Antipsychotics

Antipsychotic drugs were first discovered in 1953, and not since the late 1970s has the Handbook of Experimental Pharmacology taken up this topic. A new treatment of this topic would be due under any circumstances; however, this is now particularly true, since remarkable progress has been made on several fronts in furthering our understanding of the mechanisms of antipsychotic drug action. First, we have learned that schizophrenia is an illness with particu­ lar neuroanatomical abnormalities, many of which suggest that the illness is caused by errors in neurodevelopment. These findings have helped to form a context for understanding neurochemical aberrations in the illness and suggest new approaches for pharmacological treatment. Propelled forward by rapid advances in neurochemical anatomy, current pathophysiological hypotheses of schizophrenia and antipsychotic drug action have taken on the appearance of complex electrical circuit diagrams. Second, molecular biology studies have now revealed that there is a multiplicity of dopamine receptors (i. e. , D , DZshort' j DZlong, D , D , and D ), some of which may become entirely new targets for 3 4 s antipsychotic drug action. Ironically, the development of drugs that are selec­ tive for these receptors and that can be used to investigate their function lags behind; yet the discovery of these new receptors offers unparalleled opportu­ nities for developing drugs with improved efficacy and fewer side effects.

1 Classification Schemes for Antipsychotic Drugs.- A. Introduction.- I. Historical Perspective.- B. Classification by Patterns of Efficacy and Neurological Side Effects.- C. Classification by Chemical Structure.- I. Phenothiazines.- II. Thioxanthenes.- III. Butyrophenones.- IV. Diphenylbutylpiperidines.- V. Indoles.- VI. Benzamides.- VII. Dibenzapines.- VIII. Others.- D. Classification by Potency and Nonneurologic Side-Effect Profile.- E. Classification by Pharmacological Mechanism.- I. Selective Dopamine Receptor D2 Antagonists.- II. Combined D2/D3 Antagonists.- III. Combined D2/D1 Antagonists.- IV. Combined 5-HT2-D2 Antagonists.- F. Future Classification Schemes.- I. Selective Serotonin Receptor Antagonists.- II. Partial D2 Agonists.- III. Sigma Site Antagonists and Excitatory Amino Acid Agonists.- IV. GABA-Mimetics and Partial Benzodiazepine Agonists.- G. Conclusions.- References.- 2 Molecular Models and Structure-Activity Relationships.- A. Introduction.- B. Structure-Activity Relationships of Antipsychotic Drugs.- C. Neurotransmitter Receptor Models.- D. Molecular Modelling of Drug-Receptor Interactions.- I. Electrostatic Fields Around Drug and Receptor Molecules.- II. Molecular Dynamics of Drug-Receptor Interactions.- E. Conclusions.- References.- 3 Interaction of Antipsychotic Drugs with Dopamine Receptor Subtypes.- A. Introduction.- B. Molecular Biology of Dopamine Receptor Subtypes.- I. General Structural Features of Dopamine Receptors.- II. The D1 Family of Dopamine Receptors.- 1. The Dopamine D1 Receptor.- 2. The Dopamine D5 Receptor.- III. The D2 Family of Dopamine Receptors.- 1. The Dopamine D2 Receptor.- 2. The Dopamine D3 Receptor.- 3. The Dopamine D4 Receptor.- C. Pharmacology of Neuroleptics at Recombinant Dopamine Receptors.- I. Traditional Neuroleptics and Related Compounds.- II. Clozapine and the Atypical Neuroleptics.- III. New Antipsychotics.- 1. Olanzapine: A Second-Generation Clozapine-Like Compound.- 2. Remoxipride: A D2 Receptor-Selective Substituted Benzamide.