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Contributors V.P. Bakshi, M.E. Bardgett, D.L. Braff, E.S. Brodkin, O. Civelli J.G. Csemansky, S.G. Dahl, M. Davidson, A.Y. Deutch, H.S. Fatemi W.O. Faustman, J.Gerlach, M.A. Geyer, J.Golier, A.A. Grace, D.Hartman A.L. Hoff, P.W. Kalivas, A.R. Koreen, J.F. Leckman, J. Lieberman C.J. McDougle, H.Y. Meltzer, S.A. Minchin, F. Monsma, B.H. Mulsant P. O'Donnell S.-O. Ogren, L. Peacock, B.G. Pollock, R. Ranjan, B.L. Roth, R.E. See B. Sheitman, N.R. Swerdlow

Editor J.G. Csernaiisky

Springer Contents

CHAPTER 1 Classification Schemes for Drugs SUSAN A. MINCHIN and JOHN G. CSERNANSKY. With 1 Figure 1 A. Introduction 1 I. Historical Perspective 1 B. Classification by Patterns of Efficacy and Neurological Side Effects 4 C. Classification by Chemical Structure 6 I. 7 II. 8 III. 9 IV. 11 V. Indoles 11 VI. 12 VII. Dibenzapines 12 VIII. Others 12 D. Classification by Potency and Nonneurologic Side-Effect Profile 12 E. Classification by Pharmacological Mechanism 14 I. Selective Receptor D2 Antagonists 15 II. Combined D2/D3 Antagonists 16 III. Combined DJ/DJ Antagonists 16 IV. Combined 5-HT2-D2 Antagonists 17 F. Future Classification Schemes 17 I. Selective Receptor Antagonists 18 II. Partial D2 Agonists 19 III. Sigma Site Antagonists and Excitatory Amino Acid Agonists 19 IV. GABA-Mimetics and Partial Benzodiazepine Agonists 20 G. Conclusions 20 References 21 XII Contents

CHAPTER 2 Molecular Models and Structure-Activity Relationships SVEIN G. DAHL. With 3 Figures 29 A. Introduction 29 B. Structure-Activity Relationships of Antipsychotic Drugs 29 C. Neurotransmitter Receptor Models 32 D. Molecular Modelling of Drug-Receptor Interactions 35 I. Electrostatic Fields Around Drug and Receptor Molecules 35 II. Molecular Dynamics of Drug-Receptor Interactions 37 E. Conclusions 37 References 39

CHAPTER 3 Interaction of Antipsychotic Drugs with Subtypes DEBORAH HARTMAN, FREDERICK MONSMA, and OLIVIER CIVELLI With 3 Figures 43 A. Introduction 43 B. Molecular Biology of Dopamine Receptor Subtypes 43 I. General Structural Features of Dopamine Receptors 44 II. The Di Family of Dopamine Receptors 44 1. The Dopamine Dj Receptor 46 2. The Dopamine D5 Receptor 47 III. The D2 Family of Dopamine Receptors 47 1. The Dopamine D2 Receptor 48 2. The Dopamine D3 Receptor 49 3. The Dopamine D4 Receptor 51 C. Pharmacology of Neuroleptics at Recombinant Dopamine Receptors 52 I. Traditional Neuroleptics and Related Compounds 53 II. and the Atypical Neuroleptics 59 III. New Antipsychotics 63 1. : A Second-Generation Clozapine-Like Compound 64 2. : A D2 Receptor-Selective Substituted 65 3. : A D2/5-HT2 66 D. Future Outlook and Hopes for Subtype-Specific Drugs ...' 67 References 68 Contents XIII

