Serotonin receptor agonists Sumatriptan Dihydroergotamine Buspirone Increased serotonin release Fenfluramine Amphetamine Cocaine MDMA (“Ecstasy”) Serotonin enhancement by uncertain mechanisms Lithium

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studies of the brain tend to be normal if performed. Some of the patients, however, appear to have some overlap with the neuroleptic malignant syndrome and show mild elevation of creatine kinase (CK) along with borderline leucocytosis [10,11]. Some other patients may have more severe symptoms, with seizures, nystagmus, oculogyric crisis, opisthotonus, dysarthria, myoglobinuria, renal failure, coma, and death [10–17]. The syndrome is usually short-lived and resolves completely once the offending drug is discontinued. In some patients, treatment with serotonin antagonists such as cyproheptadine [18], methysergide [19], or propranolol [20,21] has resulted in faster resolution of symptoms, but the syndrome is selflimited and the role of these specific therapies is difficult to evaluate. Supportive measures consist of intravenous fluids and antipyretics. The use of agents such as clonazepam or other benzodiazepines to control myoclonus in this setting is not of proven benefit and may complicate the management of an already disoriented patient. Atypical forms of the syndrome, presenting with a combination of various movement disorders, have been described. Bharucha and Sethi reported two cases with very unusual movement disorders caused by fluoxetine, which was given concomitantly or in close proximity to a TCA [22]. One of the cases was a 72year-old woman who developed rhythmic palatal movements, myoclonus, chorea, tremor of the extremities, and dystonic movements of the jaw. The palatal movements were slow (about 1–2 Hz) and resembled a palatal tremor. They were not jerky and rapid as in classic palatal myoclonus. She had been on therapy with fluoxetine for over 2 years and developed the movements after the addition of doxepin. On withdrawal of fluoxetine, the movements abated in 5 days and did not recur. The second patient, a 58-year-old man, developed myoclonic jerking involving the abdominal muscles and rapid, stereotypic wiggling movements of his toes. He had been on fluoxetine therapy for over a year, and the movements followed abrupt substitution with trazodone. Lauterbach described similar abnormal movements in a patient with presumed Pick’s disease, who was prescribed fluoxetine [23]. The patient developed intermittent, rhythmically repetitive trains of myoclonus a year after treatment with fluoxetine. A dystonic component involving the shoulder region was observed. The myoclonus involved the face, palate, shoulder, neck, upper chest and back, diaphragm, hips, and upper extremities. Postural adjustments, startle, or other stimuli did not influence the movements. They proved insensitive to benztropine but abated with discontinuation of fluoxetine. Rechallenge with fluoxetine or trazodone evoked the movements, whereas clonazepam and chloral hydrate abolished the movements. These three cases represent unusual cases of the serotonin syndrome. The unusual phenomenon of rhythmic palatal movements has not been observed in other reported cases. Other reports of complex movements in patients include that of a 74-year-old woman who developed reversible choreiform movements of the tongue, lips, and masticatory muscles after 7 months of therapy

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with fluoxetine [24]. She was shown to have a genetic deficiency of the enzyme CYP2D6 [24,25]. A more recent report described a woman with reversible choreoathetotic and myoclonic perioral movements, with dystonic contractions following only 5 days of a low dose of fluvoxamine [26]. Some may argue the patients described above are distinct from the serotonin syndrome. However, all patients had myoclonic jerking in the setting of a serotonergic antidepressant, and hence they most likely represent unusual variants of the serotonin syndrome. Some of the newer antidepressants, such as mirtazepine, citalopram, and fluvoxamine, have also been reported to cause the serotonin syndrome [27–31], most often in combination with other drugs, but also as monotherapy [27]. In most cases the movement disorder develops shortly after initiation of therapy with a SSRI, but sometimes the latent period may be prolonged. The development of the syndrome appears to be more frequent in patients with neurodegenerative disorders such as Pick’s disease [23]. Patients with CYP2D6 deficiency and older individuals may also be more predisposed. Pathogenesis of the Serotonin Syndrome There is extensive literature implicating serotonin and its role in different forms of myoclonus both in animals [32–33] and humans [35,36]. Animals given MAOIs after pretreatment with L-tryptophan develop fever, myoclonus, sideto-side head movements, stiffness in the hind limbs, and continuous treading movements of the forelimbs, tremor, sedation, and autonomic signs [37]. This is identical to the serotonin syndrome seen in humans. The syndrome can be blocked by pretreatment with a 5-hydroxytryptophan decarboxylase inhibitor. In guinea pigs, Chadwick and Marsden showed that 5-hydroxytryptophan (5-HTP) induces a characteristic behavioral syndrome of altered motor activity with muscle jerking [34]. Myoclonic jerking occurred synchronously in forelimbs and hindlimbs and was associated with a stereotyped electromyographic pattern. Such myoclonus may be induced also by the administration of L-tryptophan plus a MAOI, or by agents acting as serotonin (5-HT) receptor agonists. The 5-HTP-induced syndrome was antagonized by a central decarboxylase inhibitor and by agents that block 5-HT receptors (methysergide and cyproheptadine). 5-HTP-induced jerking was abolished below the level of a spinal cord transection, but persisted in decerebrate animals. There were no electroencephalographic (EEG) changes preceding the muscle jerks. Although there are no specific studies in the context of the serotonin syndrome and SSRIs, the literature on myoclonus and serotonin is convincing to implicate excessive serotonin as the underlying neurotransmitter abnormality in this disorder. In some cases the serotonin syndrome may be confused with the neuroleptic malignant syndrome (NMS). This is associated with treatment of a patient with a neuroleptic or sudden withdrawal of a dopaminergic agent (e.g., sudden levodopa

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discontinuation in Parkinson’s disease). Some of the clinical features of NMS overlap with the serotonin syndrome and consist of mental status changes, high fever, prominent muscle rigidity, and autonomic dysfunction [38]. Resting tremor, parkinsonian gait, dyskinesias, dystonia, and chorea may also be seen. The serotonin syndrome can usually be distinguished from NMS by the presence of myoclonus. Also fever, muscle rigidity and leucocytosis and elevated CK with myoglobinuria are features more commonly seen with NMS and are not prominent in the serotonin syndrome. Criteria for the diagnosis of the serotonin syndrome based on these clinical findings have been proposed [39]. However, all cases may not manifest with myoclonus and rigidity, and minor forms of the syndrome are probably unrecognized. There are also numerous cases in the literature of other movement disorders such as dystonia or chorea occurring in the context of the SSRIs. Some of these may represent less severe variations of the serotonin syndrome, as discussed later in this chapter. Serotonin Syndrome in Parkinson’s Disease The issue of possible worsening of Parkinson’s disease (PD) by fluoxetine will be addressed later in this chapter. The serotonin syndrome is sometimes seen in PD. Often, it is precipitated by an interaction between selegiline and meperidine. The latter is usually given in the postoperative period for pain control. The interaction has been welldocumented with older nonselective monoamine oxidase A inhibitors such as tranylcypromine [40], but is often overlooked as a cause of postoperative disorientation in patients with PD. Parkinson’s disease patients may also be concomitantly prescribed TCAs and SSRIs for depression. Richard and colleagues [41,42], in conjunction with other investigators in the Parkinson Study Group (PSG), reviewed the use of antidepressants in Parkinson’s disease. Based on a survey provided by neurologists, 4568 patients were treated with a combination of selegiline and an antidepressant medication. Eleven patients (0.24%) were found to have symptoms consistent with the serotonin syndrome. Two patients had adverse effects considered to be serious, and no deaths were reported. The authors of the PSG paper [42] also obtained the following information from a series of cases provided by the manufacturer of Eldepryl (a brand name for selegiline in the United States) regarding adverse events reported to the U.S. Food and Drug Administration (FDA) (1989–1996) of possible drug interactions between deprenyl and antidepressants. Fifty-seven patients with adverse reactions were reported. Twenty-seven of these patients were treated with SSRIs, 27 with TCAs, 1 with venlafaxine, and 2 with trazodone. Of these 57 patients, 48 involved patients who had diagnoses of PD or parkinsonism, whereas 3 patients had depression, 1 had bipolar disorder, and 1 had amylotrophic lateral sclerosis (ALS). There was no information regarding diagnoses in 4 patients. The most frequent

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sign or symptom reported, mental status changes, occurred in 30 patients (53%). The other signs or symptoms reported were tremor (14%), hypertension (12%), gastrointestinal disturbance (11%), diaphoresis (9%), hyperpyrexia (9%), increased parkinsonian signs (7%), hypotension (7%), dizziness/lightheadedness (7%), rigidity (7%), involuntary movements/dyskinesias (7%), headache (4%), chest pain/tightness (4%), ‘‘serotonergic reaction/syndrome’’ (4%), seizure (4%), ataxia/falls (4%), and restlessness (4%) [42]. Some of these symptoms obviously represent autonomic dysfunction, but movement disorders were uncommon. The serotonin syndrome was reported in only 4%, tremor was seen in 14%, and ‘‘dyskinesias’’ in 7%. There is no mention of myoclonic jerking specifically, although this may be included in the category ‘‘involuntary movements/dyskinesias.’’ The authors conclude that adverse effects, including the serotonin syndrome, are rare in the context of Parkinson’s disease treated with a combination of selegiline and other antidepressants. Serotonin Syndrome in Patients with Migraine Although patients with migraine are commonly treated using a combination of antidepressants and serotonin agonists, the serotonin syndrome has been reported only infrequently in this population. It is also important to consider whether the patients received antiemetics such as promethazine (which has neuroleptic properties) or other antidopaminergic drugs, which could be responsible for ‘‘priming’’ the patient. Mathew recently reported 6 patients with migraine who developed symptoms suggestive of the serotonin syndrome [43]. Five patients were taking one or more serotomimetic agents for migraine prophylaxis (sertraline, paroxetine, lithium, imipramine, and amitriptyline). In all cases the symptoms and signs developed in close temporal proximity with use of a migraineabortive agent known to interact with serotonin receptors. In 3 instances the drug was subcutaneous sumatriptan, and it was intravenous dihydroergotamine in the other 3. All patients recovered fully. Diamond described 4 patients with migraine who developed the serotonin syndrome when venlafaxine was prescribed to migraineurs taking phenelzine, a nonselective MAOI [44]. All 4 patients were noted to have ‘‘twitching’’, but the movement disorder was not characterized further. As migraine is a common disorder and there are only a few case reports of the serotonin syndrome in migraineurs taking SSRIs, one can only conclude that the majority of patients are able to tolerate antidepressants well. Acute dystonia has been reported rarely with sumatriptan, a 5-HT1 receptor agonist frequently used to treat acute attacks of migraine. ANTIDEPRESSANTS AND OTHER MOVEMENT DISORDERS Although tremor, dystonia, chorea, myoclonus, akathisia, tardive dyskinesia, parkinsonism, bruxism, ‘‘extrapyramidal syndrome,’’ and various combinations of

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movements have been attributed to SSRIs, there are only a handful of reports in which SSRI was the sole psychotropic agent used. In most instances, the patients had previously been given dopamine blockers, or were taking them concurrently. Most case reports describe a combination of various movements involving different areas of the body. This combination of movements, which may include tremor, dystonia, myoclonus, chorea, or tics, is a hallmark of drug-induced movement disorders. In several examples cited, patients may have more than one type of abnormal movement. As fluoxetine has been available for the longest period, most of the reports pertain to this drug, but there are similar reports with the other SSRIs as well. Tremor Tremor appears to be the most common movement disorder induced by the SSRIs [45,46]. In studies looking specifically at side-effect profiles of fluoxetine in doses of 20–40 mg daily, it is estimated that new-onset tremor occurs in upto 20% of patients [47,48]. Tremor has also been noted in the context of overdose with SSRIs [49]. In another study of fluoxetine overdose [50], the authors retrospectively studied 234 cases at several centers. Fluoxetine was ingested alone in 87 cases and with ethanol or other drugs in the remaining 147 cases. Of the 87 cases in whom fluoxetine was ingested alone, 67 patients were adults and 20 were children. Tremor was noted in only 5 of 67 cases. Other symptoms that were seen in the adult group included tachycardia (15/67), drowsiness (14/67), vomiting (4/67), or nausea (4/67). Thirty patients did not develop symptoms. Twelve of the adult overdose patients had total fluoxetine levels ranging from 232 to 1390 ng/mL. The authors concluded that symptoms that develop after an acute overdose of fluoxetine appear minor and of short duration. A postural tremor is noted in a significant number of patients and may represent an exacerbation of physiological tremor. However, its characteristics, such as frequency and amplitude, have not been specifically studied. This tremor is generally not prominent, and hence most patients may be unaware of it. It has to be distinguished from a resting parkinsonian tremor, which has also been described in patients taking SSRIs (see below), and also from the prominent tremors occurring in the context of the serotonin syndrome described above. Coulter and colleagues [46] published notifications of extrapyramidal manifestations in patients given fluoxetine in the New Zealand Intensive Medicines Monitoring Program, a national system that monitored adverse reactions associated with fluoxetine over a 4-year period. In reports of adverse reactions in 5555 patients given fluoxetine throughout New Zealand, there were 15 notifications of extrapyramidal events probably or possibly caused by fluoxetine. Fluoxetine was the only psychotropic agent used for 7 of the 15 patients. Two patients were also taking lithium, 4 were taking neuroleptics, 2 were taking tricyclic

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antidepressants, and 1 was taking metoclopramide. Tremor was noted in 5 patients, 3 of whom were not taking any other psychotropic medications; the other 2 were on buspirone and metoclopramide concomitantly. The authors concluded that fluoxetine may be associated with extrapyramidal reactions and that these may occur with fluoxetine alone or in combination with other psychotropic drugs. Tremors may also be seen in the SSRI withdrawal syndrome, which results from rapid cessation of a SSRI. This is characterized by irritability, dizziness, paresthesias, anxiety, vivid dreams, and tremulousness. The tremors appear to represent an exaggeration of the normal physiological tremor common to anxiety states. It is more common with SSRIs that have a shorter half-life, such as paroxetine and fluvoxamine [51] than with fluoxetine, which has a much longer halflife. The syndrome has been noted with all the SSRIs. In some cases, the patients have been able to withdraw from shorter-acting SSRIs after substituting with fluoxetine and then proceeding to a slow taper of this drug. Tremor has also been noted as a side effect of tricyclic antidepressants (TCAs). In clinical trials of TCAs and in patients with overdoses of TCAs, a low-amplitude postural tremor has been noted. This has been postulated to be an exaggerated physiological tremor and correlates with plasma drug levels [52]. Beta-blockers such as propranolol may be benefit these tremors [53]. Dystonic Reactions Dystonic Reactions [54–56] have also been reported with SSRIs, mainly with fluoxetine. In one case, the acute dystonia occurred 2 days after withdrawal of fluoxetine [56]. There are only a few instances in which movement disorders have occurred in patients taking an SSRI alone, in the absence of concomitant antidopaminergic drug therapy. Reccoppa and colleagues reported a woman with depression who developed trismus and cervical dystonia within 10 days of increase in the dose of fluoxetine from 20 mg to 40 mg daily. She had never received neuroleptics, The dystonia responded to diphenhydramine and trihexyphenidyl, but recurred following challenge with fluoxetine. The symptoms once again resolved when fluoxetine was discontinued. George and colleagues reported a subacute dystonic reaction in a woman with Tourette’s syndrome who was given fluvoxamine as sole therapy [57]. The dystonia involved her jaw and developed over 4 weeks. It resolved with reduction of the daily dose to 100 mg and recurred when the dose was increased to 200 mg. Shihabuddin reported a patient who developed stiffness of the jaw, cervical dystonia, and possibly akathisia within 3 weeks of starting sertraline [58]. The patient responded to diphenhydramine. Dave reported blepharospasm, lip tremor, truncal, and foot dystonia in a neuroleptic-naive woman who had been on fluoxetine for 4 weeks [59]. AlAdwani described a patient with left hemiparesis from an old pontine hemorrhage who developed dystonia on his left side within days of starting paroxetine [60].

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The symptoms resolved following withdrawal of paroxetine. Poyurovsky et al. described a patient who developed trismus and dystonic spasms of the extremities following fluoxetine [61]. The authors state that the patient was not receiving any other concomitant psychotropic medications. However, he had been on haloperidol 6 weeks previously and had also received haloperidol 2 years earlier. It is important to remember that some patients may have received antidopaminergic drugs without their knowledge and hence may not be neuroleptic-naive as claimed in the case reports. Other reports of opisthotonus and trismus [46] probably represent cases of dystonia involving other parts of the body. A more recent report describes dystonia as a side effect of mirtazapine therapy [62]. Of interest is the recent report by Bhatia and colleagues of reversal of the benefits of levodopa therapy in 2 patients with dopa-responsive dystonia (DRD) who were prescribed SSRIs [63]. One of the patients was a 34-year-old woman who had complete resolution of symptoms on levodopa. She was then prescribed fluoxetine and noted recurrence of cervical and foot dystonia 5 days after starting the drug. She continued to take levodopa but had reverted to her clinical state at the time of onset. A week after discontinuing fluoxetine, her symptoms resolved completely on levodopa. The second patient, who was 32 years old and had had DRD since the age of 5, developed recurrence of her foot dystonia after being prescribed venlafaxine. Once again, the dystonia resolved on discontinuing the offending drug and continuing levodopa. The authors urge caution in using SSRIs in patients with DRD. The pathogenesis of these adverse dystonic reactions is not known, but it has been postulated that serotonergically mediated inhibition of dopaminergic transmission may play a role [64]. There is increase in serum prolactin levels [94] and a beneficial response to anticholinergic agents suggesting decreased dopaminergic activity. In areas of the rat forebrain, which is rich in dopamine, fluoxetine has been shown to inhibit its synthesis in the striatum, hippocampus, and frontal cortex [65]. Activation of sigma receptors in the rubrocerebellar pathways has also been hypothesized [66,67]. Alternative explanations have been proposed to explain extrapyramidal symptoms in patients who were no longer taking neuroleptics. Some authors have suggested that previous exposure to neuroleptics or lithium may sensitize nigrostriatal dopaminergic responses to increased serotonergic input from the raphe nuclei [68]. Finally, it is important to remember that the CYP enzymes may show considerable polymorphism, and decreased activity of CYP1A2, CYP2D6, and CYP3A4 has been reported [69,70]. Chorea Chorea has been described in the context of antidepressant therapy, with both the older tricyclics and the newer SSRIs. In some cases, orofacial choreiform movements appear following a latent period of a few months to a year after

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starting the antidepressant. These choreiform movements have been labeled as ‘‘tardive dyskinesia’’ in some reports. Fann [71] described 2 patients with orofacial dyskinesia with amitriptyline, but these clearly do not represent tardive dyskinesia as suggested in the report. It is doubtful if tardive dyskinesia is ever caused by tricyclic antidepressants or SSRIs alone. In the context of SSRIs, these cases may represent variants of the serotonin syndrome. In a significant proportion of serotonin syndrome cases the movement disorder appears after a latent period of several months. Chorea has been also been described as an adverse effect of the older tricyclic antidepressants such as amitriptyline, nortriptyline, and imipramine [71–74]. Once again, this usually occurs in the context of neuroleptic use, either concomitant or previous. It is also important to be aware of an entity described as ‘‘spontaneous dyskinesia of the elderly,’’ which is not precipitated by drugs. It involves the orofacial region and may be sometimes be incorrectly diagnosed as tardive dyskinesia. This condition affects drug-naive elderly individuals but may also be seen in younger schizophrenic individuals. Some antidepressants such as amoxapine may cause tardive dyskinesia, but as noted above, the 7hydroxy metabolite of this drug also has antidopaminergic properties [1]. In some cases antidepressants may bring out tardive or latent dyskinesias by altering the balance between cholinergic, noradrenergic, or other neurotransmitter systems. In summary, the literature is not convincing on the existence of a tardive syndrome following use of the older TCAs. The issue of ‘‘tardive dyskinesia’’ in the context of fluoxetine and other SSRIs is once again not convincing. Rare case reports exist, but it is difficult to separate these from less severe variants of the serotonin syndrome. Chorea in the context of the serotonin syndrome has been described above [22]. Sandler reported the case of a 29-year-old man who had been treated with fluoxetine for compulsions since childhood [75]. About a year later, on 80 mg/day of fIuoxetine, he developed dyskinetic movements of the limbs and orofacial region that resembled tardive dyskinesia. The limb dyskinesias resolved a couple of months after fluoxetine was discontinued, and the orofacial movements about 4 months later. In an acute setting, Fox [76] reported the case of a depressed woman who developed choreiform movements and oculogyric crisis within 14 hr of taking a first dose of paroxetine. The movements resolved with procyclidine and discontinuation of paroxetine. Rechallenge was not attempted. In most of the other reported cases, the patients were concomitantly or previously given antidopaminergic drugs, and the dyskinesia incorrectly attributed to the SSRI. In other case reports a previous drug history is omitted or may even be inaccurate. These reports are of dubious value and serve only to confuse the literature. Some of these reports, including that by Sandler [75], noted above, may represent variants of the serotonin syndrome rather than true tardive dyskinesia. The full-blown syndrome with a combination of myoclonus, dystonia, chorea, or tremor in the setting of disorientation is easily recognized. However, cases

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without myoclonus or with chorea or dystonia in isolation may represent less severe forms of the syndrome. These cases may be misdiagnosed as ‘‘tardive dyskinesia,’’ especially if there is a long latent period before symptoms appear. Also, unlike neuroleptic-induced tardive dyskinesia, the movements usually resolve quickly once the SSRI is withdrawn. This indicates a transient and subacute pathogenic process, i.e., rise in serotonin levels, as opposed to a more persistent alteration in neurotransmitter function in neuroleptic-induced tardive dyskinesia. In some instances, drug interactions may account for the appearance of a tardive dyskinesia. For instance, the serum levels of haloperidol may increase following the co-administration of fluoxetine and bring out a latent extrapyramidal side effect. It would be incorrect however, to attribute this to the SSRI. As with the TCAs, there is no hard evidence for tardive dyskinesia caused by SSRIs. Myoclonus Myoclonus in the setting of the serotonin syndrome has already been described above. In the case of the older TCAs, myoclonus is seen in patients with drug toxicity or overdose [77,78]. The authors noted that physostigmine was helpful [77], indicating that cholinergic mechanisms may be involved in the pathogenesis. In an older prospective study, the authors noted clinically insignificant myoclonus in as many as 30 of 98 patients [79]. Nine patients had clinically significant myoclonus that involved not only the upper extremities but also the jaw. The myoclonus resolved with discontinuation of the tricyclic, but persisted in patients in whom the drug could not be withdrawn. Akathisia Akathisia in the context of antidepressant therapy is a difficult topic to review. The numerous case reports do not attempt to define what was included in the term ‘‘akathisia’’. In most reports the term has been loosely applied to include patients with restlessness or inattention or even to patients having stereotypic movements. Some authors have included data from postmarketing surveys, and the issue of previous or concomitant neuroleptic use has not been addressed. In a retrospective review of 67 patients on paroxetine, Baldassono and colleagues [80] found 3 patients with akathisia, which they attributed to this drug. Other reports implicate paroxetine [81], sertraline [82,83], fluvoxamine [84], and fluoxetine [46,85–92]. Lipinski and colleagues [85] described 5 patients receiving fluoxetine for the treatment of obsessive compulsive disorder or major depression who developed akathisia. The symptoms of restlessness, constant pacing, purposeless movements of the feet and legs, and marked anxiety were indistinguishable from those of neuroleptic-induced akathisia. However, 3 patients had previously been on neuroleptics and had experienced neuroleptic-induced akathisia in the past. The authors noted that the akathisia generally responded well to treatment

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with the beta-adrenergic antagonist propranolol, dose reduction, or both. Further studies and more accurate reports in neuroleptic-naive patients are needed before the role of the SSRIs in akathisia can be conclusively established.

ANTIDEPRESSANT THERAPY IN NEUROLOGICAL DISORDERS Parkinson’s Disease There are two separate issues to be addressed here. The first is whether parkinsonism appears de novo in patients with depression treated with antidepressants. The second is whether antidepressants significantly worsen the motor symptoms in patients with established PD. Although several case reports are available, most do not distinguish between these two issues. The older antidepressants such as amitriptyline have been used in the majority of patients without any significant problems. Selegiline is not specifically used as an antidepressant in PD, and its interactions with other antidepressants have already been reviewed above in the context of the serotonin syndrome [41,42]. Drugs such as amoxapine do worsen parkinsonism, but this is secondary to its dopamine-blocking action [93]. It has also been noted that SSRIs may in isolated instances worsen the motor symptoms in PD [94] and can also induce parkinsonism in patients who have not had symptoms previously [46,95]. In a series of 9 depressed patients receiving fluoxetine, 1 patient developed a dystonic reaction, parkinsonian rigidity, and increased serum prolactin levels, all signs of decreased dopaminergic activity [96]. Homovanillic acid levels were also decreased in the cerebrospinal fluid of this subject. Caley and Friedman specifically studied the question of possible exacerbation of PD by SSRIs [97] Of 23 patients with PD treated with 40 mg/day fluoxetine, there was no worsening of motor symptoms in 20. In the other 3 patients, there was mild worsening which could not be distinguished from progression of the disease. A more recent report by Di Rocco and colleagues describes a patient on sertraline who developed parkinsonism de novo [98]. The symptoms resolved after the drug was discontinued. The authors would like to point out that several thousand patients with PD have been treated with both traditional and the newer SSRI class of antidepressants without any motor worsening. Worsening of motor symptoms in PD after antidepressant therapy is a rare occurrence. Also, the appearance of de-novo parkinsonism in patients with depression treated with antidepressants is also rare. The pathogenesis in these cases is not completely understood, and mechanisms postulated for the development of dystonia and other movement disorders induced by the SSRIs may or may not apply to cases of parkinsonism. Moreover, the mechanisms may be different for patients with depression who develop parkinsonism de novo and for patients with PD who experience worsening of symptoms

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with SSRIs. Inhibition of dopaminergic nigral neurons by serotonin has been postulated to explain the symptoms of parkinsonism in these patients [65]. This may result from increase serotonin activity due to blockade of reuptake, which in turn inhibits both the nigro-striatal and tubero-infundibular dopaminergic neurons. The effect of sertraline on dopamine metabolism in animals has been investigated in rats by Di Rocco and colleagues [98]. Sertraline (30 mg/kg, intraperitoneal) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats. Using cerebral microdialysis, extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pretreated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p ⬍ 0.01). The authors hypothesize that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome. The enzyme CYP2D6 is involved in the metabolism of the SSRIs, and its role in PD has also been studied. Tsuneoka and co-workers [70], in a Japanese study, have shown that genetic polymorphism of the CYP2D6 gene has been associated with increased susceptibility to Parkinson’s disease. The authors noted that PD patients were either poor metabolizers (PM) or extensive metabolizers (EM). They analyzed CYP2D6 genes from Japanese patients and controls, and found that EM/PM polymorphism is not a suitable marker for populations with a low PM frequency. However, a novel mutant strongly associated with Parkinson’s disease was discovered. The mutation was located at the HhaI site in exon 6 and changed a conserved amino acid residue, Arg296, to Cys296. The risk factor for the mutant homozygote was 5.56 (95% CI, 1.30–23.82). These authors suggest that the HhaI polymorphism in the CYP2D6 gene is a part of the molecular basis of Parkinson’s disease. It will be interesting to see if patients with PD who develop motor worsening with SSRIs have this genetic mutation. Finally, an alternative but rather simplistic explanation must not be overlooked in PD patients on antidepressants who experience worsening of motor symptoms. It is well known that about a third of patients with PD have a prolonged prodrome with depression lasting several years. Administration of SSRIs in these patients could theoretically coincide with the appearance of parkinsonian motor symptoms in a small number of PD patients. This theory is supported by the fact that in the majority of PD patients, SSRIs do not worsen the motor symptoms. Tics and Tourette’s Syndrome Antidepressants have been used extensively to treat the obsessive-compulsive symptoms in patients with Tourette’s syndrome (TS). Although imipramine and desipramine have been used previously, it is widely acknowledged that the SSRIs are the most effective drugs for the treatment of obsessive-compulsive symptoms

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in TS [99,100]. An open-label study of paroxetine in 45 patients with TS and episodes of rage found the drug effective in controlling these episodes [101]. Patients continued other concomitant medications, and there were no reports of increase in tic frequency or severity. A 16-year-old girl with TS who had discontinued methylphenidate 2 years previously and was then started on sertraline developed continuous generalized motor and phonic tics. The tics resolved over 6 weeks after sertraline was discontinued; rechallenge was not attempted [102]. Kurlan and colleagues carried out a double-blind, randomized, parallel-group study of fluoxetine versus placebo in 11 children with TS and obsessive-compulsive symptoms [103]. The treatment period lasted 4 months. No significant differences between treatment groups were observed for measures of obsessive-compulsive symptoms. They noted some improvement in with obsessive-compulsive symptoms, attention deficits, and also tics, but acknowledged that the sample size was small. Another double-blind, placebo-controlled study of 14 subjects with TS determined that fluoxetine had no significant effect on tic symptoms [104]. A TS patient with worsening onychophagia (nail-biting tics) secondary to fluoxetine has been reported [105]. The symptoms promptly resolved following discontinuation of fluoxetine; rechallenge was not attempted. Another TS patient who developed a frontal lobe syndrome following treatment with fluvoxamine has also been described [106]. However, sulpiride had been prescribed previously, and the symptoms did not recur following reinitiation of therapy with both drugs. There are also a few case reports of worsening of tics with SSRIs in patients with depression who do not have TS. A drug-naive 12-year-old boy who developed multiple tics (eye blinks, shoulder hunching, and rhythmic abdominal tightening) on fluoxetine has been reported [107]. The tics appeared about 8 months after fluoxetine was started and abated 2 months after fluoxetine was discontinued. Two cases of eye tics have been reported in the context of fluoxetine therapy [108]. One of the patients was taking oral contraceptives as sole therapy, and the other was receiving trazodone and lithium as well. Bruxism is discussed here, although some would argue that it is a form of dystonia and others may even consider it to be a form of akathisia. However, it can be voluntarily suppressed and may be an abnormal behavioral response similar to a motor tic. It is often a nocturnal phenomenon and occurs in both REM and non-REM sleep, but may also occur in the wakeful state under conditions of psychological stress. Bruxism has been noted in patients taking SSRIs. One paper describes 4 patients, recently started on the SSRI sertraline, who presented with new-onset complaints attributable to SSRI-induced bruxism [109]. All 4 responded to adjunctive therapy with buspirone, a serotonin-1A (5-HT1A) receptor agonist, with relief of bruxism and associated symptoms. The authors hypothesize that buspirone acts not only postsynaptically in the extrapyramidal system, but also presynaptically on serotonergic neurons that influence masticatory modulation in the mesocortical tract. SSRIs may increase extrapyramidal serotonin levels,

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thereby inhibiting dopaminergic pathways controlling movement. Previous reports have emphasized buspirone’s postsynaptic dopaminergic effect as a partial antidote to the suppressed dopamine levels. Buspirone may act as a full agonist at the presynaptic 5-HT1A somatodendritic receptors located on the cell bodies of raphe serotonergic neurons that project to the ventral tegmental area (VTA) of the midbrain. These serotonergic neurons modulate the firing of the mesocortical tract, which itself projects from the VTA to the prefrontal cortex and acts on masticatory muscle activity through inhibiting spontaneous movements such as bruxism [109]. Another case report describes improvement in venlafaxine-induced bruxism with gabapentin [110]. Paroxetine-induced bruxism has also been successfully treated with buspirone [111] as have other cases of bruxism induced by SSRIs [112]. Huntington’s Disease The SSRIs have also been shown to be effective in treating the depression and obsessive behaviors in Huntington’s disease (HD). In a randomized, double-blind, placebo-controlled trial of this fluoxetine in nondepressed HD patients [113], 30 patients with early HD who were not depressed were randomized to placebo or 20 mg/day fluoxetine and were followed up for 4 months. The fluoxetine group showed a subjective improvement in functional level and mood, but there was no change in the motor examination. The authors noted that fluoxetine may be a useful antidepressant in depressed HD patients, but failed to exert substantial clinical benefits in nondepressed HD patients. Interestingly, 3 patients were maintained on neuroleptic medications throughout the study. There were no significant differences in the two groups. Measures studied included the total functional capacity (TFC) score, with motor ratings evaluating eye movements, dystonia, resting and maximum chorea, finger tapping, and cerebellar function. As in the case of PD, patients with HD appear to tolerate SSRIs well, without significant changes in motor function. Essential Tremor There are no specific instances of the SSRIs improving or worsening essential tremor. A recent report of mirtazapine improving two cases of essential tremor [114] has been published but needs to be verified by larger controlled studies. In an older double-blind, placebo-controlled study, Koller [115] studied the effects of trazodone on essential tremor and did not find any significant benefit. The authors concluded that serotonergic mechanisms probably do not play a role in the pathogenesis of essential tremor. CONCLUSIONS Overall, the newer SSRIs appear to have a good safety profile and do not appear to cause adverse effects in the vast majority of patients. This is in marked contrast

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to the neuroleptic or antipsychotic agents that are commonly associated with a variety of movement disorders. The movement disorders induced by the older tricyclic and newer SSRIs are commonly caused by pharmacokinetic drug interactions, some of which occur in the context of a deficiency in the cytochrome P450 enzyme system. Some of these enzyme deficiencies are genetically determined. Any movement disorder occurring in the context of antidepressant drug therapy must be critically assessed. Concomitant and previous medications must be reviewed. It is of utmost importance to determine if the patient is ‘‘neuroleptic naive’’ or whether dopamine-blocking drugs have been prescribed at any time. There is a growing body of evidence that indicates that there may be a ‘‘priming effect’’ from neuroleptic drugs, at least in animal studies. Finally, one has to be aware of the serotonin syndrome and its varied presentations in the context of the SSRIs. With the development of newer antidepressants it is possible that some of these adverse effects will be minimized. REFERENCES 1. Lapierre YD, Anderson K. Dyskinesia associated with amoxapine antidepressant therapy: a case report. Am J Psychiatry 1983; 140:493–494. 2. Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 1992; 13:346–352. 3. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6:1–42. 4. Kroemer HK, Eichelbaum M. ‘‘It’s the genes, stupid.’’ Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci 1995; 56: 2285–2298. 5. Otton SV, Inaba T, Kalow W. Competitive inhibition of sparteine oxidation in human liver by beta-adrenoceptor antagonists and other cardiovascular drugs. Life Sci 1984; 34:73–80. 6. Richelson E. Pharmacology of antidepressants—characteristics of the ideal drug. Mayo Clin Proc 1994; 69:1069–1081. 7. Oates JA, Sjoerdsma A. Neurologic effects of trytophan in patients receiving a monoamine oxidase inhibitor. Neurology 1960; 10:1076–1078. 8. Mitchell RS. Fatal toxic encephalitis occurring during iproniazid therapy in pulmonary tuberculosis. Ann Intern Med 1955; 42:417–424. 9. Bodner RA, Lynch T, Lewis L, Kahn D. Serotonin syndrome. Neurology 1995; 45:219–223. 10. Brennan D, MacManus M, Howe J, McLoughlin J. ‘Neuroleptic malignant syndrome’ without neuroleptics. Br J Psychiatry 1988; 152:578–579. 11. Kline SS, Mauro LS, Scala-Barnett LS, Scala-Barnett DM, Zick D. Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharm 1989; 8:510–514.