- 3. Risperidone: A D2/5-HT2 Receptor Antagonist.- D. Future Outlook and Hopes for Subtype-Specific Drugs.- References.- 4 Atypical Antipsychotic Drugs: Clinical and Preclinical Studies.- A. Introduction.- B. Glutamate.- I. Glutamate Receptors.- II. Glutamate Hypothesis of Schizophrenia.- III. Glutamatergic Drugs.- 1. Glycine and Milacemide.- 2. Umespirone.- 3. Others.- C. ?-Aminobutyric Acid (GABA).- I. GABA Receptors.- II. GABA Hypothesis of Schizophrenia and Clinical Studies of GABA-ergic Drugs.- D. Acetylcholine.- I. Acetylcholine Receptors.- II. Muscarinic Hyperactivity in Schizophrenia? •.- E. Norepinephrine.- I. ?1-Adrenergic Receptor Involvement in Atypical Antipsychotic Drug Actions.- F. Cholecystokinin (CCK).- I. CCK-ergic Drugs.- 1. LY262691.- 2. Caerulin.- 3. Others.- G. Neurotensin.- I. Neurotensin and Schizophrenia.- II. Effects of Atypical Antipsychotic Drugs on Neurotensin Systems.- H. Sigma Receptors.- I. Sigma Receptors.- II. Preclinical Studies.- III. Specific Agents.- I. Opioids.- J. Serotonin.- I. 5-HT Receptors and Schizophrenia.- II. Selective 5-HT2A/2C Antagonists.- 1. Ritanserin.- 2. ICI169369 and MDL100907.- 3. Mianserin.- III. Mixed 5-HT2/D2 Antagonists.- 1. Clozapine.- 2. Risperidone.- 3. Melperone.- 4. Olanzapine.- 5. Amperozide.- 6. Fluperlapine.- 7. Tiosperone.- 8. Zotepine.- 9. Others.- IV. 5-HT3 Antagonists.- V. Nonselective 5-HT Receptor Antagonists.- VI. 5-HT Reuptake Inhibitors.- K. Conclusions.- References.- 5 Sites and Mechanisms of Action of Antipsychotic Drugs as Revealed by Immediate-Early Gene Expression.- A. Introduction.- B. Immediate-Early Gene Expression as a Method to Assess the Sites and Mechanisms of Action of Antipsychotic Drugs (APDs).- C. Effects of APDs on Immediate-Early Gene Induction in the Striatal Complex.- I. Effects of APDs on Regionally Specific Striatal Immediate-Early Gene Expression.- 1. Dorsal Striatum.- 2. Ventral Striatum.- II. Striatal Immediate-Early Gene Induction: Fos, Fos-Related Antigens, and Others.- 1. Fos Versus Fras.- 2. Other Immediate-Early Genes.- III. Mechanisms of Antipsychotic Drug-Elicited Striatal Fos Expression.- 1. Dopamine Receptors and APD-Elicited Increases in Striatal Fos.- a) D2 Dopamine Receptors.- b) D1 Dopamine Receptors.- c) Concurrent D2/D1 Receptor Occupancy and Striatal Fos Expression.- 2. Involvement of Excitatory Amino Acid Receptors in Neuroleptic-Elicited Striatal Fos Expression.- 3. Cholinergic and Adenosine Receptors.- a) Muscarinic Cholinergic Receptors.- b) Adenosine A2 Receptors.- IV. Acute Versus Chronic Effects of APDs on Striatal Fos Expression.- V. What Is the Transcriptional Target of APD-Elicited Striatal Fos Expression?.- 1. Neurotensin.- 2. Enkephalin.- 3. Glutamic Acid Decarboxylase.- D. Preferential Induction of Fos in the Prefrontal Cortex (PFC) by Clozapine.- I. Regional Effects of APDs on Fos Expression in the PFC.- 1. Effects of APDs on Fos Expression in the Medial PFC.- 2. Correlations Between PFC Expression and Clinical Status.- II. Receptor Mechanisms of Clozapine-Elicited Increase in PFC Fos Expression.- 1. D1 and D2 Dopamine (DA) Receptors and Clozapine-Elicited Fos Expression.- 2. Nondopaminergic Receptors and the PFC Fos Response to Clozapine.- 3. Mechanisms of Clozapine-Elicited Increases in PFC Fos Expression.- a) Possible Role of a Novel DA Receptor in Mediating Clozapine-Elicited Effects.- b) Targeting of Multiple Receptors.- c) Transsynaptic Events as a Possible Determinant of Clozapine-Induced Changes.