CHAPTER 4 Drugs: Clinical and Preclinical Studies HOSSEIN S. FATEMI, HERBERT Y. MELTZER, and BRYAN L. ROTH 77 A. Introduction 77 B. Glutamate 78 I. Glutamate Receptors 79 II. Glutamate Hypothesis of 79 III. Glutamatergic Drugs 81 1. Glycine and Milacemide 81 2. 82 3. Others 82 C. 7-Aminobutyric Acid (GABA) 82 I. GABA Receptors 82 II. GABA Hypothesis of Schizophrenia and Clinical Studies of GABA-ergic Drugs 84 D. Acetylcholine 85 I. Acetylcholine Receptors 85 II. Muscarinic Hyperactivity in Schizophrenia? • 85 E. Norepinephrine 87 I. a,-Adrenergic Receptor Involvement in Atypical Antipsychotic Drug Actions 88 F. Cholecystokinin (CCK) 88 I. CCK-ergic Drugs 89 1. LY262691 89 2. Caerulin 89 3. Others 89 G. Neurotensin 89 I. Neurotensin and Schizophrenia 90 II. Effects of Atypical Antipsychotic Drugs on Neurotensin Systems 90 H. Sigma Receptors 91 I. Sigma Receptors 91 II. Preclinical Studies 92 III. Specific Agents 92 I. Opioids 94 J. Serotonin 95 I. 5-HT Receptors and Schizophrenia 96 II. Selective 5-HT2A/ Antagonists 98 1. 98 2. ICI169369andMDL100907 98 3. 98 III. Mixed 5-HT2/D2 Antagonists 98 1. Clozapine 99 XIV Contents

2. Risperidone 99 3. 99 4. Olanzapine 100 5. 100 6. 100 7. Tiosperone 100 8. 101 9. Others 101 IV. 5-HT3 Antagonists 101 V. Nonselective 5-HT Receptor Antagonists 101 VI. 5-HT Reuptake Inhibitors 102 K. Conclusions 102 References 103

CHAPTER 5 Sites and Mechanisms of Action of Antipsychotic Drugs as Revealed by Immediate-Early Gene Expression ARIEL Y. DEUTCH ." 117 A. Introduction 117 B. Immediate-Early Gene Expression as a Method to Assess the Sites and Mechanisms of Action of Antipsychotic Drugs (APDs) 118 C. Effects of APDs on Immediate-Early Gene Induction in the Striatal Complex 120 I. Effects of APDs on Regionally Specific Striatal Immediate-Early Gene Expression 120 1. Dorsal Striatum 120 2. Ventral Striatum 122 II. Striatal Immediate-Early Gene Induction: Fos, Fos-Related Antigens, and Others 123 1. Fos Versus Fras 123 2. Other Immediate-Early Genes 125 III. Mechanisms of Antipsychotic Drug-Elicited Striatal Fos Expression 126 1. Dopamine Receptors and APD-Elicited Increases in Striatal Fos 126 a) D2 Dopamine Receptors 126 b) D, Dopamine Receptors 127 c) Concurrent D2/Di Receptor Occupancy and Striatal Fos Expression 128 2. Involvement of Excitatory Amino Acid Receptors in Neuroleptic-Elicited Striatal Fos Expression 129 Contents XV

3. Cholinergic and Adenosine Receptors 130 a) Muscarinic Cholinergic Receptors 130 b) Adenosine A2 Receptors 131 IV. Acute Versus Chronic Effects of APDs on Striatal Fos Expression 131 V. What Is the Transcriptional Target of APD-Elicited Striatal Fos Expression? 132 1. Neurotensin 133 2. Enkephalin 134 3. Glutamic Acid Decarboxylase 135 D. Preferential Induction of Fos in the Prefrontal Cortex (PFC) by Clozapine 135 I. Regional Effects of APDs on Fos Expression in the PFC 136 1. Effects of APDs on Fos Expression in the Medial PFC 136 2. Correlations Between PFC Expression and Clinical Status 137 II. Receptor Mechanisms of Clozapine-Elicited Increase in PFC Fos Expression 138 1. D! and D2 Dopamine (DA) Receptors and Clozapine-Elicited Fos Expression 138 2. Nondopaminergic Receptors and the PFC Fos Response to Clozapine 140 3. Mechanisms of Clozapine-Elicited Increases in PFC Fos Expression 141 a) Possible Role of a Novel DA Receptor in Mediating Clozapine-Elicited Effects 141 b) Targeting of Multiple Receptors 143 c) Transsynaptic Events as a Possible Determinant of Clozapine-Induced Changes 143 III. Transcriptional Targets of Clozapine's Actions in the PFC 144 E. Effects of APDs on Immediate-Early Gene Expression in Other CNS Sites 145 I. Thalamic Paraventricular Nucleus 145 II. Lateral Septal Nucleus 147 III. Other CNS Regions 147 F. Conclusions 148 I. Methodological Issues 149 II. Validity of Fos Expression as a Model of the Actions of APDs 150 III. Future Directions 150 References 151 XVI Contents