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53. Kronfol Z, Greden JF, Zis AP. Imipramine-induced tremor: effects of a beta-adrenergic blocking agent. J Clin Psychiatry 1983; 44:225–226. 54. Reccoppa L, Welch WA, Ware MR. Acute dystonia and fluoxetine. J Clin Psychiatry 1990; 51:487. 55. Black B, Uhde TW. Acute dystonia and fluoxetine. J Clin Psychiatry 1992; 53: 327. 56. Stoukides JA, Stoukides CA. Extrapyramidal symptoms upon discontinuation of fluoxetine. Am J Psychiatry 1991; 148:1263. 57. George MS, Trimble MR. Dystonic reaction associated with fluvoxamine. J Clin Psychopharmacol 1993; 13:220–221. 58. Shihabuddin L, Rapport D. Sertraline and extrapyramidal side effects. Am J Psychiatry 1994; 151:288. 59. Dave M. Fluoxetine-associated dystonia. Am J Psychiatry 1994; 151:149. 60. Al-Adwani A. Brain damage and tardive dyskinesia. Br J Psychiatry 1995; 167: 410–411. 61. Poyurovsky M, Schneidman M, Weizman A. Successful treatment of fluoxetineinduced dystonia with low-dose mianserin. Move Disord 1997; 12:1102–1105. 62. Lu R, Hurley AD, Gourley M. Dystonia induced by mirtazapine. J Clin Psychiatry 2002; 63:452–453. 63. Mathen D, Marsden CD, Bhatia KP. SSRI-induced reversal of levodopa benefit in two patients with dopa-responsive dystonia. Move Disord 1999; 14:874–876. 64. Lipinski JF, Mallya G, Zimmerman P, Pope HG. Fluoxetine induced akathisia: clinical and theoretical implications. J Clin Psychiatry 1989; 50:339–342. 65. Baldessarini RJ, Marsh E. Fluoxetine and side effects. Arch Gen Psychiatry 1990; 47:191–192. 66. Faherty CJ, Earley B, Leonard BE. Behavioural effects of selective serotonin reuptake inhibitors following direct micro injection into the left red nucleus of the rat. J Psychopharmacol 1997; 11:53–58. 67. Faherty CJ, Harkin AJ, Leonard BE. The functional sensitisation of sigma receptors following chronic selective serotonin reuptake inhibitor treatment. Eur J Pharmacol 1998; 346:15–21. 68. Budman CL, Bruun RD. Persistent dyskinesia in a patient receiving fluoxetine (letter). Am J Psychiatry 1991; 148:1403. 69. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992; 34:262–265. 70. Tsuneoka Y, Matsuo Y, Iwahashi K, Takeuchi H, Ichikawa Y. A novel cytochrome P-450IID6 mutant gene associated with Parkinson’s disease. J Biochem (Tokyo) 1993; 114:263–266. 71. Fann WE, Sullivan JL, Richman BW. Dyskinesias associated with tricyclic antidepressants. Br J Psychiatry 1976; 128:490–493. 72. Sedivec V, Valenova Z, Paceltova L. Persistent extrapyramidal oral dyskinesias following treatment with thymoleptics. Act Nerv Super 1970; 12:67–68. 73. Dekret JJ, Maany I, Ramsey TA, Mendels J. A case of oral dyskinesia associated with imipramine treatment. Am J Psychiatry 1977; 134:1297–1298.

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74. Woogen S, Graham J, Angrist B. A tardive dyskinesia-like syndrome after amitriptyline treatment. J Clin Psychopharmacol 1981; 1:34–36. 75. Sandler NH. Tardive dyskinesia associated with fluoxetine. J Clin Psychiatry 1996; 57:91. 76. Fox GC, Ebeid S, Vincenti G. Paroxetine-induced chorea. Br J Psychiatry 1997; 170:193–194. 77. Burks JS, Walker JE, Rumack BH, Ott JE. Tricyclic antidepressant poisoning. Reversal of coma, choreoathetosis, and myoclonus by physostigmine. JAMA 1974; 230:1405–1407. 78. Noble J, Matthew H. Acute poisoning by tricyclic antidepressants: clinical features and management of 100 patients. Clin Toxicol 1969; 2:403–421. 79. Garvey MJ, Tollefson GD. Occurrence of myoclonus in patients treated with cyclic antidepressants. Arch Gen Psychiatry 1987; 44:269–272. 80. Baldassano CF, Truman CJ, Nierenberg A, Ghaemi SN, Sachs GS. Akathisia: a review and case report following paroxetine treatment. Compr Psychiatry 1996; 37:122–124. 81. Adler LA, Angrist BM. Paroxetine and akathisia. Biol Psychiatry 1995; 37: 336–337. 82. LaPorta LD. Sertraline-induced akathisia. J Clin Psychopharmacol 1993; 13: 219–220. 83. Klee B, Kronig MH. Case report of probable sertraline-induced akathisia. Am J Psychiatry 1993; 150:986–987. 84. Poyurovsky M, Meerovich I, Weizman A. Beneficial effect of low-dose mianserin on fluvoxamine-induced akathisia in an obsessive-compulsive patient. Int Clin Psychopharmacol 1995; 10:111–114. 85. Lipinski JF, Mallya G, Zimmerman P, Pope HG. Fluoxetine-induced akathisia: clinical and theoretical implications. J Clin Psychiatry 1989; 50:339–342. 86. Baldwin D, Fineberg N, Montgomery S. Fluoxetine, fluvoxamine and extrapyramidal tract disorders. Int Clin Psychopharmacol 1991; 6:51–58. 87. Fallon BA, Liebowitz MR. Fluoxetine and extrapyramidal symptoms in CNS lupus. J Clin Psychopharmacol 1991; 11:147–148. 88. Fleischhacker WW. Propanolol for fluoxetine-induced akathisia. Biol Psychiatry 1991; 30:531–532. 89. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991; 52:491–493. 90. Hamilton MS, Opler LA. Akathisia, suicidality, and fluoxetine. J Clin Psychiatry 1992; 53:401–406. 91. Wirshing WC, Van Putten T, Rosenberg J, Marder S, Ames D, Hicks-Gray T. Fluoxetine, akathisia, and suicidality: is there a causal connection. Arch Gen Psychiatry 1992; 49:580–581. 92. Lavin MR, Mendelowitz A, Block SH. Adverse reaction to high-dose fluoxetine. J Clin Psychopharmacol 1993; 13:452–453. 93. Gammon GD, Hansen C. A case of akinesia induced by amoxapine. Am J Psychiatry 1984; 141:283–284. 94. Steur EN. Increase of Parkinson disability after fluoxetine medication. Neurology 1993; 43:211–213.

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fluoxetine in nondepressed patients with Huntington’s disease. Move Disord 1997; 12:397–401. 114. Pact V, Giduz T. Mirtazapine treats resting tremor, essential tremor, and levodopainduced dyskinesias. Neurology 1999; 53:1154. 115. Koller WC. Trazodone in essential tremor. Probe of serotoninergic mechanisms. Clin Neuropharmacol 1989; 12:134–137.

12 Involuntary Movements Caused by Levodopa Peter A. LeWitt Wayne State University School of Medicine Southfield, Michigan, U.S.A.

Dragos Mihaila Henry Ford Hospital Detroit, Michigan, U.S.A.

BACKGROUND In Parkinson’s disease (PD), the occurrence of dyskinesias represents interplay between disease and treatment. Dyskinesias can be defined as involuntary, patterned movements affecting any part of the body. They often have a torsional or fidgeting quality. The term chorea pertains to the dancing-like quality of these involuntary movements, while athetosis refers to twisting movements along the axis of a limb. Sustained and abnormal postures characterize dystonia. Dyskinesia is a more general term that can describe each of these and sometimes more unusual types of motions, as will be discussed below. PD’s primary identity is that of diminished speed and dexterity of volitional movements. In PD, the only involuntary movements encountered in the unmedicated disorder are tremor (usually occurring at rest or with position maintenance), and dystonic posturing (especially equinovarus positions of the feet). Sometimes PD patients experience an internal sense of tremor and can respond to restless feelings by carrying out stereotyped movements such as pacing or rocking the legs. The movements made 259

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in response to such sensations (akathisia) can be suppressed, since they are voluntary in origin. In addition to long-term relief of all parkinsonian features, the chronic use of levodopa (LD) is prone to generate dyskinesias in the PD patient. This outcome affects a significant number of patients after years of therapy for its development. Other bradykinetic disorders that can respond to LD, such as neurological disease with acanthocytosis, and neuroleptic-induced parkinsonism, generally do not exhibit dyskinesias from LD. However, patients with multiple system atrophy treated with levodopa may rarely exhibit dyskinesias, primarily facial. In contrast, the occurrence of involuntary movements in the LD-treated idiopathic PD patient is a relatively common outcome. Although other forms of dopaminergic therapy can exacerbate dyskinesias in PD, their initiation appears to be specific to the chronic use of LD. This report provides an overview of the extensive literature and research regarding the origin and phenomenology of LD-induced dyskinesias in PD. The several options for management of this problem are also discussed. The history of LD-induced movements began shortly after the introduction of LD in the late 1960s. In addition to enacting a dramatic reversal of parkinsonism, LD was observed occasionally to cause stereotyped choreic movements [1]. In some instance, these movements began to occur within months of starting the drug, although more commonly dyskinesias evolved only after a year or more of treatment. Some early reports of these idiosyncratic effects of LD attributed them to a state of restlessness. The choreiform nature of these movements was clearly described and on this basis was thought to implicate the extrapyramidal system. Another clue as to the relationship of these movements with LD therapy was their timing, which tended to coincide with the onset of antiparkinsonian benefit produced by each dose of LD. The phenomenology of LD-induced movements bore some resemblance to tardive dyskinesia, another disorder that in the early 1970s was becoming increasingly recognized as an outcome of chronic dopamine-blocking agent use [2,3]. Often, the occurrence of dyskinesias after chronic LD use occurred in concert with other problems in control of parkinsonism, such as fluctuations in mobility [4]. The possible link to the severity of the dopaminergic lesion in PD was emphasized by observations that dyskinesias tended to appear first in parts of the body more affected with parkinsonism [5]. Early on, it was recognized that the use of LD for symptomatic relief of other movement disorders, such as Huntington’s and Wilson’s diseases, could exacerbate preexisting dyskinetic movements [6]. In situations of chronic LD use by nonparkinsonian individuals, they seemed to be spared the development of these involuntary movements. For example, persons with essential tremor and mistakenly treated with LD for more than two decades did not experience dyskinesias [7]. Similarly, patients with restless legs syndrome treated with LD do not develop dyskinesias. Other reports in the medical literature have demonstrated other instances in which long-term use of LD did not result in dyskinesias. A trial

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in which daily administration LD to normal elderly individuals was conducted for experimental purposes did not induce involuntary movements (or any changes in motor performance, for that matter) [8]. These findings contrast to the common occurrence of dyskinesias in many PD patients even a few years of LD therapy. LD-induced dyskinesias can add to the range of disabilities experienced by PD patients [9]. These movements can range in severity from virtually undetectable to highly disturbing gyrations of the entire body. In general, the circumstances that lead some patients to be affected (and others to be spared) are not fully understood. However, their relationship to LD exposure is underscored by an increased prevalence as a function of length of duration or higher daily intake. Whether severity of the disease is, by itself, a risk factor for occurrence of dyskinesias is not known, since virtually all PD patients will ultimately receive LD. The relationship between PD severity and risk for dyskinesia is not possible to explore currently, since most patients receive this drug before much disability evolves. The opportunity to observe such a relationship may have been present when LD was first introduced more than 30 years ago. Unfortunately, the first experiences of treating PD patients with LD did not provide insight into correlations between the risk for developing dyskinesias and either the severity or duration of parkinsonism. When LD first became available, a diversity of PD patients started to receive the drug at the same time. If either the severity or the duration of parkinsonism were factors increasing the likelihood for developing dyskinesias, it seems likely that such factors would have been recognized at the time. However, neither the medical reports of the period nor the memories of clinicians treating PD patients at that time have provided much insight into these questions. Nonetheless, a consensus view for many years has been that the dose and duration of exposure to LD are major determinants of dyskinesias. Other evidence suggests that the severity of parkinsonism (a correlate of substantia nigra neuronal dropout) adds to the risk for occurrence of dyskinesias. This was illustrated in a group of persons who became severely parkinsonian after exposure to the neurotoxin 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant in a synthetic narcotic. Following the start of LD treatment at conventional doses, several of these MPTPparkinsonians developed dyskinesias within several weeks [10]. Other studies in animal models of Parkinsonism induced by MPTP, as discussed below, have further supported the link between striatal dopaminergic deficit and the risk for dyskinesias. One unmistakable trend is the cumulative increase of dyskinesias after sustained use of LD [11]. Prevalence studies have shown that treatment for 3 or more years leads to involvement of more than half of all parkinsonians [12]. A retrospective analysis of 100 consecutive patients with dyskinesias in a PD clinic population was conducted to identify risk factors for the development of dyskinesias [13]. This group had received LD for 1–18 years. After a mean of 2.9 years, 56% of patients had developed one or more manifestations of dyskinesia. Though dyskinetic patients tended to be younger, the duration between start of LD and

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onset of dyskinesias did not change as a function of age. The cumulative dose of LD did not discriminate between those patients who developed or did not develop dyskinesias, though patients with involuntary movements tended to be receiving higher LD doses than those spared dyskinesias. Delaying the initiation of levodopa therapy for more than 3 years after the onset of PD did not increase the probability for developing dyskinesia, nor did the use of LD in bilaterally affected patients as compared to unilateral involvement. The search for other pertinent clinical features has revealed only a few additional factors linked to dyskinesia risk. In an analysis of 98 patients treated with LD for 5 years, for example, two factors associated with the development of dyskinesia were female gender and the lack or only minimal occurrence of resting tremor [12]. In the latter study, younger age did not appear to correlate with risk for dyskinesia. Since dyskinesia requires LD both for its causation and expression, studies of prevalence may underestimate how often dyskinesia is caused by LD. For example, patients are often unaware of mild, unobtrusive involuntary movements and so may tend to ignore their occurrence in reports to physicians (who, in turn, may miss opportunities to observe dyskinesias during brief office visits). Dyskinesias will not be observed if the dose of LD is insufficient for their expression. Unmasking latent LD-induced dyskinesias requires a dose greater than some PD patients are receiving on a daily basis. To determine the true prevalence of dyskinesias might require PD patients temporarily to receive larger doses of LD for test purposes. If the management of parkinsonian disabilities does not require LD intake exceeding the threshold for bringing out dyskinesias, the opportunity for a patient to unmask involuntary movements may never happen. Pertinent to this matter is the experience of administering LD to persons at risk for Huntington’s disease [14]. At the time, it was postulated that a LD, by unmasking a latent tendency for choreic movements, might help in determination of those individuals carrying the gene for Huntington’s disease. The trial involved subjects who did not spontaneously manifest chorea or other features of neurological impairment. Although this pharmacological challenge induced choreic movements in some of the at-risk subjects, the test proved to be unreliable for diagnosing Huntington’s disease. It is not known if PD patients predisposed for developing LD-induced dyskinesias could have this tendency unmasked by earlier challenges with large doses of LD. The problem of LD-induced dyskinesias is a topic of active research and several options for therapy are available, as discussed below. The clinical study of LD-induced dyskinesias has been aided by the development of rating scales that can be used to gauge the severity and other features of these involuntary movements [15]. Neuroimaging techniques in dyskinetic patients have been used to explore the topography of brain activation during involuntary movements. Using H215O-positron emission tomography (PET), comparison of patients with and without limb dyskinesia has revealed patterns of regional cerebral activation

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during predictable occurrences of the involuntary movements [16]. In the latter studies, increased metabolic activity was evident in the lentiform nuclei as well as dorsal prefrontal, premotor, and motor cortex. Other PET analyses of dyskinesias have revealed no distinctive pattern of dopamine receptor subtypes distinguishing dyskinetic and nondyskinetic PD patients [17]. Clinical electrophysiological studies have not been revealing as to the possible mechanisms underlying LD-induced dyskinesias [18]. CLINICAL FEATURES OF DYSKINESIAS IN PARKINSON’S DISEASE Dyskinesias can take several forms. The most common are choreic or athetotic, involving any part(s) of the body. Most commonly, the face, neck, shoulders, or arms are involved. As in Huntington’s disease or tardive dyskinesia, the involuntary movements tend to be irregular and uncoordinated, but sometimes they can be incorporated into seemingly purposeful actions. Dyskinesias may be intermittent or near continuous. Observation of the movements over time may reveal a stereotyped quality of consistent involvement of the same body parts, and other characteristics, such as torsional or hyperextended posturing may be prominent features. LD-induced dyskinesias usually can be differentiated from tremors or dystonic postures that also may develop in Parkinsonian patients, although these movement disorders can occasionally coincide. Sometimes the involuntary movements are not observed when the subject is at rest. Their onset or increase during actions such as walking or speech may suggest their relationship to an ‘‘overflow’’ from activation of the volitional motor system. In general, the features of LDinduced dyskinesias are quite uniform from day to day. Rarely, patients experience prominent dyskinetic or dystonic symptoms only in the evening hours despite intake of comparable amounts of LD during the day. Evidence from studying such patients suggests that they represent a variant of the ‘‘diphasic’’ pattern of response to LD, as described below [19]. Dyskinesias bear a close relationship to dystonic phenomenology. Sometimes they develop at sites that were dystonic prior to the start of LD, such as the foot on the side where parkinsonism develops [20]. When patients have asymmetrical severity of parkinsonism, the side of predominance for dyskinesia is generally on the side either with greater clinical signs or else an earlier onset of parkinsonism. However, dyskinesias can also develop on a side of the body with less Parkinsonism or in limbs unaffected with parkinsonian features. Normal individuals receiving relatively high doses of LD do not develop dyskinesias. The same is true for mildly affected parkinsonians treated for the first time with LD. Exceptional patients have been encountered who manifest dyskinesias at the onset of treatment with LD. In one report, a patient experienced severe choreic movements immediately following ingestion of LD, which was taken at a dose

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below the threshold for achieving any relief of his parkinsonian symptoms [21]. Repeated trials of single LD doses over several years led to the same result. For this patient, a high-dose regimen of bromocriptine as an alternative to LD provided good control of parkinsonism without the type of dyskinesias occurring with LD. Grimacing, orofacial lingual movements, respiratory muscle involvement, or more complex patterns of involuntary movements can be manifestations of dyskinesia. Among the more grotesque types of LD-induced movements are repetitive gasping or moaning, ballistic limb movements, a ‘‘Minister of Silly Walks’’type gait, or a truncal rocking that can be misinterpreted for astasia-abasia. Movements can be severe enough to cause orthopedic problems such as shoulder dislocation [22]. Involuntary movements can cause an upset of the center of gravity, providing the basis for falling even if the patient lacks a primary deficit in balance mechanisms. Other movement disorders can coexist with LD-induced dyskinesia, including the rare occurrence of myoclonus, exacerbation of resting or action tremor, or akathisia. The latter condition, a fairly common feature observed both in unmedicated and treated parkinsonism, can cause the patient to pace, cross legs, tap limbs, and engage in other activities that, while stereotyped, differ from dyskinesia in that they are volitional. Tic-like movements are sometimes included on lists of LD induced movement disorders. Careful analysis of dyskinesias usually shows that tics are not an outcome of dopaminergic stimulation in treating parkinsonism, although oculogyric-like eye movements can coincide with limb dyskinesias [23]. The temporal pattern of dyskinesias can help in their classification and, to some extent, understanding of mechanisms. The most common is peak-effect dyskinesias, occurring only when dopaminergic stimulation is at its maximum. The peripheral pharmacokinetics of LD is such that the greatest CNS actions of an oral carbidopa/LD dose will be experienced between 15 and 45 min after ingestion. Since the half-life of conventional carbidopa/LD preparations is between 2.5 and 3.5 hr, the extent of peak-effect dyskinesia is usually shorter than this interval. Multiple dosing with LD during the day can result in the gradual accumulation of the drug and rising plasma concentration; hence, afternoons and evenings might be times of greater intensity or duration of peak-effect dyskinesias. The occurrence of peak-effect dyskinesias coincides with the maximal anti-parkinsonian effect. Such a pattern may not be evident in those individuals whose sensitivity to the drug is such that they are always dyskinetic when ‘‘on.’’ In this situation, the threshold at which involuntary movements are initiated is the same (or even lower) than the LD level needed for improvement of parkinsonism [11,24]. Another pattern, diphasic dyskinesia has a different chronology with respect to the pharmacokinetic profile of LD. This disorder is often a frustrating management challenge for clinicians and patients. Diphasic dyskinesia originally described as the ‘‘dystonia (or dyskinesia)– improvement–dystonia (or dyskinesia)’’

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type [25–27], is less common than peak-effect dyskinesias and harder to conceptualize as to its mechanism. In contrast to the situation in which dyskinesias are initiated when dopaminergic stimulation is at its peak, diphasic dyskinesias are elicited only when dopaminergic stimulation is in flux (either rising or falling). Choreic or dystonic movements are generally experienced within 10 min after oral ingestion of conventional carbidopa/LD. The timing of this event thus is tends to be in the mid-portion of a rising plasma LD concentration, rather than at its peak (at which time dyskinesias do not occur). The recurrence of dyskinesia or dystonia movements 3 hr or more after ingestion of LD is not just an exacerbation of the parkinsonian rigid state (the ‘‘wearing-off’’ effect); at such times, patients can exhibit choreic movements just as prominent as when the blood concentrations of the drug were on the rise. Patients affected with diphasic dyskinesia can be subject to bizarre gait disturbances or ballistic movements of the limbs at times of dose onset and offset. Diphasic dyskinesia often arises in individuals with young-onset parkinsonism treated with LD for only a few years. In some persons experiencing diphasic dyskinesias, a variation of this condition is the occurrence of dyskinesia during the rise of LD blood concentrations but sometimes-painful dystonic reactions occurring as LD’s effects wear off 2–3 hr later. The absence of dyskinesia during the period of maximal LD action suggests that the mechanism responsible for the initiation of involuntary movements is different that initiating peak-effect dyskinesias. CONSIDERATIONS AS TO THE ETIOLOGY OF LEVODOPAINDUCED DYSKINESIAS The pathogenesis of dyskinesia has proven to be complex and difficult to study [11,27,28]. Several experimental methods (including treatment with reserpine, 6hydroxydopamine, dopamine-blocking drugs, and MPTP) have been utilized to simulate the disorder in animals [29]. Severe lesioning of the dopaminergic outflow pathway from the substantia nigra appeared to be a prerequisite for the ability of LD to induce dyskinesias [30]. Until recently, a number of studies reported that, in nonhuman primates lacking parkinsonism, dyskinesias could not be produced from LD exposure [31–33]. These conclusions have been challenged by recent work showing that typical dyskinesias could be induced in nonparkinsonian cynomolgus monkeys [34]. The involuntary movements occurred in 75% of monkeys given high doses of LD (up to 80 mg/kg daily for 3 months) but were not observed after exposure to lower-dose regimens (20- and 40-mg/kg daily). Substantially lower daily doses and shorter periods of LD exposure produce dyskinesias in monkeys rendered parkinsonian by neurotoxin lesioning of the substantia nigra. The doses of LD necessary for producing dyskinesias in MPTP-treated monkeys, for example, correspond to the per-kilogram daily doses

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of LD used in humans to treat PD [35,36]. The dyskinetic movements in the monkeys tended to occur after shorter periods of exposure than are typically necessary to induce dyskinesias in PD patients. In general, animal models do not offer a complete rendition of the most common outcomes from chronic LD treatment in PD. Some studies have indicated that chronic dopaminergic stimulation, whether from dopamine or other agonists, results in a supersensitivity of dopaminergic receptors [37]. As mentioned above, dyskinesias typical of those seen from LD stimulation in PD can be produced in nonhuman primates rendered parkinsonian by pharmacological means. After administration of MPTP (which produce highly selective damage to nigrostriatal dopaminergic pathways and thereby simulates all the motor features of PD), dyskinesia almost always develops when LD is used on a sustained basis. Investigations employing selective dopaminergic agonists have shown that stimulation of D2 receptors is responsible for generating involuntary movements [37]. Stimulation of the D1 class of dopamine receptors seems to facilitate LD-induced dyskinesias [34], although the role of this system is complex and repeated D1 stimulation appears to confer a tolerance phenomenon that can also abolish dyskinesias [38]. Studies using a kainic acid-induced model of choreic movements in the monkey have suggested that the mechanism of choreic movements has a contribution from presynaptic activation of the nigrostriatal dopaminergic pathways beyond any postsynaptic effects [39]. Studied in the MPTP-lesioned primate have provided several important insights. Although the D1 dopamine receptor predominates in the striatum, its role in the mediation of dyskinesia (or, for that matter, control of parkinsonism) is not known. Studies carried out with monkeys rendered Parkinsonian with MPTP have shown that sensitization of striatal D2 receptors is all that is necessary to initiate LD-induced dyskinesias, although stimulation of the D1 receptor may have a synergistic contribution. Using a novel D1-selective agonist, A-77636, it was possible to evaluate the contribution of D1 dopaminergic mechanisms on the promotion of LD-induced dyskinesias [40]. Challenges with A-77636 were effective at reversing the parkinsonian state but less potent than a selective D2 agonist at initiating dyskinesias. The relationship between higher-order dopamine receptors and dyskinesias has not been clarified at this time. Clozapine, an atypical antipsychotic drug not acting at striatal D2 receptors but which blocks the D4 receptor, has been shown in clinical trials to lessen dyskinesia as well as dystonia [41–43]. Unlike other antipsychotics, clozapine does not seem to induce or exacerbate parkinsonian features. For this reason, it has been a useful means for eliminating hallucinations in patients needing simultaneous control of parkinsonism. Clozapine has several neuropharmacological actions that differ from other drugs with neuroleptic properties, and it is unclear how this drug can achieve relief of dyskinesia, dystonia, and resting tremor during concomitant use with LD. Its usefulness in treating parkinsonian

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adverse effects such as hallucinations can be augmented by its actions at attenuating motor fluctuations [44]. Clozapine poses a rare but serious risk of producing agranulocytosis acutely. For this reason, blood counts at 1–2-week intervals are mandatory in the United States. The weekly prescription for this drug and the blood testing can make its use an expensive option (even in the 6.25–50-mg/day range in which clozapine usually will achieve its effects against dyskinesias, tremor, or hallucinations). Other neuroleptic medications might be useful for the abolition of dyskinesias. In several European studies, small doses of the substituted benzamide sulpiride have been employed, and for similar purposes a lowpotency neuroleptic, molindone, can be useful in the dose range of 2.5–10 mg/ day. Two newer neuroleptics, risperidone and olanzapine, do not fully possess the ‘‘atypical’’ neuroleptic profile of clozapine, but can be useful for managing dyskinesias. However, each drug tends to exacerbate parkinsonism in the lowest dosing forms available. The neuroleptic quetiapine appears to have fewer propensities for exacerbating parkinsonism and can also suppress dyskinesias. Other neuroleptics are under development that might lack the tendency to exacerbate parkinsonism and so might prove to be useful for management of dyskinesias (if the two properties are not closely linked). In animal investigations, there has been evidence in dopaminergically denervated rodents that several types of motor effects (such as stereotypies and increased motor activity) arise from the use of dopaminergic therapy. In order for facilitation of agonist-induced dyskinesia, most of the presynaptic dopaminergic neurotransmission needs to be depleted (although it is not known whether the dyskinesias can be explained fully by the resultant postsynaptic supersensitivity). Furthermore, the pharmacological experience in animals does not explain why the occurrence of dyskinesias in humans is sporadic and develops only after months to years of LD treatment. Other lines of animal research have explored the possibility that it is not just the category of dopaminergic stimulation but rather the temporal pattern of stimulation that facilitates dyskinesia [45]. In the rat brain, surges of dopaminergic stimulation result in different patterns of dopaminergic response than occurs from continuous stimulation. Similar findings have come from studies in the MPTPlesioned primate. Pulsatile administration of a selective D2 dopamine receptor agonist, U-91356A, to 3 MPTP-lesioned monkeys led to the development of choreiform movements in all during the first week of treatment. In contrast, continuous delivery of the same drug over 10 days produced transient, minor dyskinesia in only 1 of 3 monkeys. These studied implicate intermittent dosing with dopaminergic agents as a factor in the development of dopaminergically induced dyskinesias [46]. The diphasic dyskinesia pattern occurs in a way to suggest that both the onset and decline of dopaminergic stimulation provides the impetus for stimulation of dyskinesia. In other clinical circumstances, the highest concentrations of

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LD (and, presumably, the dopamine produced from it in the brain) are temporally associated with the occurrence of dyskinesia [11,27]. No alternative compounds other than dopamine have been linked to dyskinesia, although those patients who produce increased amounts of the LD metabolite 3-O-methyldopa in the periphery seems to have a higher risk for occurrence of dyskinesia [47]. The latter observation may merely be the result of larger LD intake producing larger plasma concentrations of 3-O-methyldopa. Clinical experience using the inhibitors of catecholO-methyltransferase, tolcapone and entacapone, have not shown that slowing the clearance of LD helps in managing diphasic dyskinesias. Even though they extend the duration of LD action without increasing peak LD concentration, the COMT inhibitors do not offer improvement in this frustrating variant of LD-related dyskinesias. The nature of the relationship between LD dose and occurrence of dyskinesia has been difficult to explore. Although it suggests that the dose of LD might be the major predisposition for dyskinesia, it could also be coincidental that those individuals who have a more severe disease needing larger doses of LD are at greater risk for occurrence of dyskinesia. Some studies have argued that prescribing LD early in the course of PD (i.e., shortly after the onset of signs and symptoms) does enhance the likelihood of dyskinesias [48]. This topic has been controversial [11,49]. In most viewpoints, a major risk factor for the development of dyskinesia is age. After 3 years of LD treatment in one study, the occurrence of dyskinesias in subjects ⬍40 years of age was more than double the prevalence in older subjects [50]. Another analysis of a 194-patient cohort found that age of onset for PD was the major factor predicting risk for dyskinesias as well as other types of response fluctuations [51]. In addition to typical choreic movements, dystonia is more common in the young-onset group. These spasms may have predated the onset of dyskinesias or even parkinsonism, but their exacerbation by LD may be revealing a similar mechanism with the dyskinesia that develops only after use of LD. One unanswered question is whether use of LD ‘‘promotes’’ the development of dyskinesias, especially when the degree of parkinsonism is relatively mild. Several studies have given support to the notion that the duration and dose of LD treatment are the major factors in the occurrence of dyskinesias. This view has been disputed in some reviews of cases, and the problem may be multifactorial, in that the amount of drug given per dose may also be a relevant factor. Several clinical studies have investigated the effect of using constant intravenous infusions of levodopa with respect to the severity of dyskinesias. In one, there was no change in the severity of dyskinesia during several days of constantrate levodopa infusion [52]. Another found that 1–2 days of continuous infusion of LD lessened the intensity of dyskinesias by shifting the dose–response curve to the right (i.e., lowering the intensity of response at any particular rate of LD delivery). There was not a similar effect with respect to relieving features of

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parkinsonism in these experiments [53]. While there may be other interpretations to the author’s conclusions that tolerance to continuous dopaminergic stimulation might develop, this observation gives a rationale to the use of continuous dopaminergic stimulation, as can be achieved with the use of certain direct-acting agonists with long pharmacological half-lives such as cabergoline. The MPTP-treated marmoset can be ‘‘primed’’ by repeated levodopa treatment to manifest dyskinesias. Whereas dopamine agonists used alone in the MPTP monkey rarely produce dyskinesias, they readily do so after the animal has been pretreated with LD. The role of ‘‘priming’’ in humans remains unclear. Studies with ropinirole showed that this nonergot dopaminergic agonist has shown a very low propensity to induce dyskinesia, in comparison to other agonists studied [54]. However, the relevance of this study to human experience has not been verified. MANAGEMENT OF LEVODOPA-INDUCED DYSKINESIAS Not all patients who exhibit dyskinesias experience discomfort or disability. Since the occurrence of such involuntary movements is often regarded as the ‘‘price that needs to be paid’’ for the long-term use of LD, many clinicians do not modify their use of LD with respect to the risk for causing dyskinesias. Apart from younger age, there do not appear to be strongly predictive characteristics of other patients who will develop dyskinesias. There have been clues to suggest that regimens with less abrupt rise and fall of dopaminergic stimulation might lead to more favorable outcomes with respect to the occurrence of dyskinesias and other problems of motor fluctuation after chronic LD treatment. A 5-year study comparing the long-term outcomes of immediate-release carbidopa/LD (Sinemet 25/100) with Sinemet CR 50/200 was recently completed. The results showed that either dyskinesia or wearing-off occurred in 21% of patients, regardless of which carbidopa/LD preparation was used [55]. In this study of 618 patients, the rate of developing dyskinesias at 5 years was 20.6% of the immediate-release carbidopa/levodopa treatment group and 21.8% of the Sinemet CR group. This study demonstrated that the somewhat more sustained plasma LD concentrations, as achieved by Sinemet CR, did not prevent the initiation of dyskinesias for those patients. Observations made in a clinical setting can be puzzling with respect to the occurrence of dyskinesias. For example, in one retrospective study [56], patients treated with LD alone had a lower incidence of dyskinesias after chronic treatment than when an equivalent amount was administered in the form of LD/carbidopa. While alternative factors might better explain this apparent influence of carbidopa on the occurrence of dyskinesias, these observations merit follow-up. Protection against the occurrence of dyskinesias may be afforded by one or more treatment strategies. Several long-term studies with bromocriptine and lisuride (another dopaminergic ergot) indicate that the risk of dyskinesias occur-

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ring with an LD/carbidopa regimen can be substantially reduced. The intriguing (but uncontrolled) studies with lisuride have been carried out for more than 7 years [58]. Monotherapy regimens of the dopaminergic ergots are also unlikely to result in problems of dyskinesia, but their inefficacy at treating parkinsonian disability results in most patients needing supplemental LD within a few years after starting the dopaminergic ergot. The presence of a dopaminergic agonist together with LD-generated dopamine may be useful way to improve the longterm outcome with respect to wearing-off problems as well, and further investigation of these possibilities is needed. In a recent study comparing 5-year outcomes of monotherapy regimens with either carbidopa/LD or ropinirole, the dopaminergic agonist had a greatly reduced risk of inducing dyskinesias [59]. A similar finding came from a 2-year comparison of monotherapy with either LD or pramipexole (CALM-PD study) [57a]. Similar results have been obtained with pergolide. If monotherapy with dopaminergic agonists (or combination of them with levodopa) is convincingly shown to achieve better outcomes with respect to risks for dyskinesia, then these alternatives to levodopa regimens may become more widely used in the future. In some of the studies mentioned above, the adjunctive benefits of using dopaminergic agonists appear to be more than those that would be achieved by a partial substitution of the LD intake. One of the ways that the severity of dyskinesias can be lessened in many patients, however, is to reduce the LD intake while adding a dopaminergic agonist [60]. With reduction of up to one-half the previous LD dosing, the same degree of anti-Parkinsonian control is possible. Usually, such patients do not tolerate decreasing LD intake (in the form of carbidopa/LD) below 300 mg/day. Sometimes, low-dose regimens of dopaminergic agonists can be helpful [61]. Other approaches for decreasing the intensity of involuntary movements include the use of smaller, divided doses. For example, a patient receiving one tablet of carbidopa/LD 25/100 every 4 hr might change to 1/2 tablet at 2-hr intervals. In the afternoons, when there is some cumulative effect from morning doses, the intervals between doses might be increased to lessen a peak-effect dyskinesia. Other patients will use the strategy of taking LD with food, which may slow the rate of drug absorption and, hence, the intensity of the dyskinesias. Sustained-release carbidopa/LD (such as Sinemet CR) is another means by which the pharmacokinetic profile of LD can be tailored to cause less peak-effect dyskinesias. Unfortunately, dyskinesias experienced by many patients are a by-product of the dopaminergic stimulation improving parkinsonism. To reduce the dopaminergic stimulation causing the involuntary movements also takes away from the anti-Parkinsonian actions. In such situations, substitution of a dopamine agonist is one strategy that can help. This appears to be the best option available for those affected with the diphasic dyskinesia pattern, since more frequent dosing or sustained-release preparations of LD seem only to exacerbate this problem.