- III. Transcriptional Targets of Clozapine’s Actions in the PFC.- E. Effects of APDs on Immediate-Early Gene Expression in Other CNS Sites.- I. Thalamic Paraventricular Nucleus.- II. Lateral Septal Nucleus.- III. Other CNS Regions.- F. Conclusions.- I. Methodological Issues.- II. Validity of Fos Expression as a Model of the Actions of APDs.- III. Future Directions.- References.- 6 Basic Neurophysiology of Antipsychotic Drug Action.- A. Introduction.- B. The Dopamine Hypothesis of Schizophrenia.- I. Antipsychotic Drugs as D2 Blockers.- II. Shortcomings of the Dopamine Hypothesis.- C. Acute Physiology of Antipsychotic Drug Action.- I. Dopamine Cell Identification and Physiology.- II. Acute Actions of Antipsychotic Drugs on Dopamine Cell Physiology.- 1. Acute Antipsychotic Drugs Increase Firing Rate.- 2. Acute Antipsychotic Drug Administration Increases Dopamine Cell Burst Firing.- 3. Acute Antipsychotic Drug Treatment Increase the Number of Dopamine Cells Firing Spontaneously.- D. Physiology of Chronic Antipsychotic Drug Treatment.- I. Tolerance to Antipsychotic Drug Action.- II. Chronic Treatment with Antipsychotic Drugs and Dopamine Cell Depolarization Block.- III. Analysis of Mechanisms Contributing to Depolarization Block: Compensatory Systems Involved in the Recovery of Function After Dopamine Lesions.- E. Dual Mode of Dopamine Release: Tonic Versus Phasic.- F. Antipsychotic Drug Treatment and Electrotonic Transmission Within the Basal Ganglia.- I. Dopaminergic Control of Electrotonic Coupling in the Striatum.- II. Effects of Subchronic Treatment with Haloperidol or Clozapine on Striatal Cell Dye Coupling Observed In Vitro.- III. Effects of Subchronic Treatment with Haloperidol or Clozapine on Striatal Cell Dye Coupling Observed In Vivo.- G. Conclusions.- References.- 7 Tolerance and Sensitization to the Effects of Antipsychotic Drugson Dopamine Transmission.- A. Introduction.- B. Effects of Single Administration on Dopamine and Related Behaviors.- C. Effects of Repeated Administration and the Induction of Sensitization and Tolerance.- I. Tolerance.- II. Sensitization.- D. Atypical Antipsychotic Drugs.- E. Conclusions.- References.- 8 The Behavioural Pharmacology of Typical and Atypical Antipsychotic Drugs.- A. Introduction.- B. Typical and Atypical Antipsychotic Drugs.- I. Concepts and Nomenclature.- II. Atypical Antipsychotic Drugs.- III. Behavioural Testing Procedures for Typical and Atypical Antipsychotic Drugs.- C. Basic Actions of Antipsychotic Drugs and Their Behavioural Effects.- D. Effects on Motor Function.- I. Spontaneous Locomotor Activity.- II. Catalepsy and the Paw Test.- E. Effects of Antipsychotic Drugs on Behavioural Effects Elicited by DA Receptor Agonists or Glutamate Antagonists.- I. d-Amphetamine (Methylphenidate)-Induced Behavioural Effects.- II. Apomorphine-Induced Behavioural Effects.- III. Phencyclidine-Induced Behavioural Effects.- F. Action on Conditioned Avoidance.- G. Animal Models of Psychosis and Antipsychotic Drugs.- H. Conclusions.- References.- 9 Antipsychotic Drug Action After Lesions to the Hippocampus or Frontal Cortex.- A. Introduction.- B. Mechanisms of Antipsychotic Drug Action.- I. Dopaminergic Mechanisms.- II. Glutamatergic Mechanisms.- C. Neuropathology and Antipsychotic Drug Action.- D. Effect of Hippocampal Neuropathology on Mechanisms of Antipsychotic Drug Action.- I. Anatomy.- II. Consequences for Glutamatergic Mechanisms of Antipsychotic Drug Action.