CHAPTER 6

Basic Neurophysiology of Antipsychotic Drug Action PATRICIO O'DONNELL and ANTHONY A. GRACE. With 9 Figures 163

A. Introduction 163 B. The Dopamine Hypothesis of Schizophrenia 163 I. Antipsychotic Drugs as D2 Blockers 163 II. Shortcomings of the Dopamine Hypothesis 164 C. Acute Physiology of Antipsychotic Drug Action 165 I. Dopamine Cell Identification and Physiology 165 II. Acute Actions of Antipsychotic Drugs on Dopamine Cell Physiology 167 1. Acute Antipsychotic Drugs Increase Firing Rate 167 2. Acute Antipsychotic Drug Administration Increases Dopamine Cell Burst Firing 169 3. Acute Antipsychotic Drug Treatment Increase the Number of Dopamine Cells Firing Spontaneously 171 D. Physiology of Chronic Antipsychotic Drug Treatment 171 I. Tolerance to Antipsychotic Drug Action 171 II. Chronic Treatment with Antipsychotic Drugs and Dopamine Cell Depolarization Block 172 III. Analysis of Mechanisms Contributing to Depolarization Block: Compensatory Systems Involved in the Recovery of Function After Dopamine Lesions 175 E. Dual Mode of Dopamine Release: Tonic Versus Phasic 177 F. . Antipsychotic Drug Treatment and Electrotonic Transmission Within the Basal Ganglia 181 I. Dopaminergic Control of Electrotonic Coupling in the Striatum 181 II. Effects of Subchronic Treatment with or Clozapine on Striatal Cell Dye Coupling Observed In Vitro 185 III. Effects of Subchronic Treatment with Haloperidol or Clozapine on Striatal Cell Dye Coupling Observed In Vivo 187 G. Conclusions 189 References 191 Contents XVII

CHAPTER 7 Tolerance and Sensitization to the Effects of Antipsychotic Drugs on Dopamine Transmission RONALD E. SEE and PETER W. KALIVAS. With 1 Figure 203 A. Introduction 203 B. Effects of Single Administration on Dopamine and Related Behaviors 204 C. Effects of Repeated Administration and the Induction of Sensitization and Tolerance 205 I. Tolerance 206 II. Sensitization 209 D. Atypical Antipsychotic Drugs 212 E. Conclusions 213 References 217

CHAPTER 8 The Behavioural Pharmacology of Typical and Atypical Antipsychotic Drugs SVEN OVE OGREN. With 1 Figure 225 A. Introduction 225 B. Typical and Atypical Antipsychotic Drugs 226 I. Concepts and Nomenclature 226 II. Atypical Antipsychotic Drugs 228 III. Behavioural Testing Procedures for Typical and Atypical Antipsychotic Drugs 230 C. Basic Actions of Antipsychotic Drugs and Their Behavioural Effects 232 D. Effects on Motor Function 234 I. Spontaneous Locomotor Activity 234 II. Catalepsy and the Paw Test 236 E. Effects of Antipsychotic Drugs on Behavioural Effects Elicited by DA Receptor Agonists or Glutamate Antagonists ... 240 I. d- (Methylphenidate)-Induced Behavioural Effects 240 II. -Induced Behavioural Effects 245 III. Phencyclidine-Induced Behavioural Effects 249 F. Action on Conditioned Avoidance 250 G. Animal Models of Psychosis and Antipsychotic Drugs 255 H. Conclusions 256 References 257 XVIII Contents