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The use of clozapine, discussed above, is an option even in patients not experiencing the usual primary indications for this drug (vivid dreams, other sleep disruptions, or hallucinations). Regimens of 6.25–25-mg/day can help to lessen dyskinesias without pharmacologically worsening parkinsonian features. There are few other treatment options for managing dyskinesia. Drug ‘‘holidays’’ are one strategy proposed as a means for lessening a putative supersensitivity responsible for LD-induced dyskinesias. A drug holiday involves abrupt discontinuation of LD for 1–2 weeks, an uncomfortable and potentially hazardous procedure because of the severe immobility and rigidity it may produce. Abrupt withdrawal of antiparkinsonian medication also carries the risk of inducing a potentially life-threatening clinical syndrome highly similar to the neuroleptic malignant syndrome [62]. Drug holidays were claimed to be highly effective in the medical literature of a decade ago, though the benefits of this procedure lasted only a few weeks in some of the longer-term assessments. Today, however, withdrawal of LD as a means for diminishing LD-induced dyskinesias is not regarded as an effective option. However, the concept of lowering LD intake to assess the benefit of less LD is still a good idea to explore with each patient. In some instances, the use of LD for tremor relief has an alternative option such as amantadine or an anticholinergic. Finally, it is important to recognize that many patients with prominent and seemingly uncomfortable dyskinesias are in fact not as disturbed by them as by the problem of being immobile. When given the choice, many patients will opt to have the involuntary movements rather than to take the risks of becoming ‘‘off’’ on a lower-dose regimen of LD intake. Dyskinesias do not inevitably worsen in their severity over time, and so it is not mandatory to seek alternative forms of treatment once they are observed to occur. However, their contribution to the risks of falling (by altering the trunk’s center of gravity), choking (by interfering with smooth deglutition), and incoordination of movement should be carefully assessed. It can be valuable to follow a patient through a cycle of LD effect at the physician’s office in order to observe the severity of dyskinesias at their worst. EXPLORATION OF NONDOPAMINERGIC MECHANISMS While the direct stimulus for LD-induced involuntary movement appears to be via dopamine receptors, motor pathways beyond the striatum may harbor the pathophysiology of dyskinesias. Several recent reports have explored the multiplicity of pathophysiological alterations that might explain changes in the PD patient who experiences these problems [34,63–69]. While there is no consensus as to any single mechanism for the induction of dyskinesias, the effects of intermittent dopaminergic stimulation seem be the means by which LD-induced dyskinesias arise. The brief pulses of dopaminergic stimulation resulting from LD

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administration may be capable of permanent alterations of systems beyond the dopamine receptor and its linked effector systems. There have been few practical applications from explorations of the complex pharmacology linked to striatal dopaminergic pathways [70]. Recently, a low-dose (30–60-mg/day) regimen of propranolol has been advocated as a means for lessening severe LD-induced dyskinesias. This regimen did not benefit dystonia, nor did it affect other features of parkinsonism [71]. Trials of medications increasing cholinergic [72] or GABAergic [73,74] tone have not led to relief of LD-induced dyskinesias. However, an antagonist of the N-methyl-aspartate (NMDA) glutamate receptor subtype, LY235959, has been effective at suppressing dyskinesias in an animal model of LD-induced dyskinesias [75]. Amantadine, which also has the property of glutamate antagonism, can be highly effective at blocking dyskinesias in some (but not all) patients [76]. The potential for opioid antagonists to suppress LD-induced dyskinesias has been proposed on the basis of increased synthesis of the opioid peptides enkephalin and dynorphin after LD treatment in animal models of PD [77]. PET studies using a labeled opioid ligand, 11 C-diphrenorphine, have been carried out in dyskinetic PD patients, who have decreased striatal binding as compared to nondyskinetic patients [78]. While these findings suggest that the pathophysiology of dyskinesia involves enkephalin or endorphin pathways that are ‘‘downstream’’ from striatum, these results have not corresponded to practical applications. Clinical trials of the oral opiate antagonist naltrexone in LD-induced dyskinesia have not shown benefit [79,80]. However, dextromethorphan (an opiate analogue with multiple sites of action) has shown promise in suppressing LD-induced dyskinesias [81], though it can be quite sedating. The MPTP-lesioned monkey with LD-induced dyskinesias has been used to explore other medication approaches to suppression of these involuntary movements [82]. As in the clinical experience mentioned above, propranolol lessened dyskinesias. Benefits were also seen with trials of clonidine, physostigmine, methysergide, 5-MDOT, and MK-801; in some instances, however, these treatments led to a worsening of parkinsonian scores. Other drugs that could dampen dyskinesias included yohimbine and meperidine. The utility of these treatments in human LD-induced dyskinesias in PD remains to be studied. A new class of drugs acting on adenosine receptors is currently undergoing human trials. Antagonists of the A2a adenosine receptor modulate striatal dopaminergic actions, and compounds such as KW-6002 have been shown to offer antiparkinsonian effects in the MPTP-treated monkey independently of dopaminergic stimulation. Of great interest is that even in monkeys previously primed with LD for dyskinesias, KW-6002 administration does not bring out dyskinesias even in doses reversing parkinsonian features [83]. Although antagonism of the A2a adenosine receptor does not appear to block LD-induced dyskinesias, the observations made with KW-6002 offer hope that certain drugs might be able to relieve

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parkinsonism without producing dyskinesias or possibly other undesired dopaminergic actions. Several other nondopaminergic pharmacological concepts have been investigated for their potential in diminishing LD-induced dyskinesias. For example, intraventricular infusion of glial-derived neurotrophic factor (GDNF) to MPTP-lesioned common marmosets resulted in lessening of involuntary movements from LD challenges [34]. The GDNF treatments also lessened motor deficits and appeared to have acted by increasing the amount of tyrosine hydroxylase activity in substantia nigra. Serotonin 5-HT1a agonists show promise in animal models of LD-induced dyskinesias, and this novel approach is being investigated in humans. [84]

NEUROSURGICAL TREATMENT OF LEVODOPA-INDUCED DYSKINESIA Neurosurgical approaches for relief of dyskinesia have been a topic of great interest in recent years [85,86]. The procedure that can be highly effective for lessening tremor or dystonia, ventrolateral thalamotomy, is only rarely helpful for dyskinesia [87–89]. Experience with lesioning or high-frequency stimulation of the globus pallidus interna, in contrast, has indicated great benefit for most patients so treated. In many instances, complete relief of dyskinesias has been achieved contralateral to the side of the lesioning. Sometimes improvement of dyskinesias has also occurred ipsilaterally. The results of pallidotomy, when successful several weeks after the procedure, may remain as a permanent benefit for patients [90]. High-frequency stimulation of the medial globus pallidus (GPi) or the subthalamic nucleus (STN) may offer even greater degrees of improvement [91]. Whereas in GPi stimulation the dyskinesias diminish as a direct result of the stimulation, in STN stimulation the reduction in dyskinesias is primarily a result of LD dose reduction.

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13 Pathophysiology of Levodopa and Dopamine Blocking Agent-Induced Movement Disorders Aninda B. Acharya St. Louis University School of Medicine St. Louis, Missouri, U.S.A.

Cheryl A. Faber Neurology Associates St. Louis, Missouri, U.S.A.

Rajesh Pahwa University of Kansas Medical Center Kansas City, Kansas, U.S.A.

Kapil D. Sethi Medical College of Georgia Augusta, Georgia, U.S.A.

INTRODUCTION Dopamine receptors have long been the target of pharmacological agents. The discovery in the 1950s that the dopamine antagonist chlorpromazine acts as a potent antipsychotic ushered in an age of psychopharmacology. Similarly, the development of the dopamine precursor levodopa (L-dopa) in the 1960s as a therapy for Parkinson’s disease (PD) revolutionized the management of this ill279

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ness. However, shortly after the inception of these drugs it became clear that a significant side effect of these medications is the development of drug-induced movement disorders (DIMD). Movement disorders caused by dopamine antagonists include parkinsonism, tardive dyskinesias, and akathisia. Long-term use of L-dopa results in the development of dyskinesias in a majority of the patients with PD. Even with the advances in our understanding of dopamine metabolism, and basal ganglia (BG) organization, DIMD still presents a serious challenge for the clinician. In some patients DIMD can be more disabling than the symptoms related to the primary illness. The recent thrust of drug development has been to create agents that target one receptor subtype while having limited affinity for others. This trend is most noticeable in the development of recent ‘‘atypical’’ antipsychotics, and the newer dopamine agonists. Recent understanding of the role of the different dopamine receptor subtypes has guided much of this endeavor. The hope is that targeted therapy can treat the illness and avoid the DIMD. Although there are clear gaps in our understanding, contemporary models of BG anatomy and physiology are shedding light on the mechanisms of DIMD. This chapter will give overview of contemporary models of BG circuitry, pointing out controversies where they exist. Then, in light of these models, there will be an exploration of the pathophysiology of DIMD. Then we will review the neurochemical pathophysiology of tardive dyskinesia. Although Kinnier Wilson was among the first to recognize the profound influence of the BG on motor function, he was also cognizant of their profound complexity [1]. The recent advent of new tools has enabled investigators to shed light on these intricate interconnections. Methods for studying these connections include using (3H)-2-deoxyglucose (2DG) to look at synaptic arborization [2], electrophysiological recordings [3], in-situ hybridzation of GADmRNA which looks at long-term changes in GABA neurotransmission [4], and cytochrome oxidase expression (COmRNA) studies [4]. COmRNA activity is considered a marker for metabolic activity of neurons [4]. In addition, 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced lesions in the substantia nigra pars compacta (SNpc) serve as a useful model for studying loss of dopamenergic input to the striatum as seen in PD [4]. Models using surgical lesions have also been helpful [4]. Finally, models using drugs such as GABA agonists and antagonists and glutamate antagonists applied to specific areas of the BG have proved useful in understanding the roles of different neurotransmitters [4]. An overall picture of the BG has developed from the work of various researchers [4]. The traditional model of BG activity is based on two fundamental concepts. First, the BG are a component of larger cortico-BG-thalamo-cortical circuits. These circuits have traditionally been thought to be functionally distinct. Second, the motor circuits are composed of a direct and an indirect pathway arising from different populations of striatopallidal neurons, both under the influ-

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ence of dopamine from the substantia nigra (Fig. 1). This model, originally delineated by DeLong among others, has been demonstrated to have scientific and clinical utility [5]. Over time there have been modifications to our traditional concepts of the BG. As described above, one tenet of the original model is that there are specific cortico-BG-thalamo-cortical circuits that are anatomically segregated and functionally distinct. Five such circuits have been described: two motor, two association, and one limbic [6]. The two motor circuits consist of the oculomotor circuit and the traditional motor circuits involved in initiation of movement. The two association circuits are dorsolateral and orbitofrontal. The limbic circuit involves the anterior cingulate gyrus. Thus, the BG appear to play a role in behavior, cognition, and emotions in addition to its involvement in the control of movement. Recent authors have challenged the strict functional and anatomic segregation of these different circuits, and proposed some degree of convergence between these parallel circuits [6]. This issue of open versus closed circuits is reviewed in detail elsewhere [6]. The discussion here will be limited to the BG’s role in the development of movement disorders and will thus focus on the traditional motor circuits. With this basic understanding of the BG and its connections to other areas of the brain, we will focus on details of the BG regarding how its divergent parts communicate. The BG, as the name implies, is a designation given to a group of interconnected subcortical nuclei: the putamen, caudate, nucleus accumbus, globus pallidus (external and internal segments), subthalamic nucleus, and substantia nigra (pars reticulata and pars compacta). The BG receive input from almost all cortical areas, and intralaminar and midline nuclei of the thalamus, substantia nigra pars compacta (SNpc) with dopaminergic projections, and retrorubral areas. The striatum (caudate, putamen, and nucleus accumbus) receives and integrates these signals from divergent areas [5]. It is believed that there are two routes of signal processing in the motor system, the direct and indirect [5]. The direct pathway consists of projections from the motor cortex to the putamen. Neurons from the putamen project to the globus pallidus interna (GPi). Neurons from the GPi project to the thalamus, which in turn feed back to the cerebral cortex. In the indirect route, striatal output is channeled first through the globus pallidus externa (GPe) and from there to the subthalamic nucleus (STN), and then to the GPi. The GPi projects to the thalamus that feeds back to the cerebral cortex, completing the indirect pathway. The indirect and direct routes are not only anatomically distinct, they also differ in their biochemical modulators. The direct pathway projects from mainly D1-bearing striatal neurons to the GPi and SN. These neurons are GABAnergic and also contain the peptide Substance P. The indirect pathway projects from primarily D2-bearing neurons to GPe. The indirect pathway is also GABAergic neurons but contains enkephalin (ENK). As shown in Fig. 1, the net effect of the

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FIGURE 1 The motor circuits of the basal ganglia are shown in schematic form. The cortex activates the striatum with glutamate acting as the major neurotransmitter. The SN influences the striatum with dopamine. Activation of the D1 receptors stimulate a population of neurons in the striatum, whereas activation of the D2 receptor inhibits a population of neurons in the striatum. The direct pathway represents a monosynaptic connection with the output nuclei of the basal ganglia (SNpr/GPi). The direct pathway releases GABA in addition to SP and Dyn. This results in inhibition of the activity of SNpr/GPi. The indirect pathway utilizes the GPe and STN. The net effect of activation of the indirect pathway is activation of the SNpr/GPi. The SNpr/ GPi in turn inhibits the thalamus and cortex. Thus, the net effect of the direct pathway is disinhibiton of the thalamus and cortex which facilitates movement. The net effect of the indirect pathway is activation of SNpr/GPi which results in increased inhibition of the thalamus/cortex.

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FIGURE 2 The motor circuits of the basal ganglia affected by Parkinson’s disease. There is overinhibition of the thalamus/cortex.

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direct pathway is to inhibit the GPi, while the indirect pathway activates the GPi through a process of disinhibiton. The GPi/SNR projections are inhibitory to the thalamus and cortex. Therefore, the overall effect of the indirect pathway is a net reduction of activity of the thalamic/cortical areas modulated by this pathway. In PD, loss of dopamine neurons that project to the putamen results in D1 receptorbearing neurons of the direct pathway becoming underactive and the D2-bearing neurons becoming overactive (Fig. 2). This results in an increase in inhibition from GP to thalamus which results in slowness and rigidity. It must be stated that this is an ovesimplification and there are a lot of inconsistencies with this model. L-DOPA-INDUCED DYSKINESIAS L-dopa-induced dyskinesias (LID) are commonly encountered among patients on chronic L-dopa therapy. Patients who develop LID have been on L-dopa therapy for a period of several months to years. Peak dose dyskinesias occur in 30–80% of parkinsonian patients treated with L-dopa [7]. The dyskinesias may be asymmetric and tend to be more prominent on the side of the body most affected by PD [8]. Functionally defined, LID denotes any excess movement induced by Ldopa in patients with striatonigral denervation. Chorea, dystonia, ballismus, periodic leg movements, and myoclonus have all been described [9]. Furthermore, LID may occur at peak dose, in a biphasic form, or during ‘‘off’’ periods. The ‘‘off’’-period LID is usually dystonic in nature, exemplified by early-morning foot dystonia [9]. Aside from a denervated striatum, the presence of an intact striatal outflow system is required for the development of dyskinesias. Experimental models with MPTP have focused on the peak-dose LID. With doses of 50–100 mg/kg of L-dopa, dyskinesias can be elicited in this model [10]. Interestingly, when drug is withdrawn the dyskinesias will disappear, only to return immediately if L-dopa is reinitiated [10]. This suggests that exposure to L-dopa induces some persistent modification in the BG response which leads to inappropriate modulation of movement. This may be a form of pathological learning similar to the process of kindling. The model of BG circuitry sheds some light on how L-dopa may induce dyskinesias. First, consider what happens to GPi activity with the administration of L-dopa to patients with dopaminergic denervation of the striatum due to PD. When L-dopa is first initiated in such a patient, it is taken up by remaining nigrostriatal neurons and converted to dopamine, which, in turn, stimulates dopamine receptors in the striatum. This results in a net reduction in the Gpi that is the main output of the BG (Fig. 3). Theoretically, this reduction of GPi output would cause disinhibition of the thalamus/cortex, potentially leading to pathological movements. However, this simple model of LID does not explain several

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FIGURE 3 Proposed circuit changes leading to levodopa induced dyskinesias. There is an underactivity of the indirect pathway and an overactivity of the direct pathway leading to excessive inhibition of the globus pallidus interna. This results in a release of inhibition of the Vl/Vim thalamic nuclei leading to dyskinesia.

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clinical observations. First, it does not explain why LID appears only after a long period of exposure to dopaminergic drugs. Second, it does not explain the clinical observation that unilateral lesioning of the GPi does not produce dyskinesias. In fact, pallidotomy in patients with PD often abolishes LID. The current thinking is that it is not drug-induced hypoactivity of the GPi, but rather it is an alteration in the pattern of BG activation resulting from chronic denervation that leads to LID. This alteration of BG circuitry on a biochemical level leads to dyskinesias in response to dopaminergic input. Current models hold that the balance between the direct and indirect pathway is shifted in such a way that the direct pathway is overactive in relation to the indirect pathway [11]. This change appears to occur when damage has been done to the nigrostriatal pathway that is then exposed to L-dopa [11]. This fits with the concept that the BG both activates the thalamus/cortex via the direct pathway and inhibits via the indirect pathway. The balance between these two leads to normal control of movement. When dopaminergic input is diminished to these pathways, inhibitory output to the thalamus/cortex is augmented, leading to parkinsonian symptoms [5]. When reactivation occurs in an unbalanced way, favoring the direct pathway, then dyskinesias develops [11]. Thus, the cause of LID is a nonphysiological signal from the GPi to the cortex through the thalamus. Substantial changes in biochemical signal appear to be responsible for this nonbalanced pathological response to dopamine replacement [11]. It is clear that two elements are necessary for LID to develop. First, the patient must have denervation of the striatonigral pathway, as seen in PD. Next, the patient must be exposed to an exogenous dopaminergic compound. The following section will look at the experimental evidence that has shed light on potentially important biochemical changes in the BG which may play a role in the development of LID. Early observations demonstrated that bromocriptine, a predominantly D2 agonist, was less likely to induce dyskinesias [12]. Therefore, the D1 receptor was thought to play a major role in the development of LID. However, as more selective D1 and D2 agonists became available, it became clear that stimulation of both receptor subtypes could lead to dyskinesias [13]. It appears that L-dopainduced dyskinesias are a consequence of a functional imbalance in the striatal outflow following D1-receptor-mediated neurotransmission [14]. However, stimulation of both subtypes seems to induce dyskinesias. The type of stimulation of these receptors is also relevant. Continuous stimulation tends not to lead to dyskinesias, whereas pulsatile stimulation appears to do so [11]. Thus, the current evidence suggests that dyskinesias result from an imbalance in D1 and D2 receptor activities relating to DA denervation and the pulsatile administration of L-dopa. The imbalance between the direct and indirect pathway has been assessed by measurement of mRNA for the peptides that are related to the relative degree of D1 and D2 activation. Destruction of the nigrostriatal dopaminergic system

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has been shown to decrease Substance P levels and to increase ENK levels, indicating a predominance of D2 over D1 output. In MPTP-treated monkeys it was found that denervation by MPTP caused increased expression of preproenkephalin (PPE), the precursor for ENK, and decreased expression of preprotachkinin, the precursor to Substance P. The addition of pulsatile D1 agonist appeared to increase this expression [11]. Thus, denervation and pulsatile stimulation with dopaminergic medications seem to augment the upregulation of the PPE gene, leading to greater levels of ENK in the BG. ENK is thought to play a key role in the regulation of GABA in the BG. Chronic L-dopa treatment reverses the decrease in preprotachykinin mRNA, but only has a partial effect on mRNA for preproenkephalin. Thus, treatment with L-dopa does not normalize the imbalance in the outflow pathways and creates a new imbalance in these pathways. In other studies, examination of GABA-A receptors in the BG of MPTPtreated monkeys showed that denervation appears to lead to GABA-A supersensitivity at the GPi, making it more susceptible to the activity of GABA [15]. Furthermore, denervation appeared to increase the activity of GAD 67 that is important in the production of GABA in the indirect pathway. However, when the MPTPtreated monkeys were exposed to L-dopa, the GAD expression was increased in both the direct and indirect pathway [16]. Yet another important line of evidence comes from examination of ⌬ Fos B and its isoforms called Fos-related antigens (FRAs). FRAs have attracted much interest among researchers because they appear to be induced in a region-specific manner. Chronic injury appears to cause expression of these antigens. Studies have shown that dopamine antagonist use also causes induction of FRA genes, most likely by causing chemical denervation [17]. Chronic pulsatile use of dopamergic agents appears to augment this expression [11]. Denervation appears to also induce the production of a compound Jun D. ⌬ Fos B and Jun D form a dimer that increases binding of AP1 to the striatum. The AP1 complex binds to several important cellular elements including cAMP-responsive elements (CREs). The CREs are responsible for increasing gene expression of PPE (Fig. 3). PPE forms ENK that appears to regulate the GABA in the BG [11]. Furthermore, the AP1 complex appears to upregulate the expression of the glutamate receptor, NMDAR2B. This upregulation may make the striatum more susceptible to cortical input and lead to deficient gating of the glutamatergic input to the striatum from the cortex [11]. Overall, there appear to be several biochemical changes in play. Each of these changes is a response to chronic denervation and/or exposure to pulsatile dopaminergic stimulation. Taken together, each may play a role in development of LID. To summarize, there is increased GABA-A binding in the GPi, making the BG output supersensitive to GABA in the BG. Also, there is increased expression of ⌬ Fos B that leads to increased expression of PPE and thus ENK, which

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in turn appears to regulate GABA. Furthermore, there is increased expression of NMDAR2B that may lead to pathological cortical input to the striatum. DOPAMINE ANTAGONISTS AND THE DEVELOPMENT OF DRUG-INDUCED PARKINSONISM Shortly after dopamine antagonists were introduced into the pharmacopia in the 1950s, it became clear that a major side effect of these medications is the development of parkinsonism that in some cases is clinically indistinguishable from PD [18]. In fact, this observation lead to the development of a rodent reserpine model of dopamine depletion and played a crucial role in the understanding of the fundamental role of dopamine depletion in the development of PD. Subsequent observations have shown that drug-induced parkinsonism (DIP) is much more likely to occur in older patients than younger patients. This has been attributed to the age-related dropout of dopaminergic neurons [18]. Parkinsonism can begin within days of initiating dopamine antagonists. When the dopamine antagonist is withdrawn, most patients recover from parkinsonian symptoms over a course of weeks to months. However, in some the parkinsonism persists. Epidemiological observations about DIP reveal that 50–75% of patients who develop DIP will do so within the first month. About 90% of cases will manifest symptoms within 3 months [12]. The more potent the dopamine antagonist, the more likely it is that the drug will induce DIP. However, any of the traditional dopamine antagonists given at high enough doses can induce parkinsonism. DIP occurs twice as commonly in women as men. The overall incidence of DIP has been placed between 5% and 60%, but clinically significant parkinsonism occurs in approximately 15% of patients on chronic dopamine antagonists [12,19]. TARDIVE DYSKINESIAS Tardive dyskinesias (TD) may take many forms, including classic TD (orobuccolinguomasticatory dyskinesia), tardive akathisia, tardive dystonia, withdrawalemergent syndrome (a self-limiting course of movement disorders usually seen in children after cessation of dopamine antagonists), tardive Tourettism, and tardive myoclonus. The orofacial and lingual muscles tend to be involved earliest and most frequently in classic TD. Lingual movements can be brief, as in ‘‘fly catcher’s tongue,’’ or quite prolonged, representing tardive dystonia. Epidemiological studies have been problematic because of lack of consensus on diagnostic criteria, and accepted rating scales. Further complicating the issue is the fact that many psychiatric patients have received many different dopamine antagonist drugs. Compliance is often difficult to establish. Furthermore, psychiatric patients may have dyskinesias originating from other organic or functional etiologies. After taking into account these confounding factors, the

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overall prevalence of dopamine antagonist-induced TD is thought to be 13% [20]. However, with the recent introduction and acceptance of ‘‘atypical’’ antipsychotics with less extrapyramidal side effects, the current incidence and prevalence is not known precisely but may be lower. The pathophysiology of TD has been an area of very active research. The major antipsychotic activity of dopamine blocking agents (DBA) appears to be its inhibition of ventral tegmental dopaminergic projections to the mesolimbic/ mesocortical areas. Likewise, the extrapyramidal side effect of DBA appears to be from blockade of dopamine receptors in the striatum [21]. However, TD that is a hyperkinetic movement disorder differs fundamentally from DIP. TD, like chorea, appears to be a manifestation of excessive dopaminergic activity in the BG. This may seem paradoxical given dopamine blocking-action agents. However, there are several lines of clinical evidence to support a relative dopaminergic excess. First, reduction of DBA dose can often precipitate TD (withdrawal-emergent syndrome or covert dyskinesia). Likewise, increasing the DBA dose can temporarily mask TD symptoms. Second, dyskinesias induced by L-dopa in PD patients may closely resemble the movements seen in TD. Animal studies have shown that DBA use results acutely in increased turnover of dopamine [21]. This increased turnover may be stimulated by feedback mechanisms set off by postsynaptic blockade of dopamine receptors [21]. This increased turnover, however, attenuates on chronic use. Furthermore, chronic dopamine blockade may precipitate dopamine receptor hypersensitivity by causing chemical denervation [15]. Tardive dyskinesia is thought to result from an increased number and affinity of postsynaptic D2 dopamine receptors [22]. This is based on the rodent models of tardive dyskinesia, in which, after 2 weeks of therapy with the conventional DBA, there is increased affinity and numbers of dopamine D2 receptors [23]. However, this is a universal effect in animals, whereas tardive dyskinesia occurs in only about 20% of patients exposed to the DBA. Moreover, the role of other neurotransmitters such as GABA and noradrenaline may be important [24]. Excitatory neurotransmission may play a role, as shown by a decrease in the chewing movements in the rodent TD model by the use of NMDA-blocking agents [25]. Human studies investigating the mechanism of TD have been limited. In one human postmortem study of patients with TD who were neuroleptic-free for 1 year prior to death, the dopamine D2 receptor density was diminished in the striatum but increased in the pallidum [26]. A PET study using N-11c-methylspiperone failed to show a difference in D2 receptor density in patients with or without TD [27]. However, recently, another study found that that the D2 receptor density was increased in patients exposed to both typical and atypical antipsychotics [28]. A PET study using FDG uptake showed that the metabolic rates were increased in the motor cortex and the globus pallidus, suggesting overactivity of these regions [29].

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An attempt has been made to study genetic polymorphisms for an association with TD in various ethnic populations. Ser9Gly variant in the MscI restriction site of the dopamine D3 receptor gene was reported to be associated with TD [30,31]. However, others have failed to find such an association [32]. CSF markers of oxidative stress were investigated in one study. Tardive dyskinesia patients had significantly higher concentrations of N-acetylaspartate, N-acetylaspartylglutamate, and aspartate in their CSF than patients without tardive dyskinesia when age and neuroleptic dose were controlled for [33]. Tardive dyskinesia symptoms correlated positively with markers of excitatory neurotransmission and protein carbonyl group and negatively with CSF superoxide dismutase activity. Thus, the role of dopamine receptor supersensitivity in the development of TD has not been conclusively established. Ideally, a model for TD would explain why only a minority of patients treated with DBA develop TD, why the onset requires long-term exposure, and why the movement disorder persists in many cases even when the DBA is withdrawn. Recently, study has focused on the idea that GABAergic changes occur in the BG of subjects exposed to chronic dopamine antagonists, leading to an imbalance in BG output. In this scenario, the activity of the indirect pathway would be diminished in relation to the direct pathway, a possible explanation for the origin of this hyperkinetic disorder [22]. Currently, it is thought that a complex interaction between dopamine, acetylcholine, GABA, and glutamate systems may be important in the development of TD [15]. AKATHISIA Akathisia appears to be the most common extrapyramidal side effect of dopamine antagonists [17]. In the vast majority of cases this side effect begins within 3 months of initiating treatment. The cause of akathisia is unknown. One possibility is that akathisia results from blockade of a population of dopamine receptors in the mesocortical areas [34]. However, the effectiveness of ␤-blockers and opioids for the treatment of akathisia suggests that a more complex process may be at work. These adrenergic and opioid receptors may mediate release of dopamine in the mesocortical areas. CONCLUSION Much has been learned about the BG on the anatomic and biochemical levels. Drugs that influence the dopamine system have come into common usage in treating psychiatric and movement disorders. The current model of BG circuitry is helping us understand why DIMD occur. With dopaminergic drugs, it appears that an imbalance caused by chronic nigrostriatal denervation is worsened by

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the use of pulsatile dopamergic agents. This leads to an abnormal response to stimulation of the dopamine receptors in the striatum. The imbalanced output of the BG in this case leads to LID. In the case of dopamine antagonists, they appear to cause chemical denervation of the nigrostriatal pathway, leading to parkinsonism. TD appears to develop from supersensitivity to dopamine that develops over time after chronic blockade of dopamine receptors. The cause of akathisia is less clear, but may be related to the activity of dopamine antagonists on the population of dopamine receptors in the mesolimbic lobe and mesocortex. As our understanding of basal ganglia circuitry evolves over the coming years, a more complete model of these disorders will undoubtedly develop. This will enable us to avoid devastating side effects and aid in the development of therapies for the future.