- III. Consequences for Dopaminergic Mechanisms of Antipsychotic Drug Action.- 1. Dopamine Receptors.- 2. Dopamine Turnover and Release.- 3. Dopamine-Mediated Behaviors.- IV. Summary.- E. Effect of Frontal Cortical Neuropathology on Mechanisms of Antipsychotic Drug Action.- I. Anatomy.- II. Consequences for Glutamatergic Mechanisms of Antipsychotic Drug Action.- III. Consequences for Dopaminergic Mechanisms of Antipsychotic Drug Action.- 1. Dopamine Receptors.- 2. Dopamine Turnover and Release.- 3. Dopamine-Mediated Behaviors.- IV. Summary.- F. Conclusions.- References.- 10 An Animal Model of Sensorimotor Gating Deficits in SchizophreniaPredicts Antipsychotic Drug Action.- A. Introduction.- I. Face Validity: Are the Eliciting Stimuli and Response Patterns of Prepulse Inhibition (PPI) Similar Across Species?.- II. Predictive Validity: Can This Model Be Used as a Sensitive and Specific Screen of Antipsychotic Potency?.- III. Construct Validity: Is This Model Consistent with Existing Constructs of Schizophrenia?.- 1. Construct Validity in a Neurochemical Domain: Mesolimbic Hyperdopaminergia.- 2. Construct Validity in a Neuroanatomical Domain: PPI After Manipulations of Limbic Corticostriatopallidopontine Circuitry.- a) The Hippocampus.- b) The Ventral Striatum.- c) The Ventral Pallidum and Pontine Reticular Formation.- 3. Construct Validity in a Neurodevelopmental Domain: PPI After Isolation Rearing or Neonatal Brain Lesions.- B. Discussion.- I. Model Limitations.- II. Model Strengths.- C. Conclusions.- References.- 11 Patterns of Clinical Efficacy for Antipsychotic Drugs.- A. Introduction.- B. Rating Scales Used to Measure Neuroleptic Effect.- I. Brief Psychiatric Rating Scale.- II. Clinical Global Impression.- III. Global Assessment Scale.- IV. Negative Symptoms and Rating Scales.- 1. Methodologic Problems in the Measurement of Negative Symptoms.- 2. Rating Scales Used to Measure Negative Symptoms and the Deficit Syndrome.- a) Positive and Negative Syndrome Scale.- b) Scale for the Assessment of Negative Symptoms.- c) Schedule for the Deficit Syndrome.- d) Quality of Life Scale.- V. Rating Scales and Phenomenology.- C. Efficacy of Neuroleptics in Schizophrenia.- I. Efficacy in the Treatment of Schizophrenic Exacerbation.- 1. Introduction of Chlorpromazine.- 2. Treatment of Psychosis.- 3. Treatment of Negative Symptoms.- 4. Neuroleptic Dose and Efficacy.- II. Efficacy of Maintenance Neuroleptic Treatment.- 1. Relapse Prevention.- 2. Neuroleptic Dose and Efficacy.- III. Neuroleptics with Special Profiles of Efficacy.- References.- 12 Efficacy of Novel Antipsychotic Drugs in Treatment-Refractory Schizophrenia.- A. Introduction.- B. The Concept of Atypicality.- C. Atypical Antipsychotic Drugs.- I. Clozapine.- 1. Effect on Psychopathology.- a) Effect on Positive Symptoms.- b) Effect on Negative Symptoms.- c) Effect on Disorganization Symptoms.- d) Effect on Cognitive Function.- e) Effect on Mood Symptoms.- f) Effect on Quality of Life.- 2. Duration of Clozapine Trials.- 3. Clozapine Dosage and Administration.- 4. Relationship Between Clinical Efficacy and Plasma Concentrations of Clozapine.- 5. Predictors of Response to Clozapine.- 6. Nonresponders to Clozapine Therapy and Augmentation Strategies.- 7. Dropouts and Withdrawal from Clozapine.- 8. Cost-Effectiveness.- II. Risperidone.- 1. Effect on Psychopathology.- 2. Risperidone Dosage and Administration.- III. Melperone.- IV. Remoxipride.- V. Amperozide.- VI. Others.- D. Conclusions.- References.