CHAPTER 9 Antipsychotic Drug Action After Lesions to the Hippocampus or Frontal Cortex MARK E. BARDGETT and JOHN G. CSERNANSKY. With 2 Figures 267 A. Introduction 267 B. Mechanisms of Antipsychotic Drug Action 267 I. Dopaminergic Mechanisms 267 II. Glutamatergic Mechanisms 270 C. Neuropathology and Antipsychotic Drug Action 272 D. Effect of Hippocampal Neuropathology on Mechanisms of Antipsychotic Drug Action 273 I. Anatomy 273 II. Consequences for Glutamatergic Mechanisms of Antipsychotic Drug Action 275 III. Consequences for Dopaminergic Mechanisms of Antipsychotic Drug Action 277 1. Dopamine Receptors 277 2. Dopamine Turnover and Release 277 3. Dopamine-Mediated Behaviors 278 IV. Summary 279 E. Effect of Frontal Cortical Neuropathology on Mechanisms of Antipsychotic Drug Action 280 I. Anatomy 280 II. Consequences for Glutamatergic Mechanisms of Antipsychotic Drug Action 281 III. Consequences for Dopaminergic Mechanisms of Antipsychotic Drug Action 281 1. Dopamine Receptors 281 2. Dopamine Turnover and Release 281 3. Dopamine-Mediated Behaviors 282 IV. Summary 283 F. Conclusions 283 References 284

CHAPTER 10 An Animal Model of Sensorimotor Gating Deficits in Schizophrenia Predicts Antipsychotic Drug Action N.R. SWERDLOW, D.L. BRAFF, V.P. BAKSHI, and M.A. GEYER With 7 Figures 289 A. Introduction 289 I. Face Validity: Are the Eliciting Stimuli and Response Patterns of Prepulse Inhibition (PPI) Similar Across Species? 291 Contents XIX

II. Predictive Validity: Can This Model Be Used as a Sensitive and Specific Screen of Antipsychotic Potency? 291 III. Construct Validity: Is This Model Consistent with Existing Constructs of Schizophrenia? 295 1. Construct Validity in a Neurochemical Domain: Mesolimbic Hyperdopaminergia 296 2. Construct Validity in a Neuroanatomical Domain: PPI After Manipulations of Limbic Corticostriatopallidopontine Circuitry 298 a) The Hippocampus 299 b) The Ventral Striatum 300 c) The Ventral Pallidum and Pontine Reticular Formation 301 3. Construct Validity in a Neurodevelopmental Domain: PPI After Isolation Rearing or Neonatal Brain Lesions 302 B. Discussion 304 I. Model Limitations 305 II. Model Strengths 306 C. Conclusions 307 References 307

CHAPTER 11 Patterns of Clinical Efficacy for Antipsychotic Drugs JULIA GOLIER and MICHAEL DAVIDSON 313 A. Introduction 313 B. Rating Scales Used to Measure Neuroleptic Effect 313 I. Brief Psychiatric Rating Scale 314 II. Clinical Global Impression 314 III. Global Assessment Scale 315 IV. Negative Symptoms and Rating Scales 315 1. Methodologic Problems in the Measurement of Negative Symptoms 315 2. Rating Scales Used to Measure Negative Symptoms and the Deficit Syndrome 315 a) Positive and Negative Syndrome Scale 316 b) Scale for the Assessment of Negative Symptoms : 317 c) Schedule for the Deficit Syndrome 317 d) Quality of Life Scale 318 V. Rating Scales and Phenomenology 318 C. Efficacy of Neuroleptics in Schizophrenia 319 XX Contents

I. Efficacy in the Treatment of Schizophrenic Exacerbation 319 1. Introduction of 319 2. Treatment of Psychosis 320 3. Treatment of Negative Symptoms 320 4. Neuroleptic Dose and Efficacy 321 II. Efficacy of Maintenance Neuroleptic Treatment 323 1. Relapse Prevention 323 2. Neuroleptic Dose and Efficacy 324 III. Neuroleptics with Special Profiles of Efficacy 326 References 329