REFERENCES 1. Wilson SAK. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain 1912; 34:295–509. 2. Mitchell IJ, Sambrook MA, Crossman AR. Subcortical change in the regional uptake of (3H)-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesias elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus. Brain 1985; 108:405–422. 3. Delong MR, Georgopoulos AP. Motor function of the basal ganglia as revealed by studies of single cell activity in the behaving primate. Adv Neurol 1979; 24:131–140. 4. Obeso JA, Rodriguez MC, Delong MR. The basal ganglia and new surgical approaches for Parkinson’s disease. In Obeso JA , DeLong MR, Eds. Advances in Neurology. Vol. 74. Philadelphia: Lippincott-Raven, 1997:3–17. 5. Wichmann T, DeLong MR. Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg Clin N Am 1998; 9(2):223–236. 6. Weiner DJI. The connections of the primate subthalamic nucleus: Indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry. Brain Res Rev 1997; 23:62–78. 7. Blanchet PJ, Allard P, Gregoire L, et al. Risk factors for peak dose dyskinesias in 100 L-dopa-treated parkinsonian patients. Can J Neurol Sci 1996; 23:189–193. 8. Paulson HL, Stern MB. Clinical manifestations of Parkinson’s disease. In: Watt RL, Koller WC, Eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:183–199. 9. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco. NY: Futura, 1989:23–115. 10. Falardeau P, Bouchard S, Bedard PJ, et al. Behavioral and biochemical effect of chronic treatment with D-1 and D-2 dopamine agonists in MPTP monkeys. Eur J Pharmacol 1988; 150:59–66. 11. Bedard PJ, Blanchet PJ, Levesque D, et al. Pathophysiology of L-dopa-induced dyskinesias. Move Disord 1999; 14(suppl 1):4–8.

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12. Bedard PJ, Di Paolo T, Falaardeau P, et al. Chronic treatment with L-dopa, but not bromocriptine induces dyskinesias in MPTP-parkinsonian monkeys: Correlation with [3H] spiperone binding. Brain Res 1986; 379:294–299. 13. Gomez-Mancilla B, Bedard PJ. Effect of chronic treatment with (Ⳮ)-PHNO, a D2 agonist in MPTP-treated monkeys. Exp Neurol 1992; 117:185–188. 14. Mouradian MM, Hueser IJE, Baronti F, Fabbrini G, Juncus JL, Chase TN. Pathogenesis of dyskinesias in Parkinson’s disease. Ann Neurol 1989; 25:523–526. 15. Calon F, Goulet M, Blanchet PJ, et al. L-dopa or D2 agonist induced dyskinesias in MPTP monkeys: Correlation with changes in dopamine and GABA-A receptors in the striatopallidal complex. Brain Res 1995; 680:43–52. 16. Soghomonian JJ, Pedneault S, Blanchet PJ, et al. L-dopa regulates glutamate decarboxylase mRNA levels in MPTP-treated monkeys. Brain Res Mol Brain Res 1996; 39:237–240. 17. Vallone D, Pellecchia MT, Morelli M, et al. Behavioural sensitization in 6-hydroxydopamine-lesioned rats is related to compositional changes of the AP-1 transcription factor: Evidence for induction of FosB-and JunD-related proteins. Brain Res Mol Brain Res 1997; 52:307–317. 18. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco. NY: Futura, 1989:599–644. 19. Hubble JP. Drug induced parkinsonism. In Watt RL , Koller WC, Eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997: 325–330. 20. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco. NY: Futura, 1989:647–677. 21. Weiner WJ, Lang AE. Movement Disorders: A Comprehensive Survey. Mount Kisco. NY: Futura, 1989:645–684. 22. Goetz CG. Tardive dyskinesias. In Watt RL , Koller WC, Eds. Movement Disorders: Neurologic Principles and Practice. New York: McGraw-Hill, 1997:519–526. 23. Hitri A, Weinery W, Borison R, et al. Dopamine binding following prolonged haloperidol pretreatment. Ann Neurol 1978; 3:134–140. 24. Jeste DV, Wyatt RJ. Dogma disputed: Is tardive dyskinesia due to postsynaptic dopamine receptor supersensitivity. J Clin Psychiatry 1981; 42:455–457. 25. Naidu PS, Kulkarni SK. Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): Possible involvement of calcium and nitric oxide. Behav Pharmacol 2001; 12(3):209–216. 26. May Reynolds GP, Brown JE, McCall JC, Mackay AV. Dopamine receptor abnormalities in the striatum and pallidum in tardive dyskinesia; A post mortem study. J Neural Transmission—Gen Sect 1992; 87(3):225–230. 27. Anderson U, Eckernas SA, Harting P, Ulin J, Langstrom B, Haggestrom JE. Striatal binding of 11C-NMSP studied with positron emission tomography in patients with persistent tardive dyskinesia; no evidence for altered dopamine D2 receptor binding. J Neural Transmission—Gen Sect 1990; 79:215–226. 28. Silvestri S, Seeman MV, Negrete JC, Houle S, Shammi CM, Remington GJ, Kapur S, Zipursky RB, Wilson AA, Christensen BK, Seeman P. Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: A clinical PET study. Psychopharmacology (Berl) 2000; 152(2):174–180.

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29. Pahl JJ, Mazziotta JC, Bartzokis G, Cummings J, Altschuler L, Mintz J, Marder SR, Phelps ME. Positron-emmission tomography in tardive dyskinesia. J Neuropsychiatry Clin Neurosci 1995; 7(4):457–465. 30. Lerer B, Segman RH, Fangerau H, Daly AK, Basile VS, Cavallaro R, Aschauer HN, McCreadie RG, Ohlraun S, Ferrier N, Masellis M, Verga M, Scharfetter J, Rietschel M, Lovlie R, Levy UH, Meltzer HY, Kennedy JL, Steen VM, Macciardi F. Pharmacogenetics of tardive dyskinesia: Combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism. Neuropsychopharmacology 2002(1):105–119. 31. Woo F, Sung-I L, Kim L, Jae Won, Rha E, Han S-H, et al. Association of the Ser9Gly polymorphism in the dopamine D3 receptor gene with tardive dyskinesia in Korean schizophrenics. Psychiatry Clin Neurosci 2002; 56(4):469–474. 32. Hori H, Ohmori O, Shinkai T, Kojima H, Nakamura J. Association between three functional polymorphisms of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Am J Med Genet 2001; 105(8):774–778. 33. Tsai G, Goff DC, Chang RW, Flood J, Baer L, Coyle JT. Markers of glutamatergic neurotransmission and oxidative stress associated with tardive dyskinesia. Am J Psychiatry 1998; 155(9):1207–1213. 34. Blin O, Durup M, Pailhons J, Serratrie G. Akathisia, motility and locomotion in healthy volunteers. Clin Neuropharmacol 1990; 13:426–435.

14 Stimulant-Induced Movement Disorders Juan Sanchez-Ramos University of South Florida College of Medicine Tampa, Florida, U.S.A.

INTRODUCTION Stimulants (or psychomotor stimulants) may be defined as central nervous system (CNS) sympathomimetic agents which, in moderate oral doses, produce an elevation of mood, a sense of increased energy and alertness, decreased appetite, and enhanced performance in tasks that have been impaired by fatigue or boredom. The subjective effects of the prototype stimulants (amphetamine and cocaine) resemble effects of other stimulants when equated for differences in potency [19]. These drugs include dextroamphetamine (d-amphetamine), methamphetamine, phenmetrazine, methylphenidate, pemoline, diethylpropion, and cathinone. Stimulants are indicated clinically for treatment of narcolepsy and attention-deficit hyperactivity disorder (ADHD), but they are often used inappropriately without medical supervision to suppress appetite, decrease sleepiness, increase concentration, enhance physical performance, or simply for the sake of the stimulantinduced ‘‘high’’ or sense of increased energy and well-being. The intrinsic reinforcing effects of stimulants can lead to compulsive self-administration and dependence. With repetitive use, or at higher doses, these drugs are known to induce stereotypic movements and occasionally to elicit or exacerbate a variety of other movement disorders ranging from tics to dystonia, and transient parkinsonism following acute cessation of a chronic cocaine regimen. 295

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STIMULANTS AND STEREOTYPIC MOVEMENTS Psychomotor stimulants are well known to elicit repetitive, unmotivated behaviors. ‘‘Unmotivated’’ refers to the fact that the movements are done with no obvious goal or purpose, and such patterns of behavior are termed ‘‘stereotypic.’’ In animals, repetitive chewing, lip smacking, licking, and grooming behaviors can be elicited by single or chronic doses of amphetamine [40,41]. In humans, the stereotypic behaviors can be more complex, exemplified by the meticulous disassembling of watches and the dismantling of objects that are in perfect working order. Other repetitive behaviors include bruxism, licking of the lips, nail biting, compulsive nail polishing, hand washing, continuous dressing and undressing, sorting or continuous rearranging of objects, and other obsessive-compulsive thoughts and behaviors. These stimulant-induced behaviors resemble to some degree the compulsive repetitive behaviors and movements characteristic of Tourette’s syndrome (TS), a similarity strong enough to suggest that both phenomena share a common mechanism related to alterations in central dopaminergic neurotransmission.

TICS AND TOURETTE’S SYNDROME Tics are sudden, involuntary, repetitive, simple or complex purposeless movements that involve multiple muscle groups [55]. Motor tics are generally preceded and accompanied by a strong subjective urge to perform the motor act. Tics occur at random intervals and can be voluntarily suppressed for varying periods of time (minutes to hours), but gradually a strong impulse builds up which results in an explosive release of the movements. Examples of simple motor tics include shoulder shrugging, eye blinking, facial gestures, head and neck jerking, arm movements, kicking, and abdominal or pelvic contractions. Tics can also occur in complex patterns combining two or more tics into a sequenced movement. An example is rapid facial grimacing, tossing of the head to the side, followed by repetitive touching of the nose. Motor tics most commonly involve the head, neck, face, and less frequently, the arms and legs. Tics can also be vocal and expressed as a range of grunts, snorts, and sniffs. More complex vocal tics include speech punctuated with explosive coprolalic language, echolalia, and palilalia. In echolalia, the patient repeats a sentence just uttered by the examiner. Repetition of only the last uttered word or phrase is called palilalia. The most common tic disorder, occurring in 12–24% of children between age 2 and adolescence, is transient and disappears permanently by adulthood [55]. There can be more than a single tic present and occasionally there may also be vocal tics. Although there may be some confusion regarding transient tics of childhood and the tics of Tourette’s syndrome, they are differentiated by the duration of symptomatology. The transient tics may last for at least 1 month but

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not more than 1 year. Chronic motor tic disorders can appear in either childhood or adult life. The course of the tic disorders is stable, and usually only one tic is present. Tic disorders are considered to be part of a clinical spectrum of disorders rather than separate entities, and this is supported by the occurrence of simple and motor tics in families of patients with Tourette’s syndrome [56]. Tourette’s syndrome (TS) is characterized by waxing and waning of multiple motor and vocal tics and is of unknown etiology. The signs and symptoms of Tourette’s syndrome characteristically vary in frequency and intensity as a function of the natural course of the illness and as a function of emotional factors, environmental stressors, and drug-induced states. A number of neuropsychiatric problems are often co-morbid with TS and may be part of the spectrum of TS. Included in the list are obsessive-compulsive disorder, mood disorders, attentiondeficit/hyperactivity disorder (ADHD), anxiety disorders, self-mutilating behavior, learning disabilities, psychotic disorders, paranoia, inappropriate sexual activity, and impulsive, aggressive, and antisocial behaviors. About 50% of children with Tourette’s disorder evidence hyperactivity or components of ADHD [59], and treatment with stimulants frequently exacerbates the tics, leading to the initial recognition of the disorder. STIMULANTS, TICS, AND TOURETTE’S SYNDROME The relationship between psychomotor stimulant drugs and tics has been extensively discussed since the early 1970s, mostly in the context of studies of children with ‘‘minimal brain dysfunction’’ (MBD). MBD is an outmoded term which has been subsumed in the diagnosis of attention-deficit/hyperkinetic disorder (ADHD). The concept and the term ‘‘minimal brain damage’’ originated in the observation that children with brain damage from infection, trauma, hypoxia (including perinatal), and exposure to toxins often exhibited ADHD. It was hypothesized that those with no other signs or symptoms of trauma had minimal brain damage, manifested only behaviorally. The inability to demonstrate brain pathology and the lack of a history of trauma in most such cases led to substitution of ‘‘dysfunction’’ for ‘‘damage’’ and a corresponding change in terminology to ‘‘minimal brain dysfunction.’’ There were several isolated reports of facial tics induced by methylphenidate in children with MBD [57,58]. In 1973, Meyerhoff and Snyder described an increase in tics in a TS patient treated with stimulants [35]. In 1974, Golden reported the first case of methylphenidate-induced TS in a 9-year-old who was being treated for hyperkinetic behavior [22]. Despite improvement in the hyperkinetic behavior 8 weeks following the initiation of methylphenidate treatment, the child suddenly developed ‘‘full-blown’’ TS. Discontinuation of the drug resulted in return to baseline motor status. Denkla et al. reported that 1.3% of a large population of patients (1520) with ‘‘minimal brain dysfunction’’ treated with methylphenidate developed transient tics [14]. Of the

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20 cases identified, 14 developed new onset of motor tics and 6 experienced an exacerbation of their preexisting tics during methylphenidate administration. Although a relationship was acknowledged between tics and methylphenidate treatment, the nature of the relationship was presented as obscure even though a linkage to the dopaminergic system was mentioned. The authors concluded that tics related to methylphenidate administration appeared to be rare and pointed to a specific susceptibility possibly related to personality profile. Denkla et al.’s study is still useful in documenting that methylphenidate treatment in MBD children only rarely elicits tics [14]. The relationship to personality profile has for the most part been discarded in favor of neurochemical explanations, although these often also fall short of explaining the phenomenon. Although there is no further large population study to dispute the 1.3% incidence of methylphenidate-induced tics, it should be noted that the incidence may in fact be higher, since Denckla et al. relied in part on phone follow-ups from the parents. Phone conversations and family member interviews are often very unreliable in trying to establish the presence or absence of abnormal movements in a given patient. In 1977, several additional case reports documented that methylphenidate can exacerbate Tourette’s syndrome symptomatology, particularly vocal or motor tics [20,38]. Also, Bremness and Sverd reported another case of a child with hyperactivity aggressive syndrome treated with methylphenidate who developed full-blown TS [4]. Golden reviewed his patient records and solicited information from the Tourette Syndrome Association to further investigate the relationship between stimulants and TS [23]. He found that 17 of 32 (53%) of TS patients who had been exposed to stimulants (primarily methylphenidate and amphetamine) experienced marked accentuation of tics. There were no apparent clinical differences between those whose symptomatology was exacerbated and those who were not affected by stimulants, except that the latter group tended to be older. Further support for a relationship between psychomotor stimulants and tics is found in several additional reports describing the use of stimulants in patients with TS. Lowe et al. identified 15 of 100 TS patients who were treated with stimulants and who experienced an exacerbation of their tics [31]. In many of their patients, a family history of TS or other tic disorders was present, and the authors stressed that a positive family history of tics may predispose the patient to stimulant-induced tics. It should be noted that in many of their patients the tics did not appear immediately after the introduction of stimulant treatment but occurred months to years later. Bachman, in a retrospective review of his patient records, found 14 of 64 TS patients who had been treated with stimulants [1]. In 3 patients treated with methylphenidate there was a worsening of tics, in 1 patient treated with amphetamine, the tics improved, and in the remaining 10 patients there was no change in tic frequency. Erenberg et al. found similar results after reviewing the records of 2000 TS patients; 48 patients had been treated with

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stimulants (42 with methylphenidate, 13 with pemoline, and 5 with amphetamine) [15]. Thirty-nine of their patients had preexisting tics, and stimulants increased tic severity in 11, produced no change in 26, and decreased tics in 2. Where a comparison could be made, various stimulant treatments had no effect on the tics. These children with TS were being treated for ADHD, and it should be noted that in 22 of 39 patients their behavior improved. The authors concluded that in patients with ADHD and TS, a cautious trial of stimulants may be of benefit in terms of managing the overall clinical situation. Nine patients in their study were treated with stimulants prior to the onset of tics. Only 4 of the patients were still receiving stimulants when the tics began. The delay in onset of tic symptomatology from the time of stimulant treatment raises the question of whether stimulants are solely precipitating the tics or whether the appearance of tics in some of these children with ADHD simply represents the normal evolution of the ADHD-TS syndrome. Price et al. identified 34 of 170 (20%) TS patients who had been treated with stimulants prior to age 18 [39]. Fifty percent of these patients reported worsening of their tics. Of considerable interest is the finding that in 6 monozygotic twin pairs there was 100% concordance for TS and complete discordance for prior stimulant use. The authors suggest that stimulant treatment may not substantially increase the risk for prematurely exacerbating tics in many individuals. On the other hand, their data does reveal a close temporal relationship in some TS patients between stimulant treatment and an exacerabation of tics. Therefore they also concluded that there may exist the real danger of worsening tics in some patients with TS. It has been proposed that lack of complete concordance in monozygotic twin pairs for TS suggests that cerebral development up to 15 years of age may play a role in the phenotypic expression of the disorder. Lechman et al. have proposed that chronic stress and exposure to stimulants may be environmental factors capable of precipitating the expression of the phenotype [30]. However, the twins data of Price et al. suggest that stimulants are not one of these factors, although the number of patients was small [39]. Castellanos et al. [7] compared the effects of methylphenidate and d-amphetamine on tic severity in boys with ADHD-TS. Utilizing a prospective 9-week, placebo-controlled, doubleblind crossover design, they administered a wide range of doses to 20 subjects in three cohorts. Relatively high doses of methylphenidate and d-amphetamine in the first cohort produced significant increases in tic severity which were sustained on higher doses of d-amphetamine but which attenuated on methylphenidate. Overall, 14 of 20 subjects continued stimulant treatment for 1 to 3 years, generally in combination with other psychotropic medications. A substantial minority of co-morbid subjects had consistent worsening of tics on stimulants, although the majority experienced improvement in ADHD symptoms with acceptable effects on tics. Methylphenidate was better tolerated than d-amphetamine. In contrast, in a recent prospective study of 34 children with ADHD and chronic

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mutiple tic disorder, Gadow et al. [21] reported that long-term follow-up did not result in changes in frequency or severity of motor or vocal tics. These patients had participated in an 8-week, double-blind, placebo-controlled methylphendiate evaluation. The behavioral improvements demonstrated during this acute drug trial were maintained during the 2-year follow-up. The authors concluded that long-term treatment with methyphenidate appears to be safe and effective for the management of ADHD behaviors in many children with mild to moderate tic disorder. Nevertheless, careful clinical monitoring is mandatory to guard against the possibility of drug-induced tic exacerbation in individual patients. For example, Feinberg and Carroll studied 2 patients with TS in whom oral administration of amphetamine definitely resulted in increased tics [17]. In a later study, Caine et al. administered oral d-amphetamine, l-amphetamine, and haloperidol to 6 patients with TS [6]. The patients experienced a heteogenous array of responses to these agents which the authors felt precluded them from making any inferences regarding the neurochemistry of TS. They did report that d-amphetamine appeared to be more consistently potent in increasing tic frequency in their patients. Overall, the authors believed that amphetamines increased tics in some but not all patients with TS. Pemoline, used to treat ADD, has also been implicated in the induction of tics. In the clearest case, Bachman reported a 9-year-old child with ADD treated with pemoline who promptly developed tics [1]. Pemoline was discontinued after 2 months of treatment but the tics persisted. During subsequent years the child developed fluctuating motor and vocal tics, and the diagnosis of TS was made. Although the tics were induced by pemoline and never resolved, it is likely that this child had incipient TS which was preciptated by pemoline. Mitchell and Matthews reported a 10-year-old who had previously been treated with thioridazine (no movement disorder reported) for hyperactivity, who was started on pemoline and developed motor tics [36]. When pemoline was stopped, the tics resolved; and when the child was rechallenged with pemoline, the tics recurred. In this case, it is possible that prior exposure to thioridazine may have sensitized the dopaminergic system to the subsequent effects of pemoline treatment. Sleator reported a 6-year-old with TS, also treated previously with thioridazine, who developed exacerbation of tics when pemoline was introduced [53]. This child had the same response to methylphenidate. Cocaine has also been reported to worsen and even to induce tics. Mesulam [33] and Factor et al. [16] both reported single patients with TS who experienced increased severity of their tics when using cocaine. The increase in tic severity was immediate to 20 min later and lasted 1–5 hr. Pascual-Leone and Dhuna reported 2 additional TS patients who experienced a marked increase in severity of both motor and vocal tics following the use of cocaine and smokable cocaine base (‘‘crack’’) [37]. In one of these patients the increased tics did not resolve for 4 days. This duration of cocaine-induced tics well beyond the time when

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cocaine is completely cleared from the body is interesting. These same authors also reported new onset of multifocal tics in 2 additonal patients who were habitual cocaine abusers [37]. In both of these patients, the onset of the movement disorder occurred during binges of cocaine use. In both of these patients there was no previous history of tics, no family history of tics, and in both patients the resolution of the tic disorder occurred over weeks to months. In the latter 2 patients CT and EEG were normal and there was no history to suggest prior central nervous system insult. These 2 patients are particularly interesting. If both were ‘‘truly’’ neurologically normal, then chronic cocaine use alone may be sufficient to induce tic disorders, possibly related to its ability to cause dopaminergic supersensitivity as documented in animal models of stereotyped behavior. MECHANISM OF ACTION OF STIMULANTS AND THE PATHOPHYSIOLOGY OF TICS The induction or exacerbation of tics and stereotypic movements by stimulant drugs is consistent with the hypothesis that dopaminergic mechanisms play a role in TS [45]. Levodopa (L-dopa) treatment, which results in increased brain DA concentrations, was reported to increase tic frequency and intensity in TS [12,25]. Psychomotor stimulants also augment activity of central dopaminergic systems by increasing synaptic concentrations of DA (and other biogenic amines). Amphetamines affect the DA system by promoting release of newly synthesized cytoplasmic DA, inhibiting DA reuptake and, at higher concentrations, blocking MAO activity [19]. Methylphenidate releases DA from terminals, but unlike amphetamine, releases the transmitter from storage vesicles. Pemoline is structurally and functionally similar to methylphenidate [19]. Cocaine acts primarily to inhibit DA (and biogenic amine) reuptake [19,42]. Although the temporal profile of action of these agents differs, the immediate euphoric effects produced by an intravenous injection of amphetamine or cocaine cannot be differentiated by experienced users [18]. The reinforcing effects (or those pharmacological effects that lead to repetitive self-administration) of the psychomotor stimulants is believed to be mediated by the action of these agents on the mesolimbic DA system [42]. Perhaps the strongest evidence for involvement of the DA system in TS is the therapeutic efficacy of DA receptor antagonists (neuroleptics) in alleviating tics. Haloperidol has long been the drug of choice to control tics and is associated with approximately 70% global improvement of TS [48]. In general, the phenothiazine class of neuroleptics is less consistently effective in the treatment of TS compared to the butyrophenones, represented by haloperidol [49]. Pimozide, a phenylbutylpiperidine which is closely related to the butyrophenones, has been shown to be effective in TS [43]. The efficacy of drugs for suppression of TS symptoms has been reported to be positively correlated with potency of their competition for [3H]haloperidol binding to D2 dopamine receptors, but not corre-

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lated with potency at inhibiting dopamine-sensitive adenylate cyclase (D1) receptors [54]. Study of biogenic amine concentrations and turnover in the CSF of TS patients has provided further evidence for the involvement of the DA system. The finding that CSF homovanillic acid (HVA) levels in children with TS was decreased suggested that dopamine turnover was reduced compared to the control population [5,10,11,50]. Cohen and colleagues reported that not only was the concentration of HVA decreased, but the concentration of 5-hydroxy-indoleacetic acid (5-HIAA) was also reduced in 25% of the patients [10,11]. TS patients treated with haloperidol were retapped and CSF HVA (but not 5-HIAA) was found to be elevated at a time of clinical improvement compared to the baseline CSF HVA value [51]. This consistent increase in CSF HVA in haloperidolimproved TS patients was interpreted to be consistent with the dopamine-receptor supersensitivity hypothesis. The blockade of those supersensitive dopamine receptors by haloperidol would decrease negative feedback inhibition of DA neurons and the level of HVA would be expected to rise. Neuroleptics are known to acutely increase HVA levels, but this is a transient effect and the prolonged increase in HVA following neuroleptic treatment in these patients was taken as additional evidence of unusual sensitivity of feedback mechanisms that may be implicated in the etiology of TS. Koslow and Cross have pointed out the potential pitfalls related to the reported CSF neurotransmitter abnormalities in TS [27]. CSF metabolites of DA, norepineprhine (NE), and 5-HT may be affected by age of subjects, sex, medical condition of the control population, various medication effects, circadian rhythms, physical activity, stress, and diet [27]. The most problematic point concerns the use of probenecid to enhance CSF metabolite levels. Probenicid at the dose employed does not completely block egress of acid monoamine metabolites in humans and probenicid itself affects CSF production, levels of NE, and plasmafree tryptophan levels. All of these changes may affect CSF 5HIAA and HVA levels, thus confounding interpretation of the results. Alterations in dopaminergic terminal density has been suggested to be abnormal in TS, but a recent report, utilizing PET scan, showed that the density of presynaptic dopamine terminals is normal in TS [34]. Eight TS patients and 22 controls underwent PET imaging to determine the density of vesicular monoamine transporter type-2 (VMAT2), a cytoplasm-to-vesicle transporter previously shown to be linearly related to monoaminergic nerve terminal density unaffected by medication. Results showed no significant difference in terminal density between patients and controls. Although the dopamine receptor supersensitivity hypothesis of TS has some flaws, it has been a useful model to guide research and provides a conceptual basis for understanding related clinical phenomena. For example, a small number of patients ranging from young adult life to old age have developed a clincial

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syndrome similar to TS as a result of chronic neuroleptic therapy. As in idiopathic TS, these patients demonstrated spontaneous vocalizations such as clicking, barking, grunting, and verbalization (including coprolalia), in addition to motor tics [24,26]. The phenomenon of tardive Tourette’s syndrome supports the theory of DA receptor supersensitivity as the basis of several hyperkinetic movement disorders. This clinical observation also raises the conundrum that the treatment of choice for TS may occasionally lead to an additional neurological problem, tardive dyskinesias [52]. STIMULANT-INDUCED CHOREA AND DYSTONIA As mentioned above, acute doses of stimulants may induce obsessive compulsive behaviors such as excessive grooming, fastidious cleanliness, and exaggerated concern about appearance. Amphetamine administration has been associated with induction of chorea, often in individuals with presumed preexisting damage to basal ganglia as in Huntington’s disease. Other individuals with no preexisting conditions may also develop dyskinesias following chronic high-dose amphetamine use [56]. In the last several years there have been a series of reports describing acute dystonic reactions associated with chronic cocaine abuse. Kumor reported that 6 of 7 cocaine abusers administered haloperidol in a research setting developed acute dystonic reactions [28,29]. These patients had been abstinent from cocaine for at least 10 days prior to treatment with haloperidol. The acute dystonia developed within 22 hr of the first haloperidol dose in 4 patients and within 3 hr of the second haloperidol dose in 2 patients. The acute dystonia was severe enough to require parenteral administration of diphenhydramine or benztropine, which promptly resolved the movement disorder in all cases. ChoyKwong and Lipton have noted that a history of cocaine abuse is associated with a threefold increased risk of dystonic reactions to neuroleptic drugs [8,9]. Kumor reported a single patient who first developed an acute dystonic response to halperidol and who, when administered cocaine 5 days later, also developed an acute dystonic response [28]. The pathogenesis of acute dystonia is not compeletely understood. However, based on these reports, altered neurotransmitter and/or receptor function has been implicated. Acute dystonic reactions have also been reported in cocaine abusers not exposed to neuroleptics. One patient developed focal dystonic movements shortly after cocaine use which lasted 45 min. These movements were transitory [32]. In another single case report a 15-year-old woman admitted to a psychiatric service developed acute generalized dystonia 16 hr after admission. She had not been treated with neuroleptics and it was postulated that the dystonia was associated with cocaine withdrawal [8]. It should be noted that in these patients in whom dystonia was associated with cocaine use and/or neuroleptic use, there was no prior history of a movement disorder.

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TRANSIENT PARKINSONISM FOLLOWING CESSATION OF CHRONIC COCAINE ABUSE There are suggestions that withdrawal from chronic cocaine use is characterized by a hypodopaminergic state evidenced by increased serum prolactin levels [13,46] and a subclinical tremor of the Parkinson’s disease type [2,3]. It was possible to detect subtle changes in hand tremor with accelerometry during cocaine abstinence. Baeur’s study of 16 cocaine-dependent patients at 1, 3, and 12 weeks of verified abstinence demonstrated that hand tremor was significantly increased in the 3–7-Hz bandwidth compared to age-matched control subjects throughout the course of the study. Using a force plate to measure body sway and whole-body tremor, a significant shift in the power spectrum of whole-body tremor toward the 3–7-Hz band was also measured in cocaine abusers who had last used cocaine 12 hr earlier [44]. Although cocaine-abstinent patients also exhibited generalized slowness of movement, no cogwheel rigidity has been reported during abstinence. The transient ‘‘parkinsonism’’ exhibited by these patients is subtle and reversible, reflecting the dynamic changes that occur at the nigrostriatal synapse following abrupt cessation of a chronic cocaine regimen. There is concern, however, that chronic high dose amphetamine use can result in more serious toxicity that ultimately may produce permanent parkinsonism. This is based on animal studies that show amphetamine and methamphetamine, when given in very high doses, result in toxicity to dopaminergic terminals [47]. Taken together with age-dependent decline in numbers of dopaminergic neurons, it is possible that chronic amphetamine abusers have an increased risk of Parkinson’s disease. There is no evidence in humans that this is the case, but there is interest in conducting epidemiological studies to test this hypothesis.

ACKNOWLEDGMENTS This work was supported in part by the Helen E. Ellis Research Fund, University of South Florida.

REFERENCES 1. Bachman DS. Pemoline-induced Tourette’s disorder: A case report. Am J Psychiatry 1981; 138:1116–1117. 2. Bauer LO. Motoric signs of CNS dysfunction associated with alcohol and cocaine withdrawal. Psychiatry Res 1993; 47:69–77. 3. Bauer LO. Resting hand tremor in abstinent cocaine-dependent, alcohol-dependent, and polydrug-dependent patients. Alcoholism: Clin Exp Res 1996; 20:1196–1201. 4. Bremness AB, Sverd J. Methylphenidate-induced Tourette syndrome: Case report. Am J Psychiatry 1979; 136:1334–1335.

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5. Butler IJ, Koslow SH, Seifert WE, Caprioli RM, Singer HS. Biogenic amine metabolism in Tourette syndrome. Ann Neuro1 1979; 6:37–39. 6. Caine ED, Ludlow CL, Polinsky RJ, Ebert MH. Provocative drug testing in Tourette’s syndrome: d- and l-amphetamine and haloperidol. J Am Acad Child Psychiatry 1984; 23:147–152. 7. Castellanos FX, Giedd JN, Elia J, Marsh WL, Ritchie GF, Hamburger SD, Rapoport JL. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: Effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997; 36: 589–596. 8. Choy-Kwong M, Lipton RB. Dystonia related to cocaine withdrawal: A case report and pathogenic hypothesis. Neurology 1989; 39:996. 9. Choy-Kwong M, Lipton RB. Lipton, Cocaine withdrawal dystonia. Neurology 1990; 40:863. 10. Cohen DJ, Shaywitz BA, Caparulo B, Young JG, Bowers MB. Chronic, multiple tics of Gilles de la Tourette’s disease. CSF acid monoamine metabolites after probenecid administration. Arch Gen Psychiatry 1978; 35:245–250. 11. Cohen DJ, Shaywitz BA, Young JG, Carbonari CM, Nathanson JA, Lieberman D, Bowers MB, Mass JW. Central biogenic amine metabolism in children with the syndrome of chronic multiple tics of Gilles de la Tourette: Norepinephrine, serotonin, and dopamine. J Am Acad Child Psychiatry 1979; 18:320–341. 12. Cooper JR, Bloom FE, Rothe RH. The Biochemical Basis of Neuropharmacology. New York: Oxford University Press, 1986. 13. Dackis CA, Gold MS. Pharmacological approaches to cocaine addiciton. J Substance Abuse Treatment 1985; 2:139–145. 14. Denckla MB, Bemporad JR, MacKay MC. Tics following methylphenidate administration. A report of 20 cases. JAMA 1976; 235:1349–1351. 15. Erenberg G, Cruse RP, Rothner AD. Gilles de la Tourette’s syndrome: Effects of stimulant drugs. Neurology 1985; 35:1346–1348. 16. Factor SA, Sanchez-Ramos JR, Weiner WJ. Cocaine and Tourette’s syndrome [letter]. Ann Neurol 1988; 23:423–424. 17. Feinberg M, Carroll BJ. Effects of dopamine agonists and antagonists in Tourette’s disease. Arch Gen Psychiatry 1979; 36:979–985. 18. Fishman MW, Schuster CR. Cocaine self-administration in humans. Fed Proc 1982; 41:137–141. 19. Franz DN. Central Nervous System Stimulants. New York: Macmillan, 1985. 20. Fras I, Karlavage J. The use of methylphenidate and imipramine in Gilles de la Tourette’s disease in children. Am J Psychiatry 1977; 134:195–197. 21. Gadow KD, Sverd J, Sprafkin J, Nolan EE, Grossman S. Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder [see comments]. Arch Gen Psychiatry 1999; 56:330–336. 22. Golden GS. Gilles de la Tourette’s syndrome following methylphenidate administration. Dev Med Child Neurol 1974; 16:76–78. 23. Golden GS. The effect of central nervous system stimulants on Tourette syndrome. Ann Neurol 1977; 2:69–70. 24. Klawans HL, Falk DK, Nausieda PA, Weiner WJ. Gilles de la Tourette syndrome after long-term chlorpromazine therapy. Neurology 1978; 28:1064–1066.