- 13 Antipsychotic-Induced Side Effects Related to Receptor Affinity.- A. Introduction.- B. Predictable and Unpredictable Side Effects.- C. Classification of Antipsychotic Drugs.- D. Side Effects in Relation to Receptor Affinities.- I. Side Effects Related to Dopamine D2 Receptor Binding.- 1. Psychological Side Effects.- 2. Acute Extrapyramidal Side Effects (EPS).- 3. Tardive EPS.- 4. Hormonal Side Effects.- II. Side Effects Related to Dopamine Receptor Blockade.- III. Side Effects Related to Binding to Receptors Other Than Dopamine Receptors.- IV. Side Effects with No Certain Relation to Receptor Binding.- 1. Neuroleptic Malignant Syndrome.- 2. Agranulocytosis.- E. Older Antipsychotics with Typical and Atypical EPS Profiles.- F. Newer Antipsychotics with Typical and Atypical EPS Profiles.- I. Dopamine-Selective Antipsychotics.- 1. Sulpiride.- 2. Other Substituted Benzamides.- 3. D1 and Combined D1/D2 Dopamine Receptor Antagonists.- II. Newer Antipsychotics with Dopamine-Serotonin-Norepinephrine Antagonism.- 1. Risperidone.- 2. Ziprasidone.- 3. Sertindole.- III. Multiple Receptor Antagonists.- 1. Clozapine.- 2. Olanzapine.- 3. Seroquel.- 4. Zotepine.- G. Management of Side Effects.- I. Prevention.- II. Early Detection of Side Effects.- III. Treatment of Side Effects.- H. Conclusions.- References.- 14 Biological Predictors of Antipsychotic Treatment Response.- A. Introduction.- B. Biochemical Predictors.- I. Homovanillinic Acid (HVA).- II. Dopamine ?-Hydroxylase (DBH).- III. Serotonin (5-HT).- IV. Norepinephrine(NE).- V. Peptides.- C. Behavioral Response to Psychostimulants.- D. Neuroendocrine Studies.- E. Neuroimaging.- I. Structural Brain Imaging.- II. Functional Brain Imaging.- F. Electrophysiologic Predictors.- I. Galvanic Skin Conductance and Heart Rate.- II. Electroencephalography (EEG).- III. Event-Related Potential (ERP).- IV. Saccadic Eye Movements.- G. Discussion.- H. Conclusions.- References.- 15 Effects of Antipsychotic Drugs on Neuropsychological Measures.- A. Introduction.- B. Biological Underpinnings of Cognitive Deficit in Schizophrenia….- C. Cognitive Impairment in Schizophrenia.- D. Anticholinergics and Cognition.- E. Dopamine and Cognition.- I. Related Evidence for the Role of Dopamine in Cognition.- II. Dopamine Agonists, Prefrontal Function, and Cognition in Schizophrenia.- F. Effects of Antipsychotic Drugs on Cognition in Healthy Nonpsychiatric Samples.- G. Effects of Typical Antipsychotics in Schizophrenic Patient Samples.- I. Methodological Limitations in Examining the Effects of Neuroleptics in Schizophrenia.- 1. Lack of Random Assignments to Groups in Studies Contrasting Groups of Medicated and Unmedicated Patients.- 2. Correlations Between Cognitive Impairments and Neuroleptic Dose or Blood Levels Does Not Equal Causation.- 3. Lack of Attention to Sampling Characteristics of the Patients Studied.- 4. Lack of Studies Comparing Multiple Antipsychotics with Different Neuropharmacologic Profiles.- 5. Use of Relatively Acute Dosage Strategies in Patients Receiving Long-Term Treatment.- 6. Lack of Information Regarding the Details of the Study.- 7. Inconsistent or Inappropriate Neuropsychological Test Selection.- H. The Effects of Standard Antipsychotics in Schizophrenia.- I. Attention/Information-Processing Measures.- II. Effects of Typical Antipsychotics on Memory Functions.- III. Antipsychotic Effects on Motor Tasks.- IV. Hemispheric Asymmetries in Cognitive Performance Patterns.- V. Standardized Neuropsychological Batterie...