CHAPTER 12 Efficacy of Novel Antipsychotic Drugs in Treatment-Refractory Schizophrenia HERBERT Y. MELTZER and RAKESH RANJAN 333 A. Introduction 333 B. The Concept of Atypicality 334 C. Atypical Antipsychotic Drugs 335 I. Clozapine 336 1. Effect on Psychopathology 338 a) Effect on Positive Symptoms 338 b) Effect on Negative Symptoms 339 c) Effect on Disorganization Symptoms 340 d) Effect on Cognitive Function 340 e) Effect on Mood Symptoms 341 f) Effect on Quality of Life 341 2. Duration of Clozapine Trials 342 3. Clozapine Dosage and Administration 342 4. Relationship Between Clinical Efficacy and Plasma Concentrations of Clozapine 343 5. Predictors of Response to Clozapine 343 6. Nonresponders to Clozapine Therapy and Augmentation Strategies 344 7. Dropouts and Withdrawal from Clozapine 345 8. Cost-Effectiveness 345 II. Risperidone 346 1. Effect on Psychopathology 347 2. Risperidone Dosage and Administration 348 III. Melperone 348 IV. Remoxipride 348 V. Amperozide 349 Contents XXI

VI. Others 350 D. Conclusions 350 References 351

CHAPTER 13 Antipsychotic-Induced Side Effects Related to Receptor Affinity LINDA PEACOCK and JES GERLACH. With 1 Figure 359 A. Introduction 359 B. Predictable and Unpredictable Side Effects 359 C. Classification of Antipsychotic Drugs 360 D. Side Effects in Relation to Receptor Affinities 362 I. Side Effects Related to Dopamine D2 Receptor Binding .. 362 1. Psychological Side Effects 362 2. Acute Extrapyramidal Side Effects (EPS) 364 3. Tardive EPS 364 4. Hormonal Side Effects 365 II. Side Effects Related to Dopamine Dt Receptor Blockade 366 III. Side Effects Related to Binding to Receptors Other Than Dopamine Receptors 366 IV. Side Effects with No Certain Relation to Receptor Binding 367 1. Neuroleptic Malignant Syndrome 367 2. Agranulocytosis 368 E. Older Antipsychotics with Typical and Atypical EPS Profiles 368 F. Newer Antipsychotics with Typical and Atypical EPS Profiles .... 371 I. Dopamine-Selective Antipsychotics 371 1. 371 2. Other Substituted Benzamides 373 3. Dj and Combined Dj/D2 Dopamine Receptor Antagonists 373 II. Newer Antipsychotics with Dopamine-Serotonin-Norepinephrine Antagonism .. 374 1. Risperidone 374 2. 375 3. 375 III. Multiple Receptor Antagonists 376 1. Clozapine 377 2. Olanzapine 379 3. Seroquel 379 4. Zotepine 381 G. Management of Side Effects 381 XXII Contents

I. Prevention 381 II. Early Detection of Side Effects 382 III. Treatment of Side Effects 382 H. Conclusions 383 References 383

CHPATER 14 Biological Predictors of Antipsychotic Treatment Response AMY R. KOREEN, BRIAN SHEITMAN, and JEFFREY LIEBERMAN 389 A. Introduction 389 B. Biochemical Predictors 389 I. Homovanillinic Acid (HVA) 390 II. Dopamine /3-Hydroxylase (DBH) 400 III. Serotonin (5-HT) 400 IV. Norepinephrine(NE) 403 V. Peptides 409 C. Behavioral Response to Psychostimulants 409 D. Neuroendocrine Studies 411 E. Neuroimaging 419 I. Structural Brain Imaging 419 II. Functional Brain Imaging 422 F. Electrophysiologic Predictors 423 I. Galvanic Skin Conductance and Heart Rate 423 II. Electroencephalography (EEG) 431 III. Event-Related Potential (ERP) 431 IV. Saccadic Eye Movements 434 G. Discussion 434 H. Conclusions 436 References 436

CHAPTER 15 Effects of Antipsychotic Drugs on Neuropsychological Measures WILLIAM O. FAUSTMAN and ANNE L. HOFF 445 A. Introduction 445 B. Biological Underpinnings of Cognitive Deficit in Schizophrenia ... 446 C. Cognitive Impairment in Schizophrenia 447 D. Anticholinergics and Cognition 450 Contents XXIII