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25. Klawans HL, Hitri A, Nausieda PA, Weiner WJ. Animals models of dyskinesia. In: Hanin I, Usdin E, Eds. Animal Models in Psychiatry and Neurology. Oxford, New York: Pergamon Press, 1977. 26. Klawans HL, Nausieda PA, Goetz CC, Tanner CM, Weiner WJ. Tourette-like symptoms following chronic neuroleptic therapy. Adv Neurol 1982; 35:415–418. 27. Koslow SH, Cross CK. CSF monoamine metabolites in Tourette syndrome and their neuroendocrine implications. Adv Neurol 1982; 35:185–197. 28. Kumor K. Cocaine withdrawal dystonia. Neurology 1990; 40:863. 29. Kumor K, Sherer M, Jaffe J. Haloperidol-induced dystonia in cocaine addicts. Lancet 1986; 2:1341. 30. Leckman JF, Cohen DJ, Price RA, Mindera RB, Anderson GM, Pauls DL. The pathogenesis of GTS: A review of data and hypothesis. In: Shah AB, Shah NS, Eds. Movement Disorders. New York: Plenum Press, 1985. 31. Lowe TL, Cohen DJ, Detlor J, Kremenitzer MW, Shaywitz BA. Stimulant medications precipitate Tourette’s syndrome. JAMA 1982; 247:1729–1731. 32. Merab J. Acute dystonic reaction to cocaine. Am J Med 1988; 84:564. 33. Mesulam MM. Cocaine and Tourette’s syndrome [letter]. N Engl J Med 1986; 315: 398. 34. Meyer P, Bohnen NI, Minshima S, Koeppe RA, Wenette K, Kilbourn MR, Kuhl DE, Frey KE, Albin R. Striatal Striatal presynaptic monoaminergic vesicles are not increased in Tourette’s syndrome. Neurology 1999; 53:371–374. 35. Meyerhoff JL, Snyder SH. Gilles de la Tourette’s disease and minimal brain dysfunction: Amphetamine isomers reveal catecholamine correlates in an affected patient. Psychopharmacologia 1973; 29:211–220. 36. Mitchell E, Matthews KL. Gilles de la Tourette’s disorder associated with pemoline. Am J Psychiatry 1980; 137: 1618–1619. 37. Pascual-Leone A, Dhuna A. Cocaine-associated multifocal tics. Neurology 1990; 40:999–1000. 38. Pollack MA, Cohen NL, Friedhoff AJ. Gilles de la Tourette’s syndrome. Familial occurrence and precipitation by methylphenidate therapy. Arch Neurol 1977; 34: 630–632. 39. Price RA, Leckman JF, Pauls DL, Cohen DJ, Kidd KK. Gilles de la Tourette’s syndrome: Tics and central nervous system stimulants in twins and nontwins. Neurology 1986; 36:232–237. 40. Randrup A, Munkvad I. Brain dopamine and amphetamine-induced stereotyped behaviour. Acta Pharmacol Toxicol 1967; 25:62. 41. Randrup A, Munkvad I. Stereotyped activities produced by amphetamine in several animal species and man. Psychopharmacologia 1967; 11:300–310. 42. Ritz MC, Lamb RJ, Goldberg SR, et al. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 1987; 237:1219–1121. 43. Ross MS, Moldovsky H. A comparison of pimozide with haloperidol in Gilles de la Tourette’s syndrome. Am J Psychiatry 1978; 135:585–587. 44. Sanchez-Ramos J, Kovera C, Mash D. Sub-clinical parkinsonism associated with cocaine abstinence. Move Disord 1996; 11:600. 45. Sanchez-Ramos J, Weiner WJ. Drug-induced tics. In: Kurlan R, Ed. Handbook of Tourette’s Syndrome and Related Tic and Behavioral Disorders. New York: Marcel Dekker, 1992.

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46. Schwartz CM, Breen K, Leone F. Serum prolactin levels during extended cocaine abstinence. Am J Psychiatry 1990; 147:777–782. 47. Seiden LS. Neurotoxicity of methamphetamine: Mechanisms of action and issues related to aging. In: Miller MA, Kozel NJ, Eds. Methamphetamine Abuse: Epidemiological Issues and Implications NIDA Research Monograph, U.S. of Health and Human Services. Vol. 115, 1991:24–32. 48. Shapiro AK, Shapiro E. The treatment and etiology of tics and Tourette syndrome. Comprehens Psychiatry 1981; 22:193–205. 49. Shapiro AK, Shapiro ES, Brunn RD, Sweet RD. Gilles de la Tourette Syndrome. New York: Raven Press, 1978. 50. Singer HS, Butler IJ, Tune LE, Seifert WE, Coyle JT. Dopaminergic dsyfunction in Tourette syndrome. Ann Neurol 1982; 12:361–366. 51. Singer HS, Tune LE, Butler IJ, Zaczek R, Coyle JT. Clinical symptomatology, CSF neurotransmitter metabolites, and serum haloperidol levels in Tourette syndrome. Adv Neurol 1982; 35:177–183. 52. Singh SK, Jankovic J. Tardive dystonia in patients with Tourette’s syndrome. Move Disord 1988; 3:274–280. 53. Sleator EK. Deleterious effects of drugs used for hyperactivity on patients with Gilles de la Tourette syndrome. Clin Pediatr 1980; 19:453–454. 54. Stahl SM, Berger PA. Cholinergic and dopaminergic mechanisms in Tourette syndrome. Adv Neurol 1982; 35: 141–150. 55. Weiner WJ, Lang AE. Movement Disorders, A Comprehensive Survey, Future. 1989. 56. Weiner WJ, Sanchez-Ramos J. Movement disorders and dopaminomimetic stimulant drugs. In: Lang AE, Weiner WJ, Eds. Drug-Induced Movement Disorders. Mt. Kisco. NY: Future, 1992:315. 57. Weiss G, Minde K, Douglas V, Werry J, Sykes D. Comparison of the effects of chlorpromazine, dextroamphetamine and methylphenidate on the behaviour and intellectual functioning of hyperactive children. Can Med Assoc J 1971; 104:20–25. 58. Winsberg BG, Press M, Bialer I, Kupietz S. Dextroamphetamine and methylphenidate in the treatment of hyperactive-aggressive children. Pediatrics 1974; 53: 236–241. 59. Wirsching WC. Neuropsychiatric aspects of movement disorders. In: Kaplan HL, Sadock BJ, Eds. Comprehensive Textbook of Psychiatry. Baltimore: Williams & Wilkins, 1992:230–232.

15 Antiepileptic Drug-Induced Movement Disorders Mark W. Kellett Hope Hospital Salford, England

David W. Chadwick Liverpool University Liverpool, England

INTRODUCTION Since the early 1990s, there has been a dramatic increase in the number of drugs available for the treatment of epilepsy. The basic mechanisms of action are known for the majority of frequently used antiepileptic drugs (AEDs) [1] (Table 1) but, in addition, most AEDs have other physiological actions that may be related or unrelated to their anticonvulsant properties and which may interact with various neurotransmitter systems. The complex neurochemistry of the basal ganglia is largely dependent on dopaminergic and cholinergic neurotransmission, but excitatory glutaminergic and inhibitory GABAergic neurones are crucial for the complex modulation of basal ganglia function. These latter neurotransmitters are obvious sites of potential action for many AEDs; indeed, based on their known mechanisms of action, AEDs have been used to treat a number of movement disorders with variable success [2–20]. It is not surprising, therefore, that AEDs resemble other drugs used for the treatment of movement disorders (levodopa, 309

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TABLE 1 Mechanisms of Action of Antiepileptic Drugs Blockade of voltage-dependant Na⫹ channel Phenytoin Carbamazepine Sodium valproate Phenobarbitone Lamotrigine Gabapentin Vigabatrin Topiramate Felbamate Zonisamide Ethosuximide Benzodiazepines Oxcarbazepine Remacemide Tiagabine

冪 冪 冪 冪 冪 冪 冪 冪 冪 冪

Enhance GABA

Reduce glutamate

冪? 冪

冪?

冪 冪 冪 冪 冪?

冪 冪

冪 冪

Reduce T-type Ca2⫹ channel

冪?

冪 冪

冪

? Reported effect but underlying mechanism unclear.

dopamine antagonists, and dopamine-depleting agents), in that they may also be associated with the development of unwanted involuntary movements. Adverse reactions of antiepileptic drugs are predominantly central nervous system-related and manifested by alterations in cognition and mentation or with a deterioration in motor performance. They result from either pharmacologically predictable dose-related toxicity or unpredictable idiosyncratic reactions. The whole spectrum of involuntary movements has been associated with AEDs, although they are rare and many reports have been anecdotal (see Tables 2 and 3). Therefore, they may go unrecognized or be passed off as signs of coincidental neurodegenerative diseases. When AED-induced involuntary movements do occur, they follow pharmacological principles. Thus ataxia, tremor, myoclonus, or asterixis usually occur as predictable manifestations of dose related drug toxicity, whereas other tremors, parkinsonism, various hyperkinetic movement disorders, and a number of miscellaneous involuntary movements may represent idiosyncratic reactions. AED-induced movement disorders may well be more frequent in brain-damaged individuals or patients with underlying learning difficulties [198,199], but they are well recognized in subjects with epilepsy who are otherwise neurologically normal. Fortunately, most resolve on withdrawal or dose reduction of the offending drug. The following account is a summary of the

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TABLE 2 Antiepileptic Drug-Induced Movement Disorders Movement disorder Dyskinesia (chorea, dystonia, ballismus, orofacial dyskinesia)

Tremor

Parkinsonism Oculogyric crisis Myoclonus Epileptic Nonepileptic

Asterixis/negative myoclonus Epileptic Nonepileptic

Akathisia Tics/Tourretism Camptocormia Hemiparesis Neuroleptic malignant syndrome Akinetic mutism Ophthalmoplegia

Antiepileptic drugs Phenytoin [21–77] Carbamazepine [78–93] Phenobarbitone [94–97] Valproate [98] Gabapentin [99–101] Ethosuximide [102,103] Valproate [113–122] Valproate and lamotrigine [123] Carbamazepine [124] Phenytoin [125] Valproate [130–138] Phenytoin [139,140] Carbamazepine [143–145] Gabapentin [100]

Methsuximide [104] Pentobarbitol/diazepam withdrawal [105] Felbamate [106,107] Benzodiazepines [108–112] Gabapentin [126,127] Tiagabine [128] Zonisamide [129]

Carbamazepine [146–149] Vigabatrin [149] Valproate [150] Phenytoin [151–153] Carbamazepine [154–156]

Gabapentin [157] Lamotrigine [158] Gabapentin [100,157]

AED withdrawal [159] Carbamazepine [160–166] Valproate [167,168] Phenytoin [33,169,170] Ethosuximide [102,103] Methsuximide [104] Carbamazepine [174–177] Lamotrigine [178] Valproate [180] Phenytoin [181–185] Carbamazepine [187] Phenytoin [189] Phenytoin [190–194] Carbamazepine [89,156,163,195,196]

Carbamazepine [87] Diazepam [141,142]

Primidone [33,171] Phenobarbitone [33] Valproate [172] Phenytoin [173] Phenobarbitone [179]

Topiramate [186] Phenytoin [188]

Barbiturates [197]

⫹⫹

⫹⫹ ⫹

⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹

PHT

⫹

⫹⫹

⫹⫹

⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹

CBZ

⫹

⫹⫹ ⫹

⫹

⫹⫹⫹ ⫹⫹ ⫹

VPA

⫹

⫹⫹ ⫹ ⫹ ⫹

PHB

⫹⫹

⫹

⫹

LTG

⫹⫹

⫹⫹ ⫹

GBP

⫹⫹

⫹⫹

ESX ⫹ ⫹ ⫹ ⫹

BZD

⫹⫹

FBP

⫹

⫹

PRM

⫹

⫹

⫹

VGB TPM

PHT Phenytoin CBZ Carbamazepine VPA Sodium Valproate PHB Phenobarbitone LTG Lamotrigine GBP Gabapentin ETX Ethosuximide BZD Benzodiazepine FBP Felbamate PRM Primidone VGB Vigabatrin TPM Topiramate ZNS Zonisamide ACT Acetozolamide ⫹Single or infrequent anecdotal reports, ⫹⫹occasional but multiple reports, ⫹⫹⫹frequent report or generally acknowledged association.

Tremor Parkinsonism Chorea Dystonia Orofacial dysckinesia Ataxia Myoclonus Asterixis Akathisia Tics/Tourretism Camptocormia Ophthalmoplegia Akinetic mutism Neuroleptic malignant syndrome Hemiparesis

Movement disorder

TABLE 3 Frequency of Observed Antiepileptic Drug-Induced Movement Disorders

⫹

ZNS

312 Kellett and Chadwick

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313

currently recognized involuntary movements associated with AED treatment. In addition, other motor impairments such as ataxia and ophthalmoplegia are considered. HYPERKINETIC MOVEMENT DISORDERS Hyperkinetic movement disorders represent the largest group of AED-induced involuntary movements, encompassing chorea, athetosis, ballismus, dystonia, tardive dyskinesia, orofacial dyskinesia, and oculogyric crisis. The classification of AED-induced hyperkinetic movement disorders is difficult due to the variable nomenclature and definitions adopted by different authors in describing their patients. Therefore, for simplicity we have used the term dyskinesia to describe hyperkinetic movement disorders as a whole, and within this group, involuntary movements are subgrouped as chorea or dystonia and their distributions classified as limb, axial, or orofacial. Most AEDs have been associated with hyperkinetic movement disorders, but phenytoin is the most frequently implicated drug. Phenytoin Harrison and colleagues recently reviewed 79 cases of phenytoin-induced dyskinesia that had appeared in the English literature up to 1993 [71]. Chorea was the predominant involuntary movement associated with phenytoin, affecting 91% of cases. Orofacial dyskinesia occurred in 67% of cases and usually occurred in conjunction with chorea, although in two cases it was the only manifestation [47] and in a further case it was associated with neck dystonia and asterixis [33]. Dystonia occurred in 23% of cases but in the vast majority it was accompanied by other involuntary movements, with only three cases of isolated dystonia. Ballismus occurred in 7% of cases, but was an isolated feature in only a single case, in whom it affected the legs only [44]. Dyskinesia are often generalized, especially when associated with phenytoin toxicity, but focal dystonia or chorea is well recognized and may be related to underlying structural abnormalities, especially those involving the basal ganglia [33,71,74,75]. Reported cases had an age range of 10 months to 81 years and there was a slight male preponderance (56%). Eighty percent of cases occurred in individuals less than age 40 years, with 35% occurring in children less than age 10. Dyskinesia appears to be unusual in subjects over the age of 60 [32,33,39,43,46,66,71]. In 68% of cases dyskinesias occurred in subjects taking phenytoin in addition to other AEDs. Single intravenous infusions were implicated in 18% of reported cases and were likely due to elevated peak levels [41], but dyskinesia may persist following single infusions despite low blood levels [65]. In such cases an underlying susceptibility to dyskinesia development may be present [71].

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Phenytoin plasma concentrations were not specified in 13% of cases of reported cases, but in 57% dyskinesia were associated with levels above the standard therapeutic range (10–21 mg/L). In a further four cases, although standard plasma concentrations were normal, free levels were elevated [52,53,66,67]. Four children developed dyskinesia with low plasma concentrations (⬍10 ␮g/ mL) and a further patient had a prior history of tardive dyskinesia that recurred with low total phenytoin levels [42]. In 23% of cases levels were within the normal range [71]. In early reports of phenytoin-induced dyskinesia, an underlying cerebral injury was thought to be a prerequisite for the development of dyskinesia. In Harrison’s review, over 70% of cases had potential predisposing factors; evidence of previous brain injury manifest by mental retardation or ‘‘static encephalopathy’’ were reported in 39% of cases. A prior history of dyskinesias was reported in 13% of cases, including two cases with a past history of Sydenhams chorea, one with tardive dyskinesia, and another with senile chorea. Previous neuroleptic treatment was reported in four cases (5%) [28,48], and one of these was known to have tardive dyskinesia [42]. Other possible predisposing factors included cardiopulmonary arrest [33], neurofibromatosis [40], abnormal metabolism of phenytoin [25], abnormal copper metabolism [25], and in another case seizures and abnormal movements occurred with meningoencephalitis [65]. Despite the high frequency of suspected underlying neurological injury, only 12% of cases have had identifiable structural lesions and many have not involved the basal ganglia. Thus, the direct relationship to the development of dyskinesia in many of these is unclear [71]. However, associated basal ganglia lesions have included multiple bilateral lacunes in the striatum [39], calcification of the globus pallidus [52,53], thalamic lesions [71], and abnormalities of the posterior putamen [74]. Other cerebral lesions have included a left frontal abscess [33], residual shrapnel in the frontal lobe [38], a history of severe head trauma [54], a probable mass lesion [32], a previously resected meningioma [48] a parasagittal glioblastoma [59], and history of an old subdural hematoma [41]. The majority of phenytoin-induced dyskinesias have resolved on drug withdrawal, but involuntary movements in the form of dystonia and/or chorea have been persistent in some subjects, in which case they may have unmasked an underlying propensity to dyskinesia [33,65]. Carbamazepine Carbamazepine-induced dyskinesias have consisted of generalized chorea or dystonia, depending on the clinical scenario. Following overdoses of carbamazepine, dyskinesia invariably takes the form of chorea that develops within a few to 24 hr. Chorea is sometimes accompanied by dystonia or orofacial dyskinesia, and on occasions dystonia may be an isolated feature (Table 4) [81,83,88,89,92].

14

19

24

17

36

51

13

[83]

[88]

[88]

[88]

[89]

[81]

[92]

↑⫽ Increased

Age (yr)

Ref.

CBZ

CBZ

CBZ PHT

CBZ 400 mg PHT 400 mg PRM 750 mg PHB 96 mg CBZ 1600 mg

18 hr

10 hr

8 hr

⬍24 hr

N ⫽ Normal

CBZ

18 hr

⬍24 hr

CBZ

Drug therapy (mg/24 hr)

30 min

Duration of CBZ therapy

NA ⫽ Not available

Acute axial and limb dystonia ↓ conscious lvel

Opisthotonus Ballistic movements Chorea Coma later Chorea Stupor Ataxia Chorea Ataxia Nystagmus Chorea Stupor Ataxia Axial dystonia Opisthotonus Chorea Dysarthria Chorea Orofacial dyskinesia

Involuntary movement

↓ ⫽ Decreased

F

M

F

F

F

F

F

Sex

TABLE 4 Dyskinesia Induced by Carbamazepine Overdoses

Resolved within 14 hr of treatment Resolved within 12 hr of treatment No recurrence on normal dose Resolved within 2 days of treatment Recurred 2 yr later after CBZ ↑ 600 mg Resolved within 2 days of treatment

CBZ overdose

Overdose of CBZ 5 g ⫹ PHT 2.5 g

29

24.5 32.5

NA

Overdose of relative drugs

Overdose of CBZ 24 g

Resolved within 20 hr of treatment

CBZ 20-g overdose

27

NA 10 70

Resolved within 40 hr of treatment

CBZ 13.2-g overdose

35

Required ventilator support Resolved within 3 days of treatment

Treatment and outcome

CBZ 12–20-g overdose

Other conditions

20

Serum levels (␮g/mL)

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These movements are almost always accompanied by other features of carbamazepine toxicity, which are probably dependent on the prevailing blood levels; chorea is usually accompanied by combativeness and hallucinations when blood levels are between 15 and 25 ␮g/mL, and higher blood levels (⬎25 ␮g/mL) may be associated with coma and paradoxical seizures while at lower levels (11–15 ␮g/ mL) ataxia and drowsiness are likely features [88]. With appropriate resuscitative treatment the dyskinesias usually resolve within 2 days and are not associated with long-term neurological sequelae [81,83,88,89,92]. When carbamazepine has been restarted at normal therapeutic doses it has not been associated with recurrence of dyskinesia [89]. Dyskinesias may also occur when carbamazepine is used in therapeutic doses. In this scenario they are frequently dystonic in nature and usually occur within days to weeks of starting treatment. Of 22 cases with carbamazepineinduced dyskinesia (Tables 5 and 6, three female cases of Arnstein [144] and four Spanish cases reported by Martinon [80]), 20 were manifest by focal [78,82,93] or generalized limb dystonia, axial dystonia or opisthotonus [78–80,82,84,91], oculogyric crisis [143–145], or blepharospasm [86]. In three cases dystonia was accompanied by myoclonus [93], respiratory dyskinesia and myoclonus [91], or orofacial dyskinesia [86]. Two cases had chorea, but one of these had high blood levels and other signs of toxicity [85,87]. Dyskinesias have occurred in all age groups, ranging from 10 months to 71 years. In children, severe dystonia with opisthotonic posturing has often occurred [79,84], and evidence of significant brain injury has been present in six of nine reported children [79,80,84]. In such children, dystonia has occurred soon after starting treatment (⬍3 weeks), and blood levels, when reported, have been within the therapeutic range [79,80]. Two children without neurological deficits had high blood levels, and dystonia developed in one after a mistaken doubling of dose. The cause of dystonia in the second case, which did not occur until after 1 year of treatment, is unclear [84]. In adult patients, dystonic movements have occurred soon after the start of treatment or after increases in dose. However, one case had been on carbamazepine for 2 years prior to the onset of focal leg dystonia, but it clearly resolved on carbamazepine withdrawal, rapidly returned on reintroduction, and increased in severity with dose [93]. Another patient had a tardive-like dystonia that occurred after being on carbamazepine for 6 years and was resistant to various treatments [91]. This patient was also taking lithium. In such cases and others with prior neurological insults or a psychiatric history, other antiepileptic or psychoactive drugs may contribute to the development of dyskinesias. Blood levels have been above the normal therapeutic range in about 50% of reported cases, although even when levels have been high, other signs of toxicity have been rare. In some adults, dyskinesias have been transient and have resolved over days to weeks on the same [78,82,86] or reduced dose of carbamazepine [145].

Age (yr)

11

11

8

5

10 mo

4

Ref.

[84]

[84]

[143]

[79]

[79]

[79] M

M

M

F

F

M

Sex

Dystonia Grimacing Ophisthotonus

Dystonia Ophisthotonus

Dystonia Ophisthotonus

Oculogyric crisis

Dystonia Opisthotnus Severe dystonia Opisthotnus

Involuntary movement

3 wk

3 wk

10 days

13 days

1 yr

2 days

Duration of CBZ therapy

CBZ 25 mg/kg PHT PHB ETX Clonazepam CBZ 25 mg/kg PHT PHB

CBZ 20 mg/kg

CBZ 400 PHT 150 PHB 30

CBZ 5.7 mg/kg bd CBZ 5.0 mg/kg bd

Drug therapy

TABLE 5 Carbamazepine-Induced Dyskinesia in Children

NA 20 NA 5.1 11 NA

NA

4.3 N N

25

21

Serum levels (␮g/mL)

Left cerebral hypoplasia Developmental delay

Neonatal sepsis Developmental delay Spastic quadraparesis Agenesis of corpus collosum Ventriculomegaly Mental retardation

2 days after double normal dose

Other conditions

Rapidly improved but took 10 days to resolve after CBZ stopped Recurred on rechallenge 3 wk after recommenced Resolved within 2 wk of stopping CBZ

Resolved after 6 hr Continued on normal dose Responded to IV diazepam Resolved within 17 hr No recurrence on ↓ dose Responded to diphenydramine in 15 min Resolved on CBZ withdrawal Resolved within 5 days of stooping CBZ

Treatment and outcome

Antiepileptic Drug-Induced Movement Disorders 317

3 adults

36

41

[78,82]

[91]

[93]

Refrence

Age (yr)

F

F

M

Sex

Intermittent Left leg dystonia ⫹? myoclonus

Dystonia Opisthotonus Respiratory dyskinesia Myoclonus

Axial dystonia

Involuntary movement

2 yr

6 yr

After CBZ added

Duration of therapy

TABLE 6 Carbamazepine-Induced Dyskinesia in Adults

6.6

41 ␮mol/L

CBZ 800

NA

Serum levels (␮g/mL)

CBZ 400 Lithium

CBZ ⬎ 1000

Drug therapy

Anxiety, depression, obsessivecompulsive symptoms Transient left hemiparesis age 19

1. Agenesis of corpus callosum 2. Old right frontal abscess 3. Posttraumatic multifocal epilepsy Bipolar disorder 2 wk treatment with haloperidol 2 yr before onset

Other conditions

Persistent ⫹ refractory to treatment with benztropine, diphenydramine trihexyphenidyl, clozapine, reserpine, tetrabenazine, clonazepam Refractory to clobazam ⫹ procyclidine, resolved after CBZ stopped

Transient ⫹ resolved in few days on same treatment

Treatment and outcome

318 Kellett and Chadwick

59

Young adult

Young

71

53

32

[87]

[78,82]

[78,82]

[85]

[86]

[145] M

F

F

F

F

M

Oculogyric crisis

Distal chorea Ataxia Confusion Blepharospasm Orofacial dyskinesia

Opisthotonus

Chorea Throwing objects ?Ballismus Hand dystonia

Within 4 days of ↑ 10 days

After dose ↑

After dose ↑

2 days

CBZ 1200 VPA 3000

CBZ 800 PRM 250 PHB CBZ 400 PHT 500 PHB 120 ACT 1000

“High dose”

CBZ ⬎1000 Haloperidol

CBZ 400

9.5 140

19 3.7 14.3 3

NA

NA

NA

Amoxapine withdrawn ⫹ cimetidine ⫹ diphenydramin e started around same time “Moderate mental retardation” cps

Idiopathic generalized epilepsy Schizophreniform psychosis Secondary GTCS

Alcohol abuse

Resolved on reduced dose CBZ 500 mg

Transient and resolved on stopping CBZ Resolved within 7 days of stopping CBZ Resolved over 3 wk with no change in treatment

Transient ⫹ resolved on same treatment within 1 mo

Resolved within 12 hr of drug cessation

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In the remainder, withdrawal of carbamazepine has been quickly followed by improvement; however complete resolution may take up to 2 weeks and dyskinesias have recurred on rechallenge in some cases [79,93]. In two patients symptomatic improvement was gained by diphenhydramine [143] or diazepam [84]. Despite the large number of people treated with carbamazepine, dyskinesias develop in only a few. In cases of overdose, dyskinesia represents one manifestation of a carbamazepine-induced toxic encephalopathy. However, in the majority of cases, which occur soon after initiation of therapeutic doses, carbamazepineinduced dyskinesia is probably a result of an idiosyncratic reaction. Sodium Valproate Only three cases of sodium valproate-induced dyskinesia have been reported, and all occurred in subjects with significant learning difficulties [98]. Two cases had refractory symptomatic generalized epilepsies and another a refractory symptomatic partial epilepsy. Orofacial dyskinesia with limb and axial chorea lasting 30 min to 8 hr occurred 90 min to 3 hr after drug ingestion. The patients had been taking valproate for 2 to 7 years before the development of involuntary movements. The reason for the development after such a long latent period is unclear. Two cases were taking phenytoin at the time of dyskinesia, and in one of these dyskinesia occurred 1 month after carbamazepine was switched to phenytoin without changing valproate dosage. Subsequent withdrawal of phenytoin had no effect, and dyskinesia settled only after manipulation of valproate dosage, suggesting that phenytoin was not directly implicated. Trough valproate blood levels were unremarkable in all cases, however, in one case dyskinesia were associated with high peak blood levels, and in the other two cases dyskinesia occurred at a time when blood levels would have been expected to be high. In two cases dyskinesia settled when valproate preparation was changed to sodium valproate sprinkles, while in the other it settled only on withdrawal. Gabapentin In premarketing studies, 1.3% of patients treated with gabapentin were reported to develop ‘‘twitches,’’ compared to 0.8% of controls, and choreoathetosis was reported in 0.1% of 1486 treated individuals (D. Benezra, cited in Ref. 100). Postmarketing, four cases with prior brain surgery or neurological deficits including significant learning difficulties and refractory partial epilepsy have developed dyskinesia (Table 7) [99–101]. Chorea has occurred within 2 weeks of starting treatment at doses between 1200 and 1800 mg/day. Three of four patients were taking other AEDs, and phenytoin levels were high in one case [99]. However, in all cases, onset was temporally related to the introduction of gabapentin and dyskinesia improved or resolved on dosage reductions. Chorea recurred in one case who was rechallenged [101]. A single dystonic episode lasting 15 hr was

Age (yr)

24

42

41

37

Ref.

[100]

[101]

[101]

[99] F

F

F

M

Sex

Orofacial dyskinesia Limb and axial chorea

Limb and axial chorea

Orofacial dyskinesia Oculogyric crisis Opisthotonus Chorea

Involuntary movement

NA 12.9 ␮g/dL

GBP 400 mg tid PHT 200 mg qd FBM 400 mg tid

5 days

45

GBP 1200 mg/d PHT 425 mg/d

⬍14 days

NA 51

GBP 600 mg tid VPA 3750/d

⬍14 days

NA

Serum levels (␮g/mL)

GBP 600 mg tid

Drug therapy

1 mo

Latency to onset after GBP started

TABLE 7 Gabapentin-Induced Dyskinesias

Severe mental retardation

Previous right frontal lobe resection for frontal lobe epilepsy Infantile encephalitis, severe mental retardation, hypotonic quadraparesis Severe mental retardation, spastic quadraparesis

Other conditions

↓ Severity after dose ↓ to 600 mg/day; rechallenge on LTG and PHT led to recurrence 7 days after dose reached 600 mg tid Improved after diphenhydramine 25 mg; gradually resolved within 3 wk of discontinuation

↓ Severity after dose ↓, but took 10 wk to stop after discontinuation of GBP

Resolved 1 min after 2 mg IV lorazepam without recurrence

Treatment and outcome

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reported in a man with normal intelligence 1 month after starting gabapentin; it responded to a single dose of lorazepam [100]. In all cases, withdrawal of gabapentin was associated with gradual resolution of dyskinesia, although this took up to 10 weeks [99,101]. Felbamate Felbamate-induced aplastic anemia has limited the use of this drug in the United Kingdom and Europe, but it is still available in the United States and other regions. Involuntary movement and gait disturbance abnormalities were noted in early monotherapy studies (data on file, studies 244 and 231, Wallace Laboratories, Cranbury, NJ [200], cited in Ref. 106) and, in add-on studies, 6 of 15 patients taking over 3600 mg/day were noted to have involuntary movements (data on file, study 221, Wallace Laboratories, Cranbury, NJ [200], cited in Ref. 106). The details of these involuntary movements are not available, but there have been case-reports of felbamate-induced dyskinesia. A 13-year-old boy with probable symptomatic generalized epilepsy developed jerking involuntary movements of the limbs, neck, and trunk, accompanied by agitation, confusion, and akathisialike symptoms, when felbamate was rapidly titrated to 1800 mg/day in addition to preexisting valproate and ethosuximide. In a second case, dystonic eye deviation occurred in a 2-month-old baby with drug-refractory seizures, after felbamate was introduced and rapidly titrated over 4 days to 240 mg/day. In both cases withdrawal of felbamate led to resolution within 1–3 days. In the first case, a questionable benefit was gained after intramuscular diphenhydramine [106]. Benzodiazepines Benzodiazepines appear to be an infrequent cause of involuntary movements, and the rare reports have concerned patients with psychiatric symptoms [108–112] or on–off ingestions [112]. Diazepam-induced dystonia [108,110,111], torticollis [112], dyskinesia [110], and buccolingual dyskinesia [109,112] have been reported. These have usually been acute and sometimes recurrent reactions [109,112], although some cases may represent a tardive-like reaction to chronic treatment [110]. In a number of cases symptomatic treatment with diphenhydramine has been successful, although most acute reactions resolve spontaneously after withholding the drug. Barbiturates Phenobarbitone-induced dyskinesia have been reported following deliberate overdose but also as apparent idiosyncratic reactions following onset of therapy at low doses (Table 8). In one case, orofacial dyskinesia, chorea, and torsion movements of the shoulder and arms accompanied by ataxia, nystagmus, and dysarthria occurred during the recovery phase following an overdose of phenobarbitone

25

[97]

[96]

[94]

36

2

2

Ref.

