Psychotropic Agents: Part I: Antipsychotics and Antidepressants

ISBN-13: 9783642675409 / Angielski / Miękka / 2011 / 736 str.

M. Ackenheil

Opis

The volumes on "psychotropic substances" in the Handbook of Experimental Phar- macology series clearly show that the classical concept of this discipline has become too narrow in recent years. For instance, what substances are psychotropic is determined not by the criteria of the animal trial, i.e. by experimental pharmacology, but by their action on the psy- che, which in the final analysis is only accessible to us in man. Psychotropic substances force experimental pharmacology (and thus also this Handbook) outside its tradition- allimits, which have essentially depended on animal studies. The antipsychotics and antidepressants were not discovered in animal ex- periments, but by chance (or more precisely, by clinical empiricism). Experienced psy- chiatrists trained in the observation of patients recognised the efficacy of drugs, the beneficial effect of which nobody had dreamed of before: DELAY and DENICKER in the case of chlorpormazine, KLINE in the case of the monoamine oxidase inhibitors and KUHN in the case of imipramine. It was only after these discoveries that the pharma- cologists developed experimental models of the psychoses in animal experiments. However, even today we still do not know with certainty which of the effects shown in animals is relevant for the clinical effect despite the vast abundance of individual investigations. For many years, this uncertainty led to the testing of antipsychotics (e.g. of the neuroleptic type) in models which actually produced the undesired effects.

Spis treści

Antipsychotics: Chemistry (Structure and Effectiveness).- 1 Tricyclic Neuroleptics: Structure-Activity Relationships.- A. Criteria for Neuroleptic Activity.- B. Chemical Classification of the Tricyclic Neuroleptics.- C. Molecular Conformation.- D. Stereospecificity of Action.- E. Nature of the Basic Side Chain.- F. Aromatic Substitution.- G. Nature of the Central Ring.- H. Non-Cataleptogenic Neuroleptics.- I. Conclusion.- References.- 2 Butyrophenones and Diphenylbutylpiperidines.- A. Introduction.- B. Structure-Activity Relationships.- I. Chemistry.- II. Pharmacology.- III. Clinical Aspects.- 1. Butyrophenones.- 2. Diphenylbutylpiperidines.- C. Conclusion.- References.- 3 Centrally Acting Rauwolfia Alkaloids.- A. Introduction and History.- B. Biologic Fate and Mechanisms of Action of Reserpine.- C. Central Actions of Reserpine.- I. Effect of Reserpine on Behavior.- II. Effect of Reserpine on the Motor System.- III. Effects of Reserpine on Bioelectric Signals.- D. Comparison with Other Neuroleptics.- I. General Clinical Effects.- II. Alleged Depression-Inducing Effect of Neuroleptics.- References.- 4 Behavioral Pharmacology of Antipsychotics.- A. Introduction.- B. Basic Aspects and Considerations in Regard to Investigations.- C. Action of Antipsychotics on Spontaneous Behavior.- I. Pattern of Action on Behavior.- II. Locomotion.- III. Immobilization.- IV. Muscle Relaxation and Ptosis.- V. Excitation Conditions.- VI. Aggression.- VII. Reproduction.- VIII. Maternal Behavior.- IX. Feeding Behavior.- X. Prey Catching.- XI. Memory and Learning.- D. Actions of Antipsychotics on Induced Behavioral Patterns.- I. Stimulant-Induced Excitation Patterns.- II. Tryptamine-Induced Convulsion.- III. Withdrawal Syndrome.- IV. Topical Brain Stimulation.- V. Self-Stimulation.- VI. Rotational Model.- VII. Brain Lesions.- E. Side-Effects Following Acute and Chronic Administration and Tolerance Phenomena.- F. Conclusions.- References.- 5 Testing Antipsychotic Drug Effects with Operant Behavioral Techniques.- A. General Advantages of Operant Procedures for the Demonstration of Behavioral Drug Effects.- B. Operant Procedures for Evaluating Antipsychotic Drug Actions.- I. Active Avoidance Tests.- II. Other Operant Procedures.- C. Value of Operant Techniques for Detecting Antipsychotic Drug Effects.- D. Summary.- References.- 6 Stereotyped Behavior and Its Relevance for Testing Neuroleptics.- A. Similarities and Differences Between Endogenous Psychoses and States Induced by Amphetamines in Man or Animals.- I. Amphetamine Psychosis and Endogenous Psychoses.- II. Comparison of Animal and Human Data.- B. Relevance of Stereotypies in Testing Antipsychotic Drugs.- References.- 7 Neurophysiologic Properties of Neuroleptic Agents in Animals.- A. Pre- and Postsynaptic Action of Antipsychotic Drugs.- B. Spinal Neurones and Descending Pathways.- C. Presence of Monoamines in the Brain Stem.- I. Arousal.- II. Analgesia and Nociceptive Reflexes.- III. Seizure Activity.- IV. Vomiting, Swallowing.- D. Nigro-Neostriatal System.- I. DA as a Transmitter.- II. The Neuronal Feedback Loop and Self-Inhibition.- III. Spinal Motor Activity.- E. Mesolimbic System.- F. Locus Coeruleus and Other Brain Stem Nuclei: Ascending Pathways.- G. Cyclic-AMP.- H. Concluding Remarks.- References.- 8 Antipsychotics: Neurophysiological Properties (in Man).- A. Future Prospects.- B. Summary.- References.- 9 Biochemical Effects of Neuroleptic Drugs.- A. Introduction.- B. General Biochemical Features of Neuroleptic Drugs.- C. Effects of Neuroleptic Drugs in Discrete Brain Structures.- I. Extrapyramidal System.- 1. Acetylcholine.- 2. GABA.- 3. Neuroleptic-Induced Feedback Activation of DA Neurons: Possible Role of ACh and GABA.- 4. Effects of Repeated Administration of Neuroleptics.- 5. Functional Correlates of Neuroleptic-Induced Biochemical Alterations.- II. Limbic System.- 1. Acetylcholine.- 2. GABA.- 3. Repeated Administration of Neuroleptics: Effects in Limbic System.- D. Atypical Neuroleptics.- References.- 10 Biochemical Effects (in Men).- A. Introduction.- B. Biochemical Findings in Urine.- C. Biochemical Findings in Blood.- D. Biochemical Findings in CSF.- E. Conclusions.- References.- 11 Toxicology of Antipsychotic Agents.- A. Introduction.- B. Butyrophenones.- I. General.- II. Animals.- 1. Acute Toxicity.- 2. Subchronic Toxicity.- 3. Chronic Toxicity.- 4. Fertility.- 5. Teratology.