E. Dopamine and Cognition 452 I. Related Evidence for the Role of Dopamine in Cognition 453 II. Dopamine Agonists, Prefrontal Function, and Cognition in Schizophrenia 454 F. Effects of Antipsychotic Drugs on Cognition in Healthy Nonpsychiatric Samples 454 G. Effects of Typical Antipsychotics in Schizophrenic Patient Samples 456 I. Methodological Limitations in Examining the Effects of Neuroleptics in Schizophrenia 457 1. Lack of Random Assignments to Groups in Studies Contrasting Groups of Medicated and Unmedicated Patients 458 2. Correlations Between Cognitive Impairments and Neuroleptic Dose or Blood Levels Does Not Equal Causation 458 3. Lack of Attention to Sampling Characteristics of the Patients Studied 459 4. Lack of Studies Comparing Multiple Antipsychotics with Different Neuropharmacologic Profiles 459 5. Use of Relatively Acute Dosage Strategies in Patients Receiving Long-Term Treatment 460 6. Lack of Information Regarding the Details of the Study 460 7. Inconsistent or Inappropriate Neuropsychological Test Selection 460 H. The Effects of Standard Antipsychotics in Schizophrenia 460 I. Attention/Information-Processing Measures 461 II. Effects of Typical Antipsychotics on Memory Functions 463 III. Antipsychotic Effects on Motor Tasks 464 IV. Hemispheric Asymmetries in Cognitive Performance Patterns 464 V. Standardized Neuropsychological Batteries and the Wechsler Scales 465 VI. Studies Employing a Combination of Selected Cognitive Measures 466 I. Effects of Atypical and Recently Developed Antipsychotics on Cognition 468 J. Conclusions 470 References 471 XXIV Contents

CHAPTER 16 Antipsychotic Drugs in Children and Adolescents EDWARD S. BRODKIN, CHRISTOPHER J. MCDOUGLE, and JAMES F. LECKMAN 479 A. Introduction 479 B. Indications 479 I. Autism 479 II. Tourette's Syndrome 480 III. Obsessive-Compulsive Disorder 482 IV. Mental Retardation 482 V. Early-Onset Schizophrenia 483 VI. Conduct Disorder and Explosive Rage 485 VII. Attention-Deficit Hyperactivity Disorder 486 VIII. Bipolar Disorder, Manic Phase 486 C. Pharmacology 486 I. Pharmacokinetics and Pharmacodynamics 486 II. Blood Levels 487 D. Mechanism of Action 488 E. Therapeutic Use 489 F. Use in Pregnancy and Nursing 489 G. Side Effects and Toxicity 490 I. Sedation, Fatigue, and Deterioration of Behavior 490 II. Cognitive Effects 490 III. Acute Dystonia 490 IV. Tardive Dyskinesia 491 V. Neuroleptic-Induced Tics 492 VI. Parkinsonism, Catatonia, and the Rabbit Syndrome 493 VII. Akathisia 493 VIII. Neuroleptic Malignant Syndrome 494 IX. Seizure Threshold 494 X. Unwanted Cardiac Effects 495 XI. Hypotension 495 XII. Weight Gain 495 XIII. Ocular Complications 496 XIV. Unwanted Cutaneous Effects 496 XV. Hypothalamic and Pituitary Functions - Adverse Effects on Growth 496 XVI. Hepatic Complications 497 XVII. Hematologic Complications 497 XVIII. Sexual Dysfunction 497 XIX. Enuresis 498 XX. Nondyskinetic Withdrawal Symptoms 498 Contents XXV

XXI. Overdosage 498 H. Conclusions and Future Directions 498 References 500

CHAPTER 17 Use of Antipsychotic Drugs in the Elderly BRUCE G. POLLOCK and BENOIT H. MULSANT. With 1 Figure 505 A. Introduction 505 B. Indications and Clinical Use of Antipsychotics in Late Life 505 I. Nosology of Late-Life Psychoses 506 II. Delirium 507 III. Dementia 508 IV. Schizophrenia 510 1. Early-Onset Schizophrenia in Old Age 510 2. Late-Onset Schizophrenia 511 V. Delusional Disorder 511 VI. Mood Disorders 512 1. Psychotic (Delusional) Major Depression 512 2. Bipolar Disorder (Mania) 513 C. Pharmacokinetics 514 I. General Changes with Age and Illness 515 1. Absorption 515 2. Distribution 516 3. Metabolism 516 4. Excretion 517 5. Need for Individualized Assessment 518 D. Pharmacodynamics 518 E. Conclusions 520 References 52(>>

Subject Index 531