[78,82, 95]

Age (yr)

F

M

F

F

Sex

Orofacial dyskinesia Limb chorea ? Dystonia

Orofacial dyskinesia Torticollis Blepharospasm

Oculogyric crisis Severe orofacial dyskinesia Oromandibular dystonic spasms

Episodic torticollis opisthotonus

Involuntary movement

⬍24 hr

9 days

6 hr

⬍ 12 hr

Duration of PHB therapy

TABLE 8 Phenobarbitone-Induced Dyskinesias

Diazepam 15 mg Dichloralphenazone 1300 mg

PHB 5 mg/kg PHT 10 mg/kg (single treatment for status)

PHB 100 mg

PHT

PHB 200 mg/day in 2 doses

Drug therapy

88

20

16

2.5

14.3

Serum levels (␮g/mL)

Overdose of PHB Accompanied by reduce conscious level ataxia, nystagmus, and dysarthria

Tuberculous meningoencephalitis age 7 Right frontal, putamen and caudate abnormalities on CT Brain left hemiparesis, dysphasia, oral apraxia Enhancing basal ganglia calcification and diffuse cortical enhancement possibly secondary to hypoxia

Recent episode of status epileptics and cardiac arrest

Other conditions

Minimal effect of anticholinergic therapy Resolved 7 days after withdrawal Recurred after 2 doses (PHB levels 7 ␮g/mL) and only resolved after 2 mo Resolved within 5 days of overdose with supportive therapy

Dyskinesia improved after ↓ PHB to 50 mg/day Resolved 40 days after withdrawal Recurred 1 day after rechallenge with PHB 50 mg (PHB level 6 ␮g/mL)

Transient ⫹ resolved within 24 hr of PHB withdrawal

Treatment and outcome

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[94]. In three other cases, orofacial dyskinesia with other dyskinesias occurred soon after commencing phenobarbitone therapy, when plasma concentrations were relatively low [95–97]. In two cases onset was within 12 hr of the first dose [96,97], although in another case involuntary movements did not occur for 9 days [95]. Dyskinesia improved after dose reductions and resolved after discontinuation but recurred in two cases who were rechallenged. Furthermore, in one case dyskinesia that resolved after 7 days on initial challenge took 2 months to settle on rechallenge [95]. Significant underlying abnormalities of the cortex and basal ganglia were present in two cases which were slow to resolve, and it is possible that such areas may be more sensitive to phenobarbitone, which is preferentially accumulated in the brain. Succinamides Involuntary movements in the form of chorea, orofacial dyskinesia, and akathisia have been reported in three children aged 3, 8, and 11 years following treatment with ethosuximide [102,103]. In all cases, motor restlessness, purposeless movements of the limbs, facial grimacing, lip smacking, and tongue protrusions began within 12 hr of the first dose and persisted until drug withdrawal. Dyskinesia rapidly resolved in two cases after oral or intravenous diphenhydramine. Methsuximide has also been associated with orofacial dyskinesia and akathisia that progressed to severe generalized chorea. The involuntary movements occurred 24 days after methsuximide was added to valproate and clobazam in a 17-year-old male. Movements limited mobility and necessitated nasogastric feeding until they spontaneously resolved over a week. In this case benztropine and diphenhydramine were ineffective in abating the chorea [104]. Summary of AED-Induced Dyskinesia The dyskinesias induced by AEDs superficially resemble the acute dyskinesia seen following neuroleptic treatment. However, tardive dyskinesias are invariably symmetrical and, in contrast, AED-induced dyskinesia are often asymmetrical and may even be focal, reflecting the influence of underlying structural lesions. Tardive-like dyskinesia and dystonia after chronic AED therapy appear to be unusual. In all but a few cases, dyskinesia occurs soon after starting treatment or as a feature of toxicity. In almost all cases, gradual improvement occurs on drug withdrawal or dosage reduction. Patients with various preexisting brain injuries may be more likely to develop dyskinesia with phenytoin as well as other AEDs. In such patients dyskinesia may take longer to settle, and indeed, in patients with focal dyskinesia, they may be persistent, suggesting that movements have been unmasked by the respective drug.

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TREMOR Nonspecific Tremor Nonspecific tremor may be a relatively common accompaniment of AED therapy, but, with the exception of the tremor associated with sodium valproate, it is rarely of clinical significance. Tremor has occasionally been reported with carbamazepine in patients with learning difficulties who are also taking other drugs [124], and a rhythmical rest tremor in association with various other involuntary movements and signs of diffuse encephalopathy is sometimes seen in the course of phenytoin toxicity [125]. Significant tremor is relatively unusual with the newer AEDs. It was not a frequently reported side effect in placebo-controlled add-on studies of lamotrigine [201,202], vigabatrin [203], topiramate [204], felbamate [205], losigamone [206], or remacemide [206]. Unspecified tremor was reported in 7–13% of patients taking gabapentin [126,127] and 9% of patients taking tiagabine [128], versus 3% taking placebo in each case, although in longer-term studies of tiagabine, tremor was reported in 20% [128]. Zonisamide was not associated with tremor in premarketing studies, but two patients have been described in the Japanese literature who developed resting and postural hand tremor with a frequency of 4–5 Hz after taking zonisamide. Mild cogwheel rigidity was seen, but there were no other parkinsonian features. The symptoms disappeared completely after cessation of the drug [129]. Sodium Valproate-Induced Tremor Clinically and neurophysiologically, sodium valproate-induced tremor resembles that of benign essential tremor [115,120]. It is most prominent on action or on antigravity posturing but often has a rest component, and may be accompanied by head titubation, or a feeling of truncal tremor [115,120]. It has a variable positional-dependent frequency between 6 and 15 Hz. The tremor is usually bilateral and is exacerbated by intentional movement and is most prominent in the dominant hand [115,120]. The rest tremor component may be of low amplitude and high frequency, and in some cases it may be more prominent than postural elements. In rare cases rest tremor may be accompanied by other features of parkinsonism [130,134,135,137,138]. Approximately 10–25% of patients taking valproate have a symptom [113,114,120], although with more careful study, including the use of accelerometric recordings, abnormalities in varying degrees can be found in up to 80% of cases [120]. On occasions sodium valproate may precipitate or exacerbate tremor in patients with an underlying propensity, such as a family history of essential tremor [115]. The latency to onset is variable. Seven of 10 patients reported by Karas et al. [120] developed tremor within a month of starting valproate, but three of Hyman’s four cases did not develop tremor until after 12 months treatment, and

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Mattson and Cramer have suggested that sodium valproate mediated tremor may increase with duration of treatment [119]. Tremor appears to be dose-related [116,117], occurring only in doses above 750 mg [120] to 1000 mg [115] per day, although many patients report maximal tremor in the mornings at times that do not correspond to peak drug levels [120]. There has been no consistent relationship between blood valproate level and tremor severity [114,115,120]. Nevertheless, tremor amplitude often decreases on dosage reduction or following the use of long-acting preparations [115,120,121], although improvement may take a few weeks [122]. Treatment of valproate-induced tremor is problematic. Mattson and Cramer reported equivocal effects of propanolol [119]. A subsequent study in 19 patients using serial tremor recordings suggested that propranolol has variable effect but is the best agent, amantadine has moderate efficacy, but cyproheptadine, diphenhydramine, and benztropine offer little if any relief [121]. The tremor associated with valproate is variable in severity but is usually nondisabling. However, in two cases, when sodium valproate was combined with lamotrigine, the amplitude of tremor increased dramatically. It interfered with hand function and the ability to feed, and was associated with dysarthria, truncal ataxia, action tremor, or head titubation [123]. Tremor was precipitated by phenytoin withdrawal, unmasking the effect of valproate on lamotrigine metabolism in one case. Improvement followed reductions of lamotrigine in one case and of valproate in the other [123]. This represents an important drug interaction. It is common in clinical practice and is probably more related to a pharmacodynamic interaction than the well-recognized pharacokinetic interaction [207].

PARKINSONISM In contrast to dyskinesias, which have been reported relatively frequently with AEDs, hypokinetic movement disorders and in particular parkinsonism are less common. A general slowness of movement may occur with drugs such as phenobarbitone and primidone. This does not have features of parkinsonism, but treatment with high-dose diazepam in psychiatric patients has been associated with the development of a parkinsonian syndrome [141,142]. A reversible atypical parkinsonian state dominated by bradykinesia has also been reported in a 13-year-old boy, who, over a 22-month period, was receiving ethosuximide, paramethiadone, phenytoin, and for a time acetazolamide. He had severe bradykinesia with few spontaneous movements and a marked paucity of facial expression, there was no spontaneous speech, and there was a coarse tremor of the outstretched hands. Electroencephalogram showed a progressive increase in slower frequencies, consist with phenytoin toxicity, but there were no other signs of toxicity and on a number of occasions phenytoin levels were in the

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therapeutic range. However, withdrawal of phenytoin and the introduction of a ketogenic diet was associated with a marked improvement in his condition, which coincided with a fall in phenytoin plasma concentration [139]. In another case an atypical parkinsonian state developed in a 15-year-old who was treated with 300 mg/day carbamazepine for 5 months. He developed a slow shuffling gait, generalized rigidity, and repeated attacks of generalized shivering-like movements. The nature of the disorder was unclear, but his symptoms resolved within a week of stopping carbamazepine [87]. Sodium valproate is known to increase brain levels of GABA, a neurotransmitter that acts in functional antagonism with dopamine, especially in the basal ganglia. In view of this mechanism, Lautin and colleagues assessed its utility in a patient with schizophrenia [208]. There was little antipsychotic effect, but a reversible dose-dependent extrapyramidal syndrome, indistinguishable from that subsequently induced by neuroleptic treatment, developed following treatment with sodium valproate monotherapy at a dose of 1 g/day. This was manifested by circumoral tremor and bilateral low-amplitude rest tremor, but rigidity was minimal and there was no bradykinesia. Anticholinergic therapy had no effect on the valproate-induced movement disorder tremor, although it abolished that induced by the neuroleptics [208]. In a number of anecdotal reports, sodium valproate has also been implicated in the development of a syndrome mimicking chronic neurodegenerative conditions manifested by parkinsonism [130,132–134,136,137] or dementia [209,210]. These parkinsonian effects are thought to be distinct from the typical valproateinduced tremor. In a review of 88 of his valproate-treated patients, Van der Zwan found three cases with coarse tremors and associated cogwheel rigidity and a further two with more typical parkinsonism, all of whom improved on valproate withdrawal [130]. Armon et al. [131] reported two patients with liver impairment in whom reversible hearing loss as well as motor and cognitive impairments were atttributed to valproate. Following these cases, Armon and colleagues described a syndrome characterized by reversible valproate-induced parkinsonism and cognitive impairment, which was surprisingly common in their patients [138]. Reversible Valproate-Induced Parkinsonism and Cognitive Impairment Armon and colleagues systematically studied all patients attending the Durham Department of Veterans Affairs Medical Center Epilepsy Clinic who had been taking sodium valproate for longer than 12 months. Initially, seven cases with marked parkinsonism requiring hospitalization, thought to be due to valproate, were studied, followed subsequently by a further 29 prospectively evaluated cases. Thirty-three of 36 patients reported some neurological symptoms, with gait instability, unsteadiness, or tremor affecting just over half. On examination, rigidity

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was present in 83%, slow alternating movements in 81%, 4–7-Hz tremor in 79%, postural instability in 70%, and bradykinesia in 62%. Seventy-five percent had three or more of these findings consistent with parkinsonism. The Unified Parkinson’s Disease Rating Scale (UPDRS) scores ranged from 0 to 78 with a median of 22 and a mean of 26. In addition to parkinsonism, abulia was present in 55%, cognitive impairment in 86%, progressive hearing loss in 63%, and upper motor neuron signs in 44% of cases [138]. Symptoms, signs, and UPDRS scores improved in 26 of 32 patients who withdrew from valproate treatment and were followed up for 3–12 months. Instability, unsteadiness, and tremor improved in over 80%. Parkinsonism improved gradually, the majority of improvement appearing within 3–6 months, but cognitive improvement was slower to appear. UPDRS scores were reduced in all patients with parkinsonism once valproate was withdrawn, with mean UPDRS scores of 29.7 and 10.1 on and off valproate, respectively. Of the 13 patients who had moderate to severe parkinsonism on a categorical measure based on the worst individual score on the UPDRS, only three were affected as severely on withdrawal of valproate and the other 10 were only mildly affected. Duration of treatment with valproate appeared to be the most significant independent factor associated with improvement after valproate withdrawal. Most patients developed reversible neurological dysfunction on monotherapy, and the presence of other AEDs did not affect the severity of parkinsonism or cognitive impairment at presentation. The improvements could not be attributed to other changes in medication [138]. In the authors’ experience, parkinsonism has not been a common accompaniment to valproate treatment, although patients are rarely examined specifically for such features. The significance of Armon et al.’s study [138] and other anecdotally reported cases [130,132–137] therefore remain unclear, and further larger studies are required. These should include careful examination because Armon et al. commented that ‘‘the manifestations may not be apparent unless looked for specifically in the minimally or mildly affected patients’’ and in the more severely affected, the insidious onset may be mistaken for Parkinson’s disease, dementia, or other neurodegenerative disease [138]. MYOCLONUS Myoclonus is a common feature of various toxic or metabolic encephalopathies, but, in addition, is a feature of a number of epilepsy syndromes, particularly juvenile myoclonic epilepsy and progressive myoclonic epilepsy [211]. Myoclonus may occur for a number of reasons following AED treatment and may be accompanied by other involuntary movements in the form of asterixis [157], tremulousness [157], orofacial dyskinesia, dystonia, or chorea [29,91,212], or tics [155].

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First, epilepsy-related myoclonus may be precipitated or exacerbated in patients with idiopathic generalized epilepsies who are treated with carbamazepine [146–149], vigabatrin, [149], gabapentin [157], or even lamotrigine [158]. In this situation myoclonus is almost always associated with the presence of other seizure types. Second, myoclonus may be a manifestation of encephalopathy due to acute drug toxicity. It may be accompanied by other signs of AED toxicity such as ataxia, asterixis, paradoxical seizures, and impaired consciousness, even coma. Overdoses of valproate [150] and phenytoin [151] may occasionally be associated with a myoclonic encephalopathy, and myoclonus was reported in about 2% of cases following carbamazepine overdose [156]. Phenytoin toxicity has been implicated as a cause of stimulus-induced generalized myoclonus [152] and postural and action myoclonus [153]. Stimulusinduced generalized myoclonus occurred in a 1-month-old baby, accompanied by lethargy, poor feeding, hypertonicity, a paradoxical increase in seizure activity, and burst suppression on EEG, and was associated with phenytoin levels of 94 ␮g/mL. On substitution of phenobarbitone for phenytoin, stimulus-sensitive myoclonus resolved over 7 days, although the background EEG rhythm took longer to normalize [152]. In another case, postural and action myoclonus in all four limbs developed in a 72-year-old man, 1 month after starting treatment with phenytoin 300 mg/day. Plasma concentrations were high at 34 ␮g/mL, but he had no other signs of toxicity. Electromyography confirmed high-amplitude myoclonic jerks with a duration of 40–50 msec occurring in agonist muscles with frequency of 1–2 Hz [153]. When myoclonus is due to drug toxicity, withdrawal of the offending drug leads to rapid resolution, although occasionally it may take up to 6 months to resolve completely. In such cases the myoclonus may have resulted from an idiosyncratic reaction rather than drug toxicity per se [153]. Finally, and least commonly, nonepileptic myoclonus may be an idiosyncratic reaction to therapeutic plasma concentrations, without other signs of toxicity. Aguglia et al. [154] reported an 11-year-old boy with benign occipital epilepsy who developed tics and myoclonic jerks involving proximal limbs, 2 weeks after starting treatment with carbamazepine. Carbamazepine levels remained within the therapeutic range. Clobazam improved the myoclonus, but it resolved only when phenobarbitone replaced carbamazepine, only to recur on rechallenge 6 months later. In a similar case, rapidly reversible multifocal myoclonus was associated with therapeutic carbamazepine levels and the authors postulated high carbamazepine-10,11-epoxide levels as the cause [155]. In addition to precipitating epileptic myoclonus in generalized epilepsies, gabapentin in doses between 1200 and 4800 mg/day has also been implicated as a cause of nonepileptic myoclonus [100,157]. In abstract form, Scheyer reported three patients with partial epilepsy who developed myoclonus, accompanied in

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two cases by asterixis or startle myoclonus with tremulousness. The nature of these reactions is unclear, but they may have been a result of idiosyncratic reactions because there were no other signs of toxicity, the EEG was normal, and all movements rapidly resolved on withdrawal [157]. ASTERIXIS AND NEGATIVE MYOCLONUS Asterixis is a form of negative myoclonus that is due to brief postural lapses associated with pauses in tonic EMG activity [211,213]. It is most commonly seen with toxic or metabolic encephalopathies, particularly hypercapnia and hepatic or uraemic encephalopathy [214]. However, it is relatively common with various AED treatments (Table 1). In one study over an 18-month period, asterixis was the most frequently observed AED-induced involuntary movement [33]. It is usually [25,28,29,33,44,50,160,163,167,169–171,215–218] but not always [161,165,219] a sign of toxicity, and it may be more likely with AED polytherapy or co-administration of other psychotropic drugs [165]. When it is due to toxicity, it may be associated with other involuntary movements such as myoclonus [157,169] chorea [28,29], dystonia [28,33], ballismus [44], orofacial dyskinesia and ataxia [33], or ophthalmoplegia [163]. Structural lesions of the brain, particularly the basal ganglia and upper midbrain, may themselves cause asterixis [220–226], and unilateral asterixis of the left arm has been reported in a patient with right anterior cerebral artery stroke who was given phenytoin and had normal therapeutic levels [213]. Negative myoclonus also occurs in various epilepsy syndromes. In three recently reported cases with partial epilepsy, continuous epileptic negative myoclonus, responsive to clonazepam, occurred on withdrawal of clobazam or valproate from other treatments (carbamazepine or phenobarbitone). Spike-wave discharges on EEG were accompanied by repetitive loss of postural EMG activity in one or more limbs [159]. Asterixis accompanied by nystagmus, confusion, and drowsiness has, in some cases, been attributed to carbamazepine [161,162] or valproate-induced hyperammonaemia [167,168]. The role of ammonia in other causes of asterixis, especially those associated with valproate, which is a known cause of hyperammonemia [227,228], is uncertain, although ammonia levels have been normal in some cases with phenobarbitone or phenytoin-induced asterixis [161,169]. MISCELLANEOUS MOVEMENT DISORDERS Tics and Tourettism Ticlike disorders have been reported with phenobarbitone [179], carbamazepine [174–177], and lamotrigine [178], and on occasion have been accompanied by

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myoclonic-like movements [154,175]. Tics following treatment with carbamazepine or barbiturates have occurred mainly in subjects with a preexisting tic disorder [174,176,179]. In these cases, tics have been precipitated or exacerbated by carbamazepine, and the response to treatment with haloperidol in some cases is suggestive of underlying Tourette’s syndrome [173]. However, a prior history of tics is not a prerequisite for the development of carbamazepine-induced tics [177]. In two cases, carbamazepine-induced tics were similar to those previously induced by treatment for hyperactivity disorders, using dextroamphetamine in one case and desipramine or methylphenidate in another [175]. Furthermore, in two patients with Huntington’s disease and Alzheimer’s disease, tics developed in addition to preexisting movement disorders following treatment with carbamazepine [176]. Plasma concentrations in all reported cases have been within the therapeutic range, suggesting idiosyncratic reactions. In children without a predisposition or a significant underlying neurological deficit, tic disorders were mild or transient and either resolve spontaneously despite continuation of carbamazepine treatment at the same or higher doses or rapidly disappeared on stopping the drug [177]. However, in other children, complex tics have persisted even after carbamazepine withdrawal, and in three cases were controlled by haloperidol [174,176]. Lamotrigine has recently been associated with the development of complex tic disorders resembling Tourette’s syndrome in three children aged 7, 8, and 12, in whom there was no family or preceding history [176]. In addition to tics in the form of repetitive facial twitches and grimacing, severe single retropulsive head jerks, blepharospasms, shoulder shrugs, sniffing, and grunting, one child developed obsessive-compulsive symptoms; he would ‘‘place a chair in the middle of the room and turn around it ten times in one direction and again in the opposite; he repeatedly opened and closed one drawer; he placed his toys in rows and then changed there order several times.’’ Lamotrigine-induced Tourettism, including obsessive-compulsive symptoms, appeared to be dose-related and resolved on withdrawal, although a minor obsessive-compulsive trait persisted for several months in one case [176]. Akathisia Motor hyperactivity is well recognized following treatment with barbiturates [199,229], but this is not entirely typical of akathisia. More convincing akathisia, accompanied by other dyskinesias, has been reported following treatment with ethosuximide [102,103] or methsuximide [102,103]. On occasions phenytoin or valproate toxicity has also induced a similar problem [102,103]. AED-induced akathisia bears some resemblance to that induced by acute neuroleptic treatment, and resolves on drug withdrawal. Tardive akathisia has not been reported following treatment with AEDs [229].

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Camptocormia Camptocormia, or ‘‘bent spine,’’ is a rare movement disorder that is characterised by severe flexion of the thoraco-lumbar spine which increases during walking and disappears when recumbent. In most cases it is thought to represent a psychogenic conversion [230–232] and was common in young soldiers during World War I, possibly exacerbated by constant stooped postures of walking in the trenches [233,234]. Organic causes include structural lesions of the spinal cord or vertebra [230], and it has recently been reported in Parkinson’s disease [235]. In a curious case, camptocormia developed following treatment with sodium valproate in a 23-year-old intellectually impaired girl with tonic-clonic, myoclonic, and astatic seizures following the withdrawal of carbamazepine due to liver toxicity. Camptocormia developed at a dose of 1500 mg/day but resolved after the dose was decreased to 900 mg/day. However, 4 months later abnormal walking returned, necessitating a further reduction to 700 mg/day. Blood valproate levels associated with these doses were 530, 440, and 300 ␮mol/L, respectively. The mechanism in this case is unclear, structural pathology within spinal cord was not excluded, but the severity of camptocormia appeared to be dose-related despite valproate blood levels being within the therapeutic range [180]. AEDs and Neuroleptic Malignant Syndrome In addition to treatment with major tranquilisers, a number of disorders that produce dopamine deficiency may lead to a disorder resembling neuroleptic malignant syndrome [236–239]. In a schizophrenic patient with prior history of classic neuroleptic malignant syndrome due to thiothixene treatment, carbamazepine induced a similar condition that resolved on its withdrawal [187]. There was no associated rigidity, but nevertheless the case satisfied the recognized diagnostic criteria of Levenson [240]. In a number of other cases, carbamazepine in combination with major tranquilizers facilitated the development of [241] or modified the presentation of classical neuroleptic malignant syndrome [241,242]. Akinetic Mutism Akinetic mutism is a rare unconscious state in which subjects seem to be awake but lack mental activity, are unable to speak, and do not respond to any environmental stimulus. Cyclical sleep and awake states are maintained, and incontinence is present. A condition resembling this developed in a 12-year-old patient with epilepsy in association with phenytoin toxicity. She appeared awake, was unable to speak or to understand, and had no movements with either spontaneous or noxious stimuli. Phenytoin plasma concentrations were high, at over 40 ␮g/mL, and other causes of akinetic mutism were excluded Following the substitution of carbamazepine for phenytoin, motor and mental function improved within 2 months and the patient was symptom free 2 years later [189].

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Ophthalmoplegia Although it is not a true movement disorder, ophthalmoplegia has been associated with the ingestion of large doses of a number of different AEDs but most commonly phenytoin and carbamazepine [163,190–197,243,244]. In such cases, ophthalmoplegia is usually, but not always [163,192], accompanied by ataxia or various states of unconsciousness varying from drowsiness to stupor. However, phenytoin-induced ophthalmoplegia with retained consciousness has occurred with therapeutic serum levels [191]. In occasional patients with carbamazepineinduced dyskinesia, ocular skew deviation and down-beating nystagmus has been noted with high serum levels [89]. The ophthalmoplegia associated with carbamazepine and phenytoin is usually out of proportion to the degree of unconsciousness. A disproportionate action on the vestibular or vestibulo-ocular pathways in the brainstem by phenytoin and carbamazepine, which both have vestibular sedative properties, has been proposed [190]. In keeping with this, changes in brainstem auditory evoked responses have been reported with phenytoin-induced ophthalmoplegia [244]. Other proposed mechanisms include anticholinergic properties of carbamazepine acting on the pontine reticular formation [163], or the ability of phenytoin to potentiate inhibitory synapses in the vestibulo-oculomotor pathway which utilize gamma-aminobutyric acid, and to increase the discharge rate of Purkinje cells which exert an inhibitory influence on the same structures [190]. Improvement in the ophthalmoplegia usually begins soon after drug withdrawal, but complete recovery may take weeks to months in some cases [192]. Hemiparesis A marked contralateral hemiparesis developed or was exacerbated in two patients who had undergone surgical resection of frontal meningiomas and been given phenytoin as seizure prophylaxis. Phenytoin toxicity was suspected because both cases had coarse horizontal nystagmus, ataxia, and confusion. As well as hemiparesis, upper motor neuron pattern facial weakness was present, and one case had bilateral extensor plantar responses. Seizures were not present in either patient, and in both cases ataxia resolved within days of stopping phenytoin. After 1 week in one case and 3 weeks in the other, all neurological abnormalities had resolved [182]. Transient hemiparesis has also been reported in ‘‘mentally retarded’’ individuals who have suffered regular seizures [181] or patients with preceding brain damage [183,184]. The pathophysiology is unclear, but phenytoin works by blockade of voltage-gated sodium channels, thereby inhibiting seizure spread in epileptogenic areas. It is possible that injured areas of brain are more sensitive to its suppressive effects even when seizures are not present. Similar mechanisms may underlie hemihyperasthesia [198] and chorea, reflecting the damage to sensory cortex or basal ganglia, respectively.

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More recently, a reversible hemiparesis has been reported in two cases following treatment with topiramate [186]. A 41-year old man with right-sided weakness and epilepsy as a result of cerebral palsy developed left-sided weakness and was unable to weight-bear after topiramate was titrated to 25 mg twice per day over a month. Reported signs on examination were slightly inconsistent with reduced tone and power but increased reflexes, however, the left-sided weakness gradually resolved over 8 weeks on drug withdrawal. In a second case, involving a 59-year-old woman who had extensive infarction of the anterior left temporal lobe as a result of herpes simplex encephalitis, reduced tone and power developed in the right arm and leg when taking 100 mg topiramate twice per day. Again there was improvement over 2 weeks. It is unclear from these brief descriptions whether the apparent weakness was of an upper or lower motor neuron pattern, and therefore it is difficult to hypothesize about the underlying mechanism. OTHER MOTOR EFFECTS Impaired Motor Performance Impaired motor performance during AED treatment may occur for various reasons. Barbiturates frequently cause slowing of motor performance [229], and carbamazepine in therapeutic doses impairs various motor functions including reaction time and postural stability [245–248]. Studies in children have shown that carbamazepine-induced motor impairments are not correlated with plasma concentrations. However, motor functions in children who ceased taking carbamazepine improved significantly compared to those who continued taking the drug [248]. These motor impairments may be more likely following polytherapy, and two cases taking carbamazepine, valproate, phenytoin, and phenobarbitone balance exemplify this. Both had impaired postural sway and reactions times compared to normal controls, but moreover, their reaction times were worse or similar to those seen in parkinsonian patients [249]. Despite these effects, the most common cause of AED-induced impaired motor performance is ataxia. Ataxia Although it is not a true dyskinesia, gait or limb ataxia is probably the most frequent AED-induced movement disorder and is a sign of toxicity of most, if not all, AEDs. In placebo-controlled add-on studies of new AEDs, ataxia was reported in 15–25% of cases [126–128,200–205]. It was most frequent with lamotrigine (22%), but it also occurred with vigabatrin (15%), gabapentin (20%), and topiramate (18%). It also occurs with older AEDs, especially carbamazepine and phenytoin. Ataxia is a dose-related effect of carbamazepine [250] and a prominent feature of overdose [88], an effect that may be exacerbated by preexist-

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ing cerebellar atrophy [251]. In animal models carbamazepine has been shown to be neurotoxic to cerebellar granule cells, an effect that is blocked by NMDA [252]. Phenytoin-Induced Ataxia Ataxia is most frequently associated with phenytoin treatment, and may occur for various reasons [253–259]. As with most AEDs, phenytoin can cause an acute reversible cerebellar ataxia due to dose-related toxicity. This is usually a symmetrical limb or gait ataxia that increases in severity with increasing plasma concentration. For most patients, the threshold for perception of impaired coordination is said to be 30–40 mg/L, but there is marked individual variability [250], and its manifestations may be altered by the presence of an underlying neurological deficit. Nystagmus is often a feature of cerebellar ataxia, but during phenytoin treatment its presence does not correlate well with plasma concentration, although its threshold for development is probably lower, at between 25 and 30 mg/L [250]. In addition to this reversible dose-related toxicity, phenytoin may also cause more long-lasting damage, with permanent cerebellar atrophy reported after shortlived periods of phenytoin toxicity [260–265]. In one case a single exposure to 7 g of phenytoin was associated with acute ataxia with irreversible cerebellar atrophy [261]. The ataxic symptoms subsequently improved, but there was no improvement in cerebellar atrophy [266], which resembled that seen in patients with chronic epilepsy treated with phenytoin [267]. Phenytoin has also been implicated as a cause of a chronic cerebellar syndrome, although this has been an area of controversy. Cerebellar atrophy is well recognized in patients with epilepsy on long-term treatment with phenytoin [267–269]. However, cerebellar atrophy was a recognized accompaniment of uncontrolled epilepsy in the era before the development of phenytoin [270,271]. Many studies examining this relationship have been complicated by the inclusion of institutionalized individuals. Many of these cases had learning difficulties and frequent convulsions that resulted from preceding neurological insults that may have damaged both cortical and cerebellar structures [268,272]. Such individuals have been found to have fewer cerebellar Purkinje cells than nonepileptic controls, a reduction that is correlated more with seizure severity than with amount of phenytoin [268]. Moreover, in one study, patients with rare seizures who were chronically treated with phenytoin were found to have similar Purkinje cell counts as nonepileptic controls [268]. Purkinje cell loss has therefore been attributed to seizure severity rather than phenytoin. However, the situation is not that straightforward because marked Purkinje cell loss has been reported in patients who have partial seizures without convulsions [265,267] or patients treated with phenytoin prophylaxis who have never suffered seizures [260,273]. Furthermore, it has been shown that seizures themselves are associated with metabolic changes in the

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cerebellum [274] and may cause damage due to associated increased Purkinje cell firing [275–278] or by release of excitatory neurotransmitters as a result of spread of the epileptic discharge along connecting pathways. Thus, it is clinically difficult to know whether seizures, phenytoin, or a combination of factors are responsible in individual cases. Animal studies have also produced conflicting data. Early studies revealed a selective loss of Purkinje cells in rats and cats acutely intoxicated with phenytoin [279], but similar experiments in pigs and monkeys failed to show a significant effect [280–282]. More recently, both phenytoin [283] and carbamazepine [252] have been shown to induce apoptosis of cerebellar granule cells at high concentrations, an effect which is dose-dependently blocked by lithium chloride [284]. Experiments in newborn mice have revealed that phenytoin induces neurotoxic damage to granule cells and Purkinje cells in the developing cerebellum and impairs selected aspects of motor coordination ability [285]. Furthermore, recent immunofluorescent studies have suggested the existence of a specific phenytoin-binding site within the Purkinje and granule cell layers through which phenytoin may exert its effects [286]. The controversy over clinical and animal studies assessing phenytoin and the cerebellum has also been matched by radiological investigations. In an uncontrolled study, among 310 patients with epilepsy who underwent computerized tomography (CT) scanning, atrophy of the vermis was found in 48, and 8 had cerebellar hemisphere atrophy. The atrophy was predominantly observed in patients treated with phenytoin who had experienced one or more phenytoin intoxications, and the presence of major generalized tonic-clonic seizures was unrelated [287]. Similarly, Young and colleagues found that in institutionalized subjects, radiological evidence of cerebellar atrophy was more common in those with higher peak phenytoin levels [288]. Magnetic resonance imaging is more sensitive to cerebellar atrophy than CT and has revealed abnormalities in over 50% of patients with epilepsy and high plasma phenytoin concentrations, albeit with no clear correlation between degree of atrophy and plasma level [273]. The absence of control populations makes interpretation of CT and MRI data difficult, with the only controlled study performed to date showing no difference in cerebellar atrophy on CT among 70 patients with seizures and a similar number of normal controls [290]. Single-photon-emission computed tomography with N-isopropyl(iodine-123) p-iodoamphetamine has been used to show relative cerebellar hypoperfusion in 4 of 13 patients with epilepsy treated with phenytoin who had normal MR and CT imaging. Furthermore, the patients with a history of acute phenytoin intoxication tended to show the abnormal relative cerebellar hypoperfusion [291]. In a single patient the cerebellar abnormality on SPECT was to a minor degree reversible on reducing the dosage of phenytoin [292]. Gabapentin-Specific Ataxia Gabapentin may also have a propensity to cause balance problems. In placebocontrolled add-on studies, the frequency of presumed dose-related ataxia

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(15–20%) was little different from other new AEDs. However, in healthy volunteers, a single dose of 1200 mg of gabapentin causes postural abnormalities with increased body sway, an effect not seen with carbamazepine, valproate, vigabatrin, lamotrigine, or losigamone [293]. This may explain why occasional patients have developed isolated ataxia on gabapentin that appears to be an idiosyncratic reaction. Such effects occurred at low doses (300 mg) and manifested as severe gait and postural ataxia leading to difficulty walking and frequent falls, nystagmus, and speech disturbance. One of two reported cases had atrophy of the cerebellar vermis and mild ataxia prior to starting 300 mg/day of gabapentin, but this markedly deteriorated and required drug withdrawal, with rapid resolution of symptoms [294]. It has been suggested that gabapentin-specific ataxia may occur in about 3% of cases, and binding to a gabapentin-specific neuronal binding site which has a high density in the cerebellum has been suggested as a cause [294].

PATHOPHYSIOLOGICAL MECHANISMS OF AED-INDUCED MOVEMENT DISORDERS Glutamate and GABA Glutamate and GABA are neurotransmitters that are crucial for normal basal ganglia function, and both are implicated in epileptogenesis. The mechanism of AED-induced movement disorders is largely a matter of conjecture, but it is entirely possible that drugs which have their prime mechanism of action through glutamate inhibition or enhancement of GABA may induce involuntary movements as a result of this. For example, increased GABAergic striatal inhibition on the medial pallidum is a possible mechanism by which gabapentin and other GABAergic drugs may cause abnormal movements [295,296]. In addition, most of the traditional and new AEDs have NaⳭ channel-blocking actions which serve to limit repetitive burst firng. Action at these channels is both use- and voltagedependent. This therapeutic effect on Na currents is enhanced by sustained depolarization and high-frequency firing as may occur in epileptic foci. This latter property accounts for the unique action of phenytoin, carbamazepine, and other voltage-dependent NaⳭ channel blockers to limit high-frequency firing characteristic of epileptic discharges without significantly altering normal patterns of neuronal firing. NaⳭ channel blockers can prevent sustained repetitive firing enhanced by prolonged depolarization such as that found in epileptic focus. Lamotrigine is thought to act by inhibiting excessive presynaptic glutamate release via voltage-gated sodium channels. Other AEDs that act on NaⳭ channels probably have similar effects on glutamate release and, on the basis of this mechanism, they may alter striatal dopamine uptake. Lamotrigine has been used as a treatment for Parkinson’s disease, and although initial reports suggested some improvements [297], further studies failed to show convincing effects [18,19].

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Like other NaⳭ channel AEDs, lamotrigine’s effect is likely to be use- and voltage-dependent and therefore it would be expected to act preferentially in abnormally depolarized areas susceptible to burst firing, with little effect in areas with normal resting membrane potentials. Lamotrigine has not been associated with the development of chorea, but this may be because AED-induced movement disorders are rare and the usage of lamotrigine is comparatively small compared to the most frequent cause of AED-induced dyskinesia—phenytoin. Most patients developing involuntary movements with phenytoin, carbamazepine, valproate, felbamate, gabapentin, and phenobarbitone have had underlying structural abnormalities or ‘‘static encephalopathies’’ which, if associated with damage to the basal ganglia, may act as predisposing factors. Such structurally damaged areas may include areas with abnormally depolarized neurons that are susceptible to the actions of NaⳭ channel AEDs and subsequent alterations of glutamate, although disturbances of other neurotransmitters are also possible. If a specific pharmacological or physiological explanation was responsible for the induction of chorea, then a certain number of patients who receive the drug should develop movement disorders regardless of the structural integrity of the basal ganglia. It is therefore possible that subjects without overt brain injuries or damage may have subclinical abnormalities that would be revealed by more extensive investigation [75] or pathological examination. Phenytoin In addition to these mechanisms related to their antiepileptic actions, many AEDs have other reported mechanisms that may also contribute to the genesis of involuntary movements. The pathophysiology of phenytoin-induced dyskinesia is unclear, with changes in concentrations of basal ganglia neurotransmitters GABA, acetylcholine, and monoamines being suggested [35]. Phenytoin increases brain GABA and has variable effects on acetylcholine. It decreases activity of acetylcholinesterase [298], but there is a dose-dependent effect on release, with low doses stimulating and higher doses inhibiting acetylcholine release [299]. Phenytoin has complex and variable actions on the dopaminergic system, which were reviewed by Harrison et al. [71]. In the striatal slice preparation, phenytoin inhibits the uptake of tritiated dopamine, which is an active transport process occurring in presynaptic dopaminergic terminals [300]. It has variable effects on dopamine metabolite levels [299,301]. In models believed to represent supersensitivity, possibly at the level of the dopamine receptor, contradictory effects were found with a potentiation of supersensitivity after neuroleptic treatment but an inhibitory effect on apomorphine turning after a 6-hydroxy dopamine lesion [47,301]. It therefore appears likely that phenytoin affects dopamine-mediated behaviors, but the mechanism appears unclear. In keeping with action at dopamine receptors, phenytoin has been shown to block the effects of levodopa

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in parkinsonian patients [302] and is recognized to worsen chorea in patients with Huntington’s disease [302]. It is therefore somewhat surprising that there have only been rare reports of phenytoin-induced parkinsonism [139,140]. Carbamazepine In addition to its NaⳭ channel properties, which may influence glutamate release, carbamazepine has a number of other potential sites of action. Dopamine antagonist properties have been suggested because of its structural similarities to tricyclic antidepressants and to phenothiazines [79], although in a rat model such effects have not been demonstrated [303]. Carbamazepine-induced increases in acetylcholine levels in various regions of the rat brain, including the striatum [304], may have implications for the genesis of some carbamazepine-induced movement disorders [78,82]. Furthermore, its noradrenaline reuptake inhibitor properties [305] may also be responsible for dyskinesia in some patients [306]. Sodium Valproate Valproate appears to be a relatively uncommon cause for dyskinesia, and this may reflect its utility in treating various types of dyskinesia including Sydenham’s chorea, senile chorea, and tardive dyskinesia. In rats, valproate induces various abnormal movements [307]. In young albino rats, head twitching occurs within minutes of injections of large doses of valproate [308]. This is followed by intermittent whole-body ‘‘wet-dog’’ shakes characterized by rapid twisting of the entire trunk with forepaws leaving the ground [309]. Sodium valproate enhances GABA-mediated neurotransmission [310], and these effects have been found to be prominent in the corpus striatum and especially the substantia nigra [311]. Serotonergic interactions are also possible [312,313], and in neuroleptic-induced tardive dyskinesia, effects on cholinergic transmission have been proposed [313]. Such effects have been implicated in the genesis of dyskinesia and tremor [120]. GABAergic actions may also influence the development of parkinsonism because there is excess activity of GABA neurons in the globus pallidus externa in patients with Parkinson’s disease and MPTP-induced parkinsonism [314]. However this GABAergic effect would be expected to manifest itself more quickly and resolve faster after discontinuation than was described in the series of patients reported by Armon [138]. Defects in mitochondrial complex 1 of the respiratory chain are implicated in the etiology of idiopathic Parkinson’s disease and possibly in MPTP-induced parkinsonism [315,316]. For this reason Armon et al. [138] proposed that reversible parkinsonism associated with valproate was most likely a result of its effect on mitochondrial function, particularly its inhibition of complex 1 [317].

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Lamotrigine With the exception of recently described Tourretism, lamotrigine has not been associated with the development of movement disorders. Disturbances of serotonin, monoamines, or secondary messengers have been implicated in tic disorders including Tourette’s syndrome, however, the most favored view is the dopamine hypothesis, which suggests disorders of presynaptic release of dopamine or abnormalities of postsynaptic function [318]. Excessive inhibition of excitatory aminoacids within the striatum can alter dopamine uptake [319,320], and thus the potent inhibitory effect of lamotrigine on presynaptic release of excitatory aminoacids, when given at high doses might also alter the striatal dopamine uptake [201,297,321–323]. Other AEDs In addition to its GABA-enhancing properties [295], gabapentin has a tendency to decrease brain monoamine release in rat brain slices, which may also contribute to its dyskinesia-provoking properties [324]. Phenobarbitone also affects the function of GABA and acetylcholine [325] and is preferentially accumulated in the brain [326], its effects persisting despite low blood levels, as has been reported with phenytoin [279].

CONCLUSIONS Significant symptomatic movement disorders are rare accompaniments of AED therapy, although more subtle abnormalities may be more common and probably go unrecognized. The majority of reports have been anecdotal or small series, and this rarity makes controlled studies difficult. There remain, therefore, difficulties about attribution of causation of many movement disorders and AEDs. AEDinduced movement disorders can be idiosyncratic reactions that may be more likely in predisposed subjects with cerebral damage or other disorders, doserelated toxic side effects, or both. Fortunately, with rare exceptions, AED-induced involuntary movements usually resolve on dosage adjustment or drug withdrawal.

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16 Other Drug-Induced Movement Disorders Gary Hotton and Chris Clough King’s College Hospital London, England

INTRODUCTION The drug-induced movement disorders discussed in this chapter are uncommon, consisting of less than 24% of all drug-induced movement disorders and less than 0.7% of all spontaneously reported adverse drug reactions [1]. The prompt identification of these disorders by the specialist neurologist or general physician prescribing the drug is critical in the effective management of the patient and in some cases the prevention of long-term sequelae. Much of the evidence that a drug causes a movement disorder is based on single case reports. It is therefore often difficult to know for certain whether there is a causal relationship. Movement disorders which improve after drug withdrawal are more likely to be attributable to the drug and can be confirmed by reintroduction of the drug (ethically this be can only justified if it is important for the patient’s long-term therapy). However, we should be alert to the possibility that some drugs may cause irreversible cellular changes which could either be the sole cause of the movement disorder or contribute in some way to its generation in susceptible individuals. The following drug groups have been implicated in the genesis of movement disorders: 1. Cardiovascular drugs: amiodarone, calcium channel antagonists, flecainide 357

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2. 3. 4. 5. 6. 7. 8. 9.

Vestibular sedatives Oral contraceptive pill Opiates Anticholinergics and antihistamines Chemotherapeutic agents: 5-flurouracil, cytosine arabinoside Antimicrobials Immunosuppresants: cyclosporin, FK 506 Miscellaneous: theophylline, buspirone

CARDIOVASCULAR DRUGS Amiodarone Amiodarone is a di-iodinated benzoflurane derivative used predominantly in the treatment of atrial, nodal, and ventricular tachyarrythmias. Estimates of the incidence of amiodarone-induced neurotoxicity vary from 3.2% to 74% [2,3], depending on the definitions used and how rigorous the search for minor adverse reactions. The most frequently observed movement disorder following exposure to amiodarone is tremor (44%); this is usually a bilateral distal postural tremor with a frequency of 6–10 Hz which is indistinguishable from essential tremor. Resting tremor with parkinsonian features and jaw tremor have also been described [4,5]. Other neurological features ascribed to amiodarone ingestion, which may exist independently or in combination, include peripheral neuropathy (10%), mild ataxia (7%), encephalopathy, and proximal myopathy [4,5]. The onset of symptoms may occur between 5 days and 12 months [4,5] from the initiation of therapy. Laboratory examination, imaging, and EEG are typically unremarkable. In most cases the symptoms resolve completely on terminating the drug, with the rapidity of symptom resolution dependent on the duration of exposure. Patients who have received treatment for more than 6 months appear more likely to experience a partial resolution of symptoms than patients who have been receiving treatment for less than 6 months [5,6]. One patient who had received amiodarone for a total of 27 months prior to seeking medical advice for a parkinsonian syndrome experienced no improvement in symptoms on terminating the drug [7]. The fact that this case showed no recovery following cessation of amiodarone argues that either it caused permanent cytotoxic damage (unlike the situation with neuroleptic drugs) or that this case developed an idiopathic parkinsonian syndrome during its administration. The question of whether amiodarone causes a permanent or reversible parkinsonian syndrome is an extremely important one, not only because of the frequency of its prescription in the cardiac population but also because it raises important issues about the putative pathophysiological mechanisms of movement disorders.

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The mechanism of amiodarone toxicity is complex. In-vitro studies have demonstrated a toxic effect of amiodarone on mitochondria. At low intracellular concentrations (100 ␮M), amiodarone inhibits ␤-oxidation of fatty acids; at higher concentrations (200 ␮M), amiodarone inhibits the electron transport system (ETS) [8]. Amiodarone-induced ETS dysfunction bears some similarity to the metabolic abnormalities observed in idiopathic and MPPⳭ-induced Parkinson’s disease. Postmortem studies demonstrate a reduced mitochondrial complex I (a critical enzyme complex in the ETS) activity in the brains of patients with Parkinson’s disease compared to controls. Furthermore MPPⳭ, a compound known to cause an irreversible parkinsonian syndrome, is a potent inhibitor of mitochondrial complex I. Inhibition of the ETS results in termination of oxidative phosphorylation, a consequent reduction in ATP, and the generation of tissue-damaging free radicals. The precise location within the ETS where amiodarone exerts its effect is unknown, however, it is likely that this is the means by which amiodarone induces CNS toxicity. The reason some patients possibly develop parkinsonism and others become ataxic or encephalopathic while the majority remain symptom free or experience a mild tremor may well be due to individual patient factors. Genetic polymorphisms of various ETS enzymes or the presence of subclinical pathology which is simply uncovered by an additional metabolic insult could select individuals at particular risk and focus toxicity on particular parts of the nervous system. Calcium Channel Antagonists The dihydropyridine and nondihydropyridine calcium channel antagonists are frequently used drugs in the control of angina, hypertension, and supraventricular tachycardias. Despite recent concerns over the safety of short-acting calcium channel antagonists, they remain one of the most frequently prescribed groups of drugs. Various movement disorders have been described with these agents; verapamil- and nifedipine-induced myoclonic dystonia [9,10], amlodipine- and diltiazem-induced parkinsonism [11,12], diltiazem-induced akathisia [13], and manidipine-induced worsening of Parkinson’s disease [14]. In all cases laboratory examination and imaging were unremarkable, with symptoms resolving shortly after termination of the drug, and rapidly returning on rechallenging in the one reported case that this was undertaken [11]. The recurrence of diltiazem-induced parkinsonism on rechallenging adds significant credence to the suggestion that this group of drugs may be causally involved in the genesis of the movement disorders described above, and not just temporally associated by chance. The clinical effects of these agents are mediated by inhibition of L-type voltage-gated calcium channels. It has recently been demonstrated that nifedipine may be able to inhibit burst activity of nigral dopaminergic neurons in vitro under particular conditions, this effect being mediated through L-type voltage-gated

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calcium channels [15]. This alone is unlikely to be responsible for the adverse reactions described above, as termination of the offending drug in two of the reported cases was followed be the introduction of another calcium channel antagonist without the reemergence of symptoms [9,14]. Nifedipine also appears to influence the striatal dopaminergic terminals; inhibiting anatoxin-a (potent nicotinic agonist) induced dopamine release from striatal synaptosomes. This is Ltype calcium channel independent, suggesting a direct effect on the presynaptic nicotinic receptors [16]. Such an effect has also been described with methoxyverapamil directly inhibiting nicotinic presynaptic receptors on catecholaminergic terminals [17]. The variety of movement disorders described with calcium channel antagonists may well arise as a result of differing contributions of the mechanisms described above, possibly combined with others yet to be described. The critical aspect of these studies is that they demonstrate that mechanisms exist whereby calcium channel antagonists may influence basal ganglia function. In conclusion, calcium antagonists remain a very useful and safe category of drugs, which only rarely may provoke a reversible dystonia, akathisia, or parkinsonism. Flecainide Flecainide is a class Ic antiarrhythmic used in the control of refractory atrial, nodal, and ventricular tachyarrhythmias. An isolated case has been reported of a drug-resistant oro-facial dystonia indistinguishable from tardive dystonia, with onset 3 days after starting flecainide therapy. Laboratory examination and imaging were unremarkable. The medication was terminated 7 months later, with a partial resolution of symptoms [18]. An isolated case report dose not confirm causation, particularly if the patient was not rechallenged as in this case, but the pattern of dystonia involving the oro-facial musculature is somewhat suggestive of a druginduced aetiology. Furthermore, flecainide is a substituted benzamide structurally similar to sulpiride and metaclopramide, both of which have been reported to cause movement disorders, and in particular tardive dystonia (see previous chapters). Its appears likely therefore that flecainide was responsible for the dystonia in this case. VESTIBULAR SEDATIVES Cinnarizine and flunarizine are piperazine derivatives with marked antihistaminergic and calcium-blocking activity. In high doses (75 mg of cinnarazine twice daily) they may be used in the control of peripheral vascular disease, while at lower doses (30 mg of cinnarizine three times per day) they may be used to control nausea of vestibular origin. It is for this later indication that these drugs are most commonly used. They are responsible for up to 15% of all drug-related

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movement disorders [1]. The most commonly observed movement disorder with these agents is tremor, which may be either a bilateral distal postural tremor indistinguishable from essential tremor or a parkinsonian tremor with associated bradykinesia and rigidity [19]. Other movement disorders reported are akathisia and tardive dyskinesia, predominantly with flunarazine [20]. In all reported cases, laboratory examination and imaging were unremarkable. Drug dosage appears to be an important factor in the development of the parkisonian syndrome, with only 8% of patients who develop the cinnarizine-induced parkinsonian syndrome taking ⬍150 mg/day, compared to 39% of those who develop postural tremor [19]. The time course to onset of symptoms is variable, with symptoms developing days to years after initiation of medication. In most instances the symptoms are reversible, but cases have been reported that remain parkinsonian over a year after terminating the drug. These drugs tend to be used in the elderly population; isolated cases that fail to respond to drug withdrawal therefore may represent the background incidence of idiopathic Parkinson’s disease. The mechanism of toxicity in cinnarizine/flunarizine is uncertain. They clearly possess calcium channel-blocking activity similar to the calcium channel antagonists, but the incidence of movement disorders with cinnarizine/flunarizine is much greater. This may well be related to the structural similarity of these compounds to particular phenothiazines and the likelihood that they possess additional dopamine receptor-blocking activity. ORAL CONTRACEPTIVES The combined oral contraceptive pill (COC) is one of the most widely prescribed medications in Europe and the United States. The role of the COC in migraine and carcinoma of the breast has been widely publicised, but it may rarely also be associated with the development of chorea. The onset of symptoms may occur between 1 and 24 weeks after starting the medication. Laboratory investigation and imaging in most cases is unremarkable [21]. A number of risk factors have been identified: a past history of rheumatic fever, Syndenham’s chorea, chorea gravidarum, congenital cyanotic heart disease, chorea secondary to HenochScho¨nlein purpura, and systemic lupus erythematosus [21]. Only 24% of patients with COC-induced movement disorders lack one of these risk factors. Unlike other drug-induced dyskinesias, e.g., amphetamine or neuroleptic, it is usually unilateral. Furthermore, when patients who have previously experienced chorea experience COC-induced chorea, there is frequently striking similarity, both in laterality and form, to the initial disorder [21]. Changes in the connectivity or the relative proportions of various neuromodulatory peptides may well follow an acute injury to the basal ganglia. The effect of such changes would be to presumably normalize the pallidal and nigral outputs. In this new steady state the basal ganglia would likely to have little

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functional reserve, such that any minor changes in the neurochemical milieu would impair function. It is likely that a scenario similar to this exists in COCinduced chorea, as it has been clearly demonstrated that estrogens increase dopamine receptor numbers in animal models [22]. It is therefore reasonable to postulate that acute striatal lesions affecting the indirect striato-pallidal pathway more than the direct striato-pallidal pathway may become subclinical as a result of altered connectivity, downregulation of the ␩-enkepalin receptors, and upregulation of the ␦-dynorphin receptors of the pallidum and striatum. Should such an injured striatum and pallidum be exposed to increased dopaminergic stimulation resulting from an increased number of dopamine receptors, further changes in neuromodulatory peptides may not be possible and a hyperkinetic movement disorder ensue. Of the 24% of patients without risk factors who develop COCinduced chorea, they may well possess minor abnormalities of the basal ganglia induced by mild perinatal trauma. This would have been asymptomatic during the perinatal period due to the immaturity of the neonatal nervous system, with the changes mentioned above occurring in synchrony with the development of motor skills. OPIATES Opiates are centrally acting analgesics which act on opiate receptors in the brainstem and spinal cord. These receptors are also located in the basal ganglia [23], and so it is not suprising that they may also induce movement disorders. There have been several case reports of opiate-induced dyskinesias. The involuntary movements have been reported with morphine, fentanyl, and methadone and may be choreic, myoclonic, or facial in nature [24–26]. The co-administration of other psychotropic medications appears to be a considerable risk factor, as the majority of reported cases were concurrently taking either benzodiazepines, antidepressants, or neuroleptics [25,26]. Reducing or stopping the opiate in all cases when it was possible to do so resulted in resolution of symptoms. The true incidence of movement disorders attributable solely to opiates is unknown, because of coprescription of other drugs but is presumably very low. The precise neuromodulatory effect of enkephalin on the GABAergic striatal neurons is unknown. However the ‘‘direct’’ and ‘indirect’’ pathways utilize different endogenous opiates, the striatal-internal pallidal fibers using dynorphin and the striatal-external pallidal fibres utilizing enkephalin. The receptors through which these opiates exert their effect are also different, dynorphin acting predominantly through ␬-receptors and enkephalin acting predominantly through ␩-receptors. Fentanyl, methadone, and morphine all exert their effect through ␩-receptors possessing relatively little efficacy for the ␬-receptor. These drugs therefore may exert an unbalancing effect on the basal ganglia, presumably reducing the efficacy of the ‘‘indirect’’ pathway, enabling the prokinetic direct pathway to exert a

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greater effect on the thalamus. Opiates may also influence intrasynaptic dopamine concentrations. Recent evidence suggests that some opiates may bind with high efficacy to the dopamine reuptake transporter [27], increasing the concentration of dopamine in the synaptic cleft [28]. Either or both of these effects could therefore be responsible for the generation of a hyperkinetic movement disorder. ANTICHOLINERGICS AND ANTIHISTAMINES Anticholinergic agents such as benzotropine and trihexiphenidyl are used in the management of various movement disorders such as generalized dystonia, botulinum-resistant focal dystonia, and parkinsonian tremor. They are also, however, associated with the exacerbation and genesis of other movement disorders. In particular, they may exacerbate levodopa-induced dyskinesias and tardive dyskinesia. There have also been several case reports of anticholinergic-induced chorea [29,30]. The chorea is dose-dependent, occurring typically at high doses (mean 31.7 mg/day of trihexiphenidyl; range 15–60 mg), with symptoms resolving on lowering the dose [29]. Acetylcholine and dopamine are believed to possess antagonistic roles in the corpus striatum, the effect of anticholinergics is therefore to enhance dopaminergic transmission. This potentiation of dopaminergic transmission is reflected in the nature of both the therapeutic and toxic effects of these drugs. Antihistamines (H1 and H2 antagonists) have also been associated with the development of hyperkinetic movement disorders, such as chorea and myoclonus. Typically, movement disorders occur in overdose with first-generation H1 antagonists which posses prominent anticholinergic activity such as promethazine, diphenhydramine hydrochloride, and cyproheptadine [31,32]. Associated with the movement disorder are other anticholinergic effects: dizziness, blurred vision, lassitude, confusion, dry mucus membranes, hypereflexia, and dilated pupils. H2 antagonists cimetidine and ranitidine have also been reported to cause a reversible choreic movement disorder, in the absence of anticholinergic symptoms [33]. The mechanism of H2 antagonist-induced chorea is uncertain, as it was reported at a therapeutic dose with drugs with minimal anticholinergic activity. CHEMOTHERAPEUTIC AGENTS 5-Fluorouracil 5-Fluorouracil (5-FU) is a synthetic antimetabolite introduced into chemotherapeutic use in 1958. It is an effective and frequently used drug in the treatment of various neoplasms. Since its introduction, several case reports relating to a 5FU-induced ataxic syndrome consisting of gait and limb ataxia, nystagmus, and dysarthria have been published [34,35]. The syndrome is generally associated

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with doses of 5-FU greater than 7.5 mg/kg of body weight and may occur independently of other markers of 5-FU toxicity such as anorexia, nausea, ulcerative stomatitis, diarrhea, and bone marrow suppression. Laboratory examination may demonstrate anemia, leukopenia, or thrombocytopenia but may also be unremarkable; imaging is of use only to exclude a metastatic deposit. Rapid discontinuation of treatment followed by reintroduction at a lower dose results in the complete resolution of symptoms. In the one patient with this syndrome who was rechallenged with the same dose, symptoms recurred within 48 hr. Limited postmortem and animal studies appear to demonstrate a specific toxic effect of 5-FU on the purkinje cells and deep nuclei of the cerebellum [34]. 5-FU along with doxorubicin has also been implicated in the genesis of focal dystonia [36]. The supporting evidence for this association is weak. Four cases of focal dystonia have been described with onset 8 days to 34 months following 5-FU and/or doxorubicin chemotherapy [36]. All the patients, however, received dopamine antagonist antiemetics during their chemotherapy. Laboratory examination and imaging were entirely unremarkable. As it is unusual for tardive dystonia to present after terminating the dopamine antagonist, and the age of onset of focal dystonia and cancer clearly overlap, these patients may well represent idiopathic focal dystonia. Cytosine Arabinoside See under antimicrobials. ANTIMICROBIALS Various commonly used antibiotics may precipitate movement disorders. Penicillin, carbenicillin, ticacillin, imipenem, and the cephalosporins are all associated with a neurotoxic syndrome in which myoclonus is a prominent element [37–39]. The myoclonus is nonrhythmic, asymmetric, and stimulus-sensitive and appears to be related to high drug levels in the plasma and CSF. Other features of the syndrome that may be present include seizures, hallucinations, and encephalopathy. Impairment of renal function and the integrity of the blood–brain barrier are recognized risk factors [37,39]. Laboratory investigation and imaging is typically unremarkable, with the EEG demonstrating a subcortical origin. The symptoms resolve completely on withdrawal of medication. The mechanism underlying this adverse reaction is unknown. High dose co-trimoxazole as used in the treatment of Pneumocystis carnii has also been associated with the generation of movement disorders. Tremor may occur in such patients, and may have resting, postural, or intentional elements to it [40,41]. The tremor may occur alone or in combination with other features of sulfamethoxazole intolerance such as rash, hallucinations, seizures, headaches,

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or leukopenia. Ataxia has also been described, but when present it typically occurs with the features described above [42]. Resolution of symptoms is usually rapid and complete on withdrawal of the drug. The mechanism underlying this adverse reaction is unknown. Amphotericin B may be associated with the development of a parkinsonian syndrome. Several cases of a leukoencephalopathy with parkinsonian and ataxic features have been described in childhood bone marrow transplantation patients exposed to intravenous amphotericin B for pulmonary or sinus aspergillosis [43]. Laboratory investigations on blood and CSF are unremarkable, EEG may demonstrate generalized slowing, and MRI typically demonstrates high-intensity white matter changes on T2, which may be diffuse or localized to the frontal lobes. Other MRI changes reported in these patients include signal change and/or atrophy of the cortex, cerebellum, and basal ganglia. Withdrawal of the drug allows almost complete resolution of the cognitive and parkinsonian symptoms, with only a partial resolution of the ataxic symptoms and MRI changes. The cause of this syndrome is uncertain, as all patients had recently received high-dose chemotherapy including cytosine arabinoside, total-body irradiation, and presumably antidopaminergic antiemetics. A similar adult case has also been reported, with the authors attributing the development of a reversible parkinsonian syndrome without cognitive or MRI changes to the high-dose cytosine arabinoside used in the chemotherapy [44]. This clearly illustrates the difficulty of attributing blame when so many variables are present. The timing of symptom onset was possibly more suggestive of amphotericin B involvement, but the lack of a documented rechallenge and the complicated medical and drug histories of these patients makes the link far from causal.

IMMUNOSUPPRESSANTS Cyclosporin Cyclosporin is a cyclic undecapeptide of fungal origin, which has revolutionised transplant medicine over the last 20 years. The mechanism of the immunosupression is uncertain; T-cell function, however, is clearly impaired. Cyclosporin may induce a number of movement disorders, with tremor being the most common. The tremor occurs in around 20% of patients, and is classically a low-amplitude distal postural tremor. Other movement disorders described are parkinsonism and, more commonly, ataxia. If present, the parkinsonism or ataxia is usually part of an acute neurotoxic syndrome including varying degrees of encephalopathy, cortical blindness, seizures, brainstem dysfunction, and spasticity, which occurs in up to 4% of patients [45–47]. MR imaging classically demonstrates diffuse, frequently parieto-ocipital high signal white matter changes on T2 [45,46] Laboratory investigations may demonstrate an elevated plasma cyclosporin level and depressed

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magnesium and cholesterol levels [45,46]. Onset of symptoms is usually acute and in the first month of therapy, but cases with symptom onset up to 3 years into treatment have been described. Risk factors for the development of toxicity include receiving a liver transplant, hypertension, hypomagnesemia, hypocholesterolemia, concomitant administration of high-dose methylprednisolone, and recent exposure to total-body irradiation [45]. It is uncertain at present if the hypertension and hypomagnesemia are independent risk factors for, or a renal effect of cyclosporin toxicity. Temporary termination and reintroduction of the drug at a lower dose usually leads to a rapid resolution of symptoms, and over time the associated imaging abnormalities. The mechanism of toxicity is uncertain, with various hypotheses relating to altered endothelial function, by either the drug or due to the solvent the intravenous form is stored in having been cited [48,49]. Cyclosporin, however, appears to possess a specific cytotoxic action, inducing a dose-dependent apoptosis of oligodendrocytes and neurons in vitro over a 1–20 M range [6]. The particular sensitivity of oligodendrocytes to the cytotoxic effects of cyclosporin [50] is consistent with the location of pathology on imaging. FK 506 FK 506 is a newer agent than cyclosporin and of greater efficacy. It is also subject to neurotoxity, with many similarities to cyclosporin. The most common neurological side effect is a postural tremor, similar to cyclosporin, which affects around 5% of patients. The other effects and imaging are also very similar to cyclosporin, except that parkinsonism and ataxia are yet to be described, and akinetic mutism is one of the more common major adverse events [51]. The major events, which also occur less frequently than with cyclosporin, respond to temporary drug withdrawal [51]. MISCELLANEOUS Theophylline Theophylline is a phosphodiesterase inhibitor with powerful bronchodilator activity and a rather narrow therapeutic index. There are four case reports in the literature of theophylline-induced stuttering [52,53]. Onset of symptoms was within the first month of therapy, with normal plasma theophylline levels and unremarkable imaging. In all cases the stutter resolved on terminating the drug, recurring on rechallenging in the case that when was undertaken [52]. Theophylline clearly appears causal in these cases, but the mechanism is unknown. Buspirone Buspirone is an azaspirodecanedione anxiolytic agent, which differs from the benzodiazepine class of drugs in both mode of action and pharmacological effect.

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Despite its efficacy in anxiolysis, buspirone is nonsedative, nonaddictive, and has no anticonvulsant activity [54]. Buspirone, however, has been associated with the precipitation of a number of movement disorders: cervical-cranial dystonia [55,56], akathisia [57], and oral dyskinesia [58]. Symptoms may appear days to months after the onset of treatment, with the majority of reported cases having had prior uncomplicated exposure to neuroleptic medication months to years earlier. Laboratory investigation and imaging is entirely normal. Rapid termination of the buspirone prevents further progression of the disorder, but in most instances there is little or no improvement on withdrawal of medication. In addition to precipitating movement disorders, there have also been reports of the use of buspirone in the treatment of various movement disorders: levodopa-induced dyskinesias in Parkinson’s disease [59], neuroleptic induced akathisia [60], and tardive dyskinesia [61]. The anxiolytic activity of buspirone appears to be mediated through the partial agonism of the 5-HT1A receptor [54]. In addition to its effect on the serotonergic system, buspirone appears to influence a number of other receptor systems, in particular the dopaminergic and GABAergic systems [54]. Buspirone is an antagonist of dopamine at all receptor subtypes, with the dominant effect at the D3 receptor [62]. This is likely to be the means by which buspirone influences movement in both a toxic and a therapeutic manner. CONCLUSIONS The relationship between the drug and symptoms is causal in most of the reactions discussed above. In some, however, the link is more tenuous, due to polypharmacology, lack of documented rechallenge, or corroborating reports of similar movement disorders in other patients. This is further compounded by the fact that idiopathic movement disorders increase with age, as does exposure to many of the medications listed above, e.g., chemotherapy, antihypertensives, and antiarrhythmics. A proportion of the irreversible ‘‘drug-induced’’ movement disorders may therefore represent the background incidence of the idiopathic disease in the patients medicated with a given drug, e.g., 5-FU- and doxorubicin-induced dystonia. Other reports do pose the interesting possibility that certain drugs do cause permanent neuropathology, e.g., the postmortem findings in a patient with irreversible amiodarone-induced parkinsonism demonstrated marked nigral cell loss in the absence of the pathognomic inclusion bodies of Parkinson’s disease or MSA type-P [7]. Although these conditions are rare, it is of critical importance to recognize them as early as possible, as the majority are reversible on stopping the drug. Whether all of the movement disorders described above as reversible will remain so if the diagnosis is missed and the drug unwittingly continued isn uncertain. It is recognized that amiodarone may induce a permanent parkinsonian syndrome

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if the initial reversible parkinsonian features are ignored or attributed to idiopathic disease. It is therefore reasonable to suggest that such an effect may also be present, but as yet unrecognized with other medications. The great majority of drug-induced movement disorders are due to drugs that manipulate the dopaminergic system, i.e., dopamine blockers, e.g., neuroleptics (and associated butyophenones, etc.) and dopamine agonists, (levodopa and direct dopa agonists e.g., bromocriptine, apomorphine). Despite this, we need to be ever more alert to the possibility that other groups of drugs may also precipitate movement disorders through novel mechanisms. Whenever a movement disorder is diagnosed, the question must be posed: Could it be due to the medication the patient is taking, either directly or contributing in some way? All physicians must maintain this diagnostic vigilance and report the toxic effects to the appropriate licensing committee (FDA in the USA, CSM in the UK). If causality can be proven, this information should be widely disseminated to all prescribing physicians.

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11. Sempere A, Duarte J, Cabezas C, Cona F, Caveria L. Parkinsonism induced by amlodipine. Move Disord 1995; 10:115–118. 12. Dick R, Barold S. Diltiazem induced parkinsonism. Am J Med 1989; 87:95–96. 13. Jacobs M. Diltiazem and akathisia. Ann Intern Med 1983; 99:794–795. 14. Nakashinia K, Shimoda N, Kono N, Takahash N. Temporary symptom worsening caused by manidipine hydrochloride in two patients with parkinsons disease. Move Disord 1994; 9:106. 15. Shepard P, Stump D. Nifedipine blocks apamin-induced bursting activity in nigral dopamine-containing neurons. Brain Res 1999; 817:104–109. 16. Soliakov C, Wonnacot S. Voltage sensitive calcium channels involved in nicotinic receptor-mediated 3H dopamine release from rat striatal synaptosomes. J Neurochem 1996; 67:163–170. 17. Boehm S, Huck S. Methoxyveropamil reduction of nicotine induced catecholamine release involves inhibition of nicotinic acetylcholine receptor currents. Eur J Neurosci 1993; 5:1280–1286. 18. Miller L, Jankovic J. Persistant dystonia possibly induced by flecainide. Move Disord 1992; 7:62–63. 19. Capella D, Laporte J-R, Castel J-M, Tristan C, Cos A, Morales-Olivas F. Parkinsonism tremor and depression induced by cinnarizine and flunarazine. Br Med J 1988; 297:722–723. 20. Chouza C, Scaramelli A, Caamano J, DeMedina O, Aljanati R, Romero S. Parkinsonism, tardive dyskinesia, akathisia and depression induced by flunarizine. Lancet 1986; 1:1303–1304. 21. Nausieda P, Koller W, Weiner W, Klawans H. Chorea induced by oral contraceptives. Neurology 1979; 29:1605–1609. 22. Hruska R, Silbergeld E. Increased dopamine receptor sensitivity after oestrogen treatment using the rat model. Science 1980; 208:1466–1468. 23. Steiner H, Gerfen C. Role of dynorphin and enkephalin in the regulation of striatal output pathways and behaviour. Exp Brain Res 1998; 123:60–76. 24. Petzinger G, Mayer S, Przedborski S. Fentanyl induced dyskinesias. Move Disord 1995; 10:679–680. 25. Wasserman S, Yahr M. Choreic movements induced by the use of methadone. Arch Neurol 1980; 37:727–728. 26. Potter J, Reid D, Shaw R, Hackett P, Hickman P. Myoclonus associated with treatment with high doses of morphine: The role of supplemental drugs. Br Med J 1989; 299:150–153. 27. Bergstrom K, Jolkkonen J, Kuikka J, Akerman K, Viinamki H, Airaksiner O, Lansimies E, Tiihonen J. Fentanyl decreases ␤-CIT binding to the dopamine transporter. Synapse 1998; 29:413–415. 28. Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 1988; 85:5274–5278. 29. Nomoto M, Thompson P, Sheehy M, Quinn N, Marsden C. Anticholinergic induced chorea in the treatment of focal dystonia. Move Disord 1987; 1:53–56. 30. Ware R, Gubbay S. Choreiform movements induced by anticholinergic therapy. Med J Austral 1979; 1:465.

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31. Schipior P. An unusual case of antihistamine intoxication. J Paediatr 1967; 71: 589–591. 32. Samie M, Ashton A. Choreoathetosis induced by cyproheptadine. Move Disord 1989; 3:81–84. 33. Lehman A. Reversible chorea due to ranitidine and cimetidine. Lancet 1988; 2:158. 34. Riehl J-L, Brown J. Acute cerebellar syndrome secondary to 5-flurouracil therapy. Neurology 1964; 14:961–967. 35. Bergevin R, Patwardhan V, Weissman J, Lee S. Neurotoxicity of 5-flurouracil. Lancet 1975; 1:410. 36. Brashaer A, Siermers F. Focal dystonia after chemotherapy; a case series. J Neurol Oncol 1997; 34:163–167. 37. Klawans H, Carvey P, Tanner C, Goetz C. Drug-induced myoclonus. Adv Neurol 1986; 43:251–264. 38. Frucht S, Eidelberg D. Imipenem induced myoclonus. Move Disord 1997; 12: 621–622. 39. Kallay M, Tabechian H, Riley G, Clessin L. Neurotoxicity due to Ticacillin in a patient with renal failure. Lancet 1979; 1:608–609. 40. Van Gerpen J. Tremor caused by trimethoprim-sulfamethoxazole in a patient with AIDS. Neurology 1997; 48:537–538. 41. Borucki M, Matzke D, Pollard R. Tremor induced by trimethoprim-sulfamethoxazole in patients with AIDS. Ann Intern Med 1988; 109:77–78. 42. Mathelier-Fusade P, Leynadier F. Intolerance to sulfonamides in HIV infected subjects. Presse Med 1993; 22:1363–65. 43. Mott S, Packer R, Vezina G, Kapur S, Dinndorf P, Conry J, Pranzatelli M, Quinones R. Encephalopathy with parkinsonian features in children following bone marrow transplantations and high dose amphoteracin. Ann Neurol 1995; 37:810–814. 44. Luque F A, Selhorst J, Petruska P. Parkinsonism induced by high dose cytosine arabinoside. Move Disord 1987; 2:219–222. 45. Reece D, Frei-Lahr D, Shepherd J, Dorovini-Zis K, Gascoyne R, Graeb D, Spinelli J, Barnett M, Klingemann H-G, Herzig G, Phillips G. Neurologic complications of allogenic bone marrow transplant patients receiving cyclosporin. Bone Marrow Transplant 1991; 8:393–401. 46. Lane R, Roche S, Leung A, Greco A, Lange L. Cyclosporin neurotoxicity in cardiac transplant patients. J Neurol Neurosurg Psychiatry 1988; 51:1434. 47. Openshaw H, Slatkin N, Smith E. Eye movement disorders in bone marrow transplant patients on cyclosporin and gancyclovir. Bone Marrow Transplant 1997; 19: 503–505. 48. Hoefangels W, Gerritsen E, Brouwer O, Souverijn J. Cyclosporin encephalopathy associated with fat embolism induced by the drugs solvent. Lancet 1988; 2:901. 49. Yokokawa K, Kohno M, Minami M, Yosunari K, Mondal A, Yoshikawa J. Heparin suppresses cyclosporin induced endothelin-1 synthesis in rat endothelial cells. J Cardiol Pharmacol 1998; 31:S 460–463. 50. Mac Donald J, Goldberg M, Gway B, Chi S, Choi D. Cyclosporin induces neuronal apoptosis and selective oligodendrocyte death in corticol slices. Ann Neurol 1987; 41:563–564.

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51. Eidelman B, Abu Elmagd K, Wilson J, Fung J, Alessiani M, Jain A, Takaya S, Todo S, Tzakis A, Van Thiel D, Shannon W, Starzl T. Neurologic complications of FK 506. Transplant Proc 1991; 23:3175–3178. 52. Gerard J-M, Delecluse F, Robience Y. Theophylline induced stuttering. Move Disord 1998; 13:847. 53. Rosenfield D, MacCarthy M, McKinney K. Stuttering induced by theophylline. Ear Nose Throat J 1994; 73:918–920. 54. Eison A, Temple D. Buspirone: Review of its pharmacology and current perspectives on its mechanism of action. Am J Med 1986; 80(3B):1–9. 55. LeWitt P, Walters A, Hening W, McHale D. Persistent movement disorders induced by buspirone. Move Disord 1993; 8:331–334. 56. Boylan K. Persistent dystonia associated with buspirone. Neurology 1990; 40:1904. 57. Patterson J. Akathisia associated with buspirone. J Clin Psychopharmacol 1988; 8: 296–297. 58. Strauss A. Oral dyskinesia associated with buspirone use in an elderly woman. J Clin Psychiatry 1988; 49:322–323. 59. Kleedorfer B, Lees A, Stern G. Buspirone in the treatment of levodopa induced dyskinesias. J Neurol Neurosurg Psychiatry 1991; 54:376–377. 60. D’Mello D, McNeil J, Harris W. Buspirone suppression of neuroleptic-induced akathisia: Multiple case reports. J Clin Psychopharmacol 1989; 9:151–152. 61. Neppe V. High dose buspirone in a case of tardive dyskinesia. Lancet 1989; 2:1458. 62. Kula N, Baldessanni R, Kebabian J, Neumeyer J. S-(Ⳮ) aporphines are not selective D3 receptors. Cell Mol Neurobiol 1994; 14(2):185–191.

Index Acquired immunodeficiency syndrome. See AIDS Acute akathisia. See under Akathisia Acute dystonia. See under Dystonia AIDS patients, use of prophylactic anticholinergics in, 114 Akathisia, 129–164 acute, 88–90, 95–96, 129–148 diagnosis, 136–145 management algorithm, 150, 156 tardive, clinical features compared, 152 antiadrenergic antagonists, 155 anticholinergic drugs, 155 antiepileptic drugs, 333 brain trauma, 133 catecholamine-depleting drugs, 155 chronic, 132 clinical characteristics, 136–145 differential diagnosis, 139–141 longitudinal course of, 139 defined, 130 diagnosis, 131 encephalitis lethargica, secondary to, 133 epidemiology, 133–135 general medical condition, secondary to, 133 hemiakathisia, 133 historical background, 129–130 lenticular infarction, 133 levodopa-induced, 292

[Akathisia] management, 145–149, 150 monoakathisia, 133 neuroleptic drugs, 133–134 Parkinson’s disease, 133 pathophysiology, 142–145 persistent, 133 predisposing factors, 136 prevention, 145–146 causative agent modification, 145 prophylactic use of medication, 145–146 risk factor modification, 145 pseudoakathisia, 132 restless legs syndrome, 141–142, 143 restlessness, neuropsychiatric causes, 142 risk factors for, 138 serotonin reuptake inhibitors, 134 subthalamic abscess, 133 subtypes of, 130–133, 131 symptoms of, 140 tardive, 88–90, 149–155 clinical manifestations, 151–153 epidemiology, 151 pathophysiology, 153–154 prevention, 154 treatment, 154–155 treatment, 146–149 alpha-adrenergic drug, 148–149 antiadrenergic drugs, 147–149 anticholinergic drugs, 146–147 373

374 [Akathisia] benzodiazepines, 148 beta-adrenergic antagonists, 147–148 serotonin antagonists, 148 usage of term, 129 withdrawal akathisia, 131 Akinetic mutism, antiepileptic drugs, 334 Alpha-adrenergic drug, akathisia, 148–149 Amantadine, parkinsonism with, 194–195 Amiodarone, 360–361 parkinsonism with, 63 Amisulpride, akathisia with, 135 Amitriptyline, serotonin potentiation, 237 Amlodipine, parkinsonism with, 63 Amoxapine akathisia with, 135 tardive syndromes, 91 Amphetamine, serotonin potentiation, 237 Amphotericin B, parkinsonism with, 63 Antiadrenergic drugs, akathisia, 147–149, 155 Antiakathisia agents, prophylactic use of, 145–146 Anticholinergic drugs akathisia with, 146–147, 155 parkinsonism with, 194 Anticholinergics, 365 Antidepressants, 241–242. See also under specific drug chorea, 244–246 dystonic reactions, 243–244 essential tremor, 250 Huntington’s disease, 250 myoclonus, 246 in neurological disorders, 248–250 Parkinson’s disease, 248–249 tics, 248–250 Tourette’s syndrome, 248–250 tremor, 242–243

Index Antiepileptic drugs, 311–358. See also Neuroleptic drugs; Specific drug name akathisia, 333 akinetic mutism, 334 asterixis, 332 ataxia, 336–339 gabapentin-specific, 338–339 phenytoin-induced, 337–338 camptocormia, 334 hemiparesis, 335–336 hyperkinetic movement disorders, 315–326 barbiturates, 324–326 benzodiazepines, 324 carbamazepine, 316–322 in adults, 320–321 in children, 319 felbamate, 324 gabapentin, 322–324, 323 phenobarbitone, 325 phenytoin, 315–316 sodium valproate, 322 succinamides, 326 impaired motor performance, 336 mechanisms of action, 312 myoclonus, 330–332 negative myoclonus, 332 neuroleptic malignant syndrome, 334 ophthalmoplegia, 335 parkinsonism, 328–330 valproate-induced, 329–330 pathophysiological mechanisms, 339–342 carbamazepine, 341 GABA, 339–340 glutamate, 339–340 lamotrigine, 342 phenytoin, 340–341 sodium valproate, 341 tics, 332–333 Tourettism, 332–333 tremor, 327–328 nonspecific tremor, 327 sodium valproate-induced tremor, 327–328

Index Antihistamines, 365 Antimicrobials, 366–367 Antioxidants, tardive dyskinesia with, 196–197 Antipsychotics. See also under specific drug atypical, tardive dyskinesia with, 197–203 Asterixis, antiepileptic drugs, 332 Ataxia, 336–339 gabapentin-specific, 338–339 phenytoin-induced, 337–338 Autonomic instability, neuroleptic malignant syndrome, 172 Ballism, 2 causes of, 3, 4 Barbiturates, hyperkinetic movement disorders, 324–326 Basal ganglia affected by Parkinson’s disease, motor circuits of, 285 motor circuits of, 283 Benzamides akathisia with, 135 substituted, tardive dyskinesia, 200 Benzisoxazoles, akathisia with, 135 Benzodiazepines akathisia, 148 hyperkinetic movement disorders, 324 mechanism of action, 311 Beta-adrenergic antagonists, akathisia, 147–148 Brain trauma, akathisia and, 133 Bupropion, parkinsonism with, 63 Buspirone, 368–369 akathisia with, 135 serotonin potentiation, 237 Butyrophenones akathisia with, 135 parkinsonism with, 63 Calcium channel antagonists, 361–362 parkinsonism with, 63

375 Camptocormia, antiepileptic drugs, 334 Carbamazepine, 341 akathisia with, 135 hyperkinetic movement disorders, 316–322 mechanism of action, 311 Cardiovascular drugs, 360–362 amiodarone, 360–361 calcium channel antagonists, 361–362 flecainide, 362 Catatonia, in unmedicated schizophrenia, 21–22 Catecholamine-depleting drugs, akathisia, 155 Cephaloridine, parkinsonism with, 63 Chemotherapeutic agents, 365–366 cytosine arabinoside, 366 5-fluorouracil, 365–366 Chloprotixene, in tardive syndromes, 91 Chlorpromazine, in tardive syndromes, 91 Chorea, 2–3 antidepressants, 244–246 etiological classification of, 5–6 lithium and, 219–221 stimulant-induced, 305 Choreiform movements. See also under specific movement disorder in unmedicated schizophrenia, 20–21 Cinnarizine akathisia with, 135 parkinsonism with, 63 in tardive syndromes, 91 Cinnarizine-induced parkinsonism, 67 Citalopram akathisia with, 135 serotonin potentiation, 237 Clebopride parkinsonism with, 63 in tardive syndromes, 91 Clozapine akathisia with, 135 effects on brain receptors, 70 in tardive syndromes, 91, 197–199

376 Cocaine risk for dystonia with abuse, 114 serotonin potentiation, 237 transient Parkinsonism following cessation of abuse, 306 Consciousness, altered level of, neuroleptic malignant syndrome, 172 Contraceptives, oral, 363–364 Co-trimoxazole, parkinsonism with, 63 Cyclosporin, 367–368 parkinsonism with, 63 Cytosine arabinoside, 366 Dextromethorphan, serotonin potentiation, 237 Diabetes mellitus, tardive dyskinesia with, 48 Dibenzoxazepines, akathisia with, 135 Differential diagnosis, movement disorders, 1–14 Dihydroergotamine, serotonin potentiation, 237 Diltiazem akathisia with, 135 parkinsonism with, 63 Disulfiram, parkinsonism with, 63 Domperidone, parkinsonism with, 63 Dopamine blocking agents, 193–208, 281–295. See also under specific drug parkinsonism, 194–196, 289–290 amantadine, 194–195 anticholinergic agents, 194 atypical antipsychotics, 196 electroconvulsive therapy, 195–196 levodopa, 195 tardive dyskinesia, 196–203 antioxidants, 196–197 atypical antipsychotics, 197–203 clozapine, 197–199 olanzapine, 199 risperidone, 199 substituted benzamides, 200 Droperidol, in tardive syndromes, 91

Index Dyskinesia epidemiology, 79–81 paroxysmal, 9–10 spontaneous, 39–41 tardive, 37–60, 196–203 age, 43–44 antioxidants, 196–197 atypical antipsychotics, 197–203 clozapine, 197–199 electroconvulsive therapy, 49–50 extrapyramidal side effects, 49 gender, 44 genetic factors, 46–48 incidence, 42–43 iron status, 50 levodopa-induced, 290–292 neuroleptic drugs, 45–46 neuropsychiatric disorder, 48–49 olanzapine, 199 prevalence, 38–39 race, 44–45 risk factors, 43–51 risperidone, 199 spontaneous dyskinesia, 39–41 substance use, 50 substituted benzamides, 200 usage of term, 81 in unmedicated schizophrenia, 26–27 prevalence of, 27–29 prognosis, 30–31 usage of term, 79 Dystonia, 3–4 acute, 82–84, 111–114 frequency, 112–113 management, 114 mechanism, 113 risk factors, 112–113 age of onset, 117–118 differential diagnosis, 122 epidemiology, 115–118 etiological classification of, 7–8 exposure duration, 117 gender and, 117–118 onset of, 118–120 primary diagnosis, 116–117

Index [Dyskinesia] risk factors, 116–118 tardive, 82–84, 93–95, 114–115 outcome, 121–122 remission, 121–122 treatment, 122–124 ‘‘Ecstasy,’’ serotonin potentiation with, 237 Edentulism, tardive dyskinesia and, 50–51 Ekbom’s syndrome, 141–142 Electroconvulsive therapy with parkinsonism, 195–196 tardive dyskinesia with, 49–50 Encephalitis lethargica akathisia secondary to, 133 in unmedicated schizophrenia, 25–26 Epileptiform movements, in unmedicated schizophrenia, 23–24 Essential tremor, antidepressants, 250 Ethosuximide akathisia with, 135 mechanism of action, 311 Extrapyramidal side effects of tardive dyskinesia, 49 Felbamate hyperkinetic movement disorders, 324 mechanism of action, 311 Fenfluramine, serotonin potentiation, 237 First-episode studies, in unmedicated schizophrenia, 29 5-fluorouracil, 365–366 FK 506, 368 Flecainide, 362 Flunarizine akathisia with, 135 parkinsonism with, 63 in tardive syndromes, 91 Fluoxetine akathisia with, 135 parkinsonism with, 63 serotonin potentiation, 237

377 Fluphenazine, in tardive syndromes, 91 Fluvoxamine akathisia with, 135 serotonin potentiation, 237 Focal motor abnormalities, in unmedicated schizophrenia, 22–23 Gabapentin ataxia, 338–339 hyperkinetic movement disorders, 322–324, 323 mechanism of action, 311 Glutamate, 339–340 Haloperidol, in tardive syndromes, 91 Hemiakathisia, 133 Hemifacial spasm, 10–11 Hemiparesis, antiepileptic drugs, 335–336 Huntington’s disease, antidepressants, 250 Hyperkinetic movement disorders, 315–326 adults, carbamazepine-induced dyskinesia in, 320–321 barbiturates, 324–326 benzodiazepines, 324 carbamazepine, 316–322 children, carbamazepine-induced dyskinesia in, 319 felbamate, 324 gabapentin, 322–324, 323 phenobarbitone, 325 phenytoin, 315–316 sodium valproate, 322 succinamides, 326 Hyperthermia, neuroleptic malignant syndrome and, 171–172 Imipramine, serotonin potentiation, 237 Immunosuppressants, 367–368 cyclosporin, 367–368 FK 506, 368 Inability to sit still. See Akathisia

378 Incoordination, in unmedicated schizophrenia, 23 Indolic derivatives, akathisia with, 135 Iron status, tardive dyskinesia and, 50 Isocarboxazid, serotonin potentiation, 237 Kinetic tremor, 10 Lamotrigine, 342 mechanism of action, 311 Legs painful, 12–13 restless legs syndrome, 10, 141–142, 143 Lenticular infarction, akathisia, 133 Lethal catatonia, neuroleptic malignant syndrome, differential diagnosis, 175–176 Levodopa, 259–279, 281–295 akathisia, 292 etiology of, 265–269 neurosurgical treatment of, 273–274 nondopaminergic mechanisms, 272–273 parkinsonism with, 195, 289–290 in Parkinson’s disease, 263–265 tardive dyskinesias, 290–292 Lithium-induced movement disorders, 209–231. See also under specific drug acute toxicity, 213–214 carbonate, akathisia with, 135 history of, 209–211 irreversible neurotoxicity, 214–216 mechanism of action, 212–213 movement disorders, 216–224 chorea, 219–221 tremor, 216–219 neuroleptic interaction with, 224–226 parkinsonism with, 63, 221–224 pharmacology, 211–212 serotonin potentiation, 237 Loxapine, in tardive syndromes, 91 L-tryptophan, serotonin potentiation, 237

Index Manganese, parkinsonism with, 63 Manidipine, parkinsonism with, 63 MDMA, serotonin potentiation, 237 Meperidine parkinsonism with, 63 serotonin potentiation, 237 Mesoridazine, in tardive syndromes, 91 Methyldopa, parkinsonism with, 63 Methylphenidate, parkinsonism with, 63 Methysergide, akathisia with, 135 Metoclopramide akathisia with, 135 parkinsonism with, 63 in tardive syndromes, 91 Metoprimazine, parkinsonism with, 63 Mianserin, akathisia with, 135 Migraine, serotonin syndrome in patients with, 241 Moclobemide, serotonin potentiation, 237 Molindone, in tardive syndromes, 91 Monoakathisia, 133 Moving toes, 12–13 Mutism, akinetic, antiepileptic drugs, 334 Myoclonus, 6–0 antidepressants, 246 antiepileptic drugs, 330–332 tardive, 85–86 Nefazodone akathisia with, 135 serotonin potentiation, 237 Negative myoclonus, antiepileptic drugs, 332 Neuroleptic drugs. See also Neuroleptic malignant syndrome akathisia, 133–134 parkinsonism, 62 tardive dyskinesia, 45–46 Neuroleptic malignant syndrome, 86–88, 96, 165–191, 334 atypical antipsychotics and, 170 in children, 169 clinical aspects, 167–169 complications of, 179–180

Index [Neuroleptic malignant syndrome] definitions of, 166 differential diagnosis, 173–176 lethal catatonia, 175–176 serotonin syndrome, 175 systemic infection, 174 drugs inducing, 167 epidemiology, 177–178 in Parkinson’s disease, 169–170 pathogenesis of, 170–173 autonomic instability, 172 consciousness, altered level of, 172 hyperthermia, 171–172 laboratory alterations, 172–173 movement disorders, 172 pathophysiology, 171–172 receptor alterations, 170–171 recurrence, 180–181 risk factors, 179 treatment, 181–184 literature review, 181–183 Neurosyphilis, in unmedicated schizophrenia, 25 Olanzapine effects on brain receptors, 70 in tardive syndromes, 91, 199 Ophthalmoplegia, antiepileptic drugs, 335 Opiates, 364–365 Oral contraceptives, 363–364 Oral movements, in unmedicated schizophrenia, 18–20 Organic disorders, in unmedicated schizophrenia, 24 Orofacial dyskinesia, in elderly, 29–30 Oxcarbazepine, mechanism of action, 311 Painful legs, 12–13 Parkinsonism, 61–75, 194–196, 328–330 amantadine, 194–195 anticholinergic agents, 194 antipsychotics, atypical, 196 cinnarizine-induced parkinsonism, 67

379 [Parkinsonism] clinical features, 65–69 calcium channel antagonists, 68 neuroleptic-induced, 65–66 non-neuroleptic, 66 valproic acid, 68–69 vestibular sedatives, 67–68 dopamine antagonists, 289–290 electroconvulsive therapy, 195–196 levodopa, 195 lithium and, 221–224 management, 69–70 neuroleptic-induced parkinsonism, 62 neurotransmitter involvement, 62–65 positron emission tomography studies, 65 ‘‘preclinical’’ Parkinson’s disease, 65 receptor blockade, 62–65 risk factors for development of, 64 transient, following cessation of cocaine abuse, 306 valproate-induced, 69, 329–330 Parkinson’s disease, 133. See also Parkinsonism antidepressants, 248–249 basal ganglia, motor circuits of, 285 levodopa-induced dyskinesia, 263–265 neuroleptic malignant syndrome, 169–170 serotonin syndrome, 240–241 Paroxetine akathisia with, 135 serotonin potentiation, 237 Paroxysmal dyskinesias, 9–10 Pentoxifylline, parkinsonism with, 63 Perazine, in tardive syndromes, 91 Perioral movements, in unmedicated schizophrenia, 18–20 Perphenazine, in tardive syndromes, 91 Phenelzine parkinsonism with, 63 serotonin potentiation, 237 Phenobarbitone, mechanism of action, 311

380 Phenomenology, movement disorders, 1–14 Phenothiazines akathisia with, 135 parkinsonism with, 63 Phenytoin, 340–341 ataxia with, 337–338 hyperkinetic movement disorders, 315–316 mechanism of action, 311 Pimozide, in tardive syndromes, 91 Postural tremor, 10 Preneuroleptic era motor phenomena described, 19 movement disorders in, 16–17 Procaine, parkinsonism with, 63 Prochlorperazine, in tardive syndromes, 91 Pseudoakathisia, 132 Quetiapine akathisia with, 135 effects on brain receptors, 70 in tardive syndromes, 91 Rauwolfia alkaloids, akathisia with, 135 Receptor alterations, neuroleptic malignant syndrome and, 170–171 Remacemide, mechanism of action, 311 Remoxipride akathisia with, 135 in tardive syndromes, 91 Repetitive movements, 9. See also Stereotypy Reserpine akathisia with, 135 parkinsonism with, 63 Rest tremor, 10 Restless legs syndrome, 10, 141–142, 143 Restlessness. See also Akathisia neuropsychiatric causes, 142 Risperidone akathisia with, 135 effects on brain receptors, 70 in tardive syndromes, 91, 199

Index Sedatives, vestibular, 362–363 Selective serotonin reuptake inhibitors, 233–257. See also under specific drug pharmacology of, 234–236 serotonin syndrome, 236–241 with migraine, 241 in Parkinson’s disease, 240–241 pathogenesis of, 239–240 substances potentiating in brain, 237 Selegiline, serotonin potentiation, 237 Serotonin, potentiation in brain, by drug action, 237 Serotonin antagonists, akathisia, 148 Serotonin reuptake inhibitors, akathisia and, 134 Serotonin syndrome, 236–241 neuroleptic malignant syndrome, differential diagnosis, 175 in Parkinson’s disease, 240–241 pathogenesis of, 239–240 in patients with migraine, 241 Sertindole akathisia with, 135 effects on brain receptors, 70 Sertraline akathisia with, 135 serotonin potentiation, 237 Sitting still, inability. See Akathisia Sodium valproate, 341 hyperkinetic movement disorders, 322 mechanism of action, 311 tremor from, 327–328 Spontaneous abnormal involuntary movements. See also under specific movement classification of, 32 differential diagnosis of, 31 Stereotypy, 9 tardive, 81–82, 92–93 Stiff muscles, 11–12 Stimulants, 297–309 chorea, 305 cocaine abuse, 306 dystonia, 305

Index [Stimulants] mechanism of action, 303–305 stereotypic movements, 298 tics, 298–303 Tourette’s syndrome, 298–303 transient Parkinsonism, 306 Substance abuse. See also under specific substance tardive dyskinesia with, 50 Substituted benzamides, tardive dyskinesia with, 200 Subthalamic abscess, akathisia, 133 Succinamides, hyperkinetic movement disorders, 326 Sulpiride akathisia with, 135 in tardive syndromes, 91 Sumatriptan, serotonin potentiation, 237 Svoxepin, akathisia with, 135 Systemic infection, neuroleptic malignant syndrome, differential diagnosis, 174 Tacrine, parkinsonism with, 63 Tardive akathisia, 88–90, 95–96, 129–164, 131, 149–155 clinical manifestations, 151–153 epidemiology, 151 pathophysiology, 153–154 prevention, 154 treatment, 154–155 Tardive dyskinesia, 37–60, 196–203 age of patient, 43–44 antioxidants, 196–197 atypical antipsychotics, 197–203 clozapine, 197–199 diabetes mellitus, 48 edentulism, 50–51 electroconvulsive therapy, 49–50 extrapyramidal side effects, 49 gender, 44 genetic factors, 46–48 incidence, 42–43 iron status, 50 levodopa-induced, 290–292 neuroleptic drugs, 45–46

381 [Tardive dyskinesia] neuropsychiatric disorder, 48–49 olanzapine, 199 prevalence, 38–39 race, 44–45 risk factors, 43–51 risperidone, 199 spontaneous dyskinesia, 39–41 substance use, 50 substituted benzamides, 200 usage of term, 81 Tardive dystonia, 82–84, 93–95, 114–115 Tardive myoclonus, 85–86 Tardive stereotypy, 81–82, 92–93 Tardive tourettism, 84–85 Tardive tremor, 86 Task-specific tremor, 10 Tetrabenazine, akathisia with, 135 Theophylline, 368 Thiethylperazine, parkinsonism with, 63 Thioridazine, in tardive syndromes, 91 Thiothixene, in tardive syndromes, 91 Thioxanthenes akathisia with, 135 parkinsonism with, 63 Tiagabine, mechanism of action, 311 Tiapride, in tardive syndromes, 91 Tics, 4–6 antidepressants, 248–250 antiepileptic drugs, 332–333 stimulant-induced, 298–303 Toes, moving, 12–13 Topiramate, mechanism of action, 311 Tourette’s syndrome, 84. See also Tourettism antidepressants with, 248–250 Tourettism antiepileptic drugs with, 332–333 tardive, 84–85 Tranylcypromine, serotonin potentiation, 237 Trazodone, serotonin potentiation, 237 Tremor, 9, 327–328 antidepressants with, 242–243

382

Index

[Tremor] classification of, 10 differential diagnosis of, 11 essential, antidepressants, 250 lithium and, 216–219 nonspecific tremor, 327 sodium valproate-induced tremor, 327–328 tardive, 86 in unmedicated schizophrenia, 22–23 Trifluoperazine, in tardive syndromes, 91

[Unmedicated schizophrenia] organic disorders, 24 orofacial dyskinesia, in elderly, 29–30 paradigms, conflict of, 17–18 perioral movements, 18–20 in pre-neuroleptic era, 16–17 preneuroleptic era, motor phenomena described, 19 spontaneous abnormal involuntary movement classification, 32 tremor, 22–23

Unmedicated schizophrenia, 15–36 catatonia with, 21–22 choreiform movements, 20–21 differential diagnosis, spontaneous abnormal involuntary movements, 31 dyskinesia, 26–27 prevalence of, 27–29 prognosis, 30–31 encephalitis lethargica, 25–26 epileptiform movements, 23–24 first-episode studies, 29 focal motor abnormalities, 22–23 historical accounts, 18 incoordination, 23 neurosyphilis, 25 oral movements, 18–20

Vaccines, parkinsonism with, 63 Valproate-induced parkinsonism, 69, 329–330 ‘‘preclinical’’ Parkinson’s disease, 65 Valproic acid, parkinsonism with, 63 Venlafaxine, serotonin potentiation, 237 Veralipride parkinsonism with, 63 in tardive syndromes, 91 Verapamil, parkinsonism with, 63 Vestibular sedatives, 362–363 Vigabatrin, mechanism of action, 311 Withdrawal akathisia, 131 Withdrawal-emergent syndrome, 82 Zonisamide, mechanism of action, 311

About the Editor KAPIL D. SETHI is Professor of Neurology at the Medical College of Georgia, Augusta. He is also Director of the Movement Disorders Clinic and the National Parkinson Foundation Center of Excellence as well as Co-Director of the Chemodenervation Clinic at the same institute. Actively researching tardive dystonia and other drug-induced movement disorders and novel treatments for Parkinson’s disease, Dr. Sethi is on the board of directors of the American Academy of Neurology (AAN) and has taught courses on drug-induced movement disorders at AAN annual meetings. He also serves on the editorial advisory board for the Neurological Disease and Therapy Series (Marcel Dekker, Inc.). He has been on the editorial board of Movement Disorders and is a section editor for Current Neurology and Neuroscience Reports. Dr. Sethi received the M.D. degree (1975) from the Christian Medical College, Ludhiana, India, and completed training at Charing Cross Hospital, London, United Kingdom and the Medical College of Georgia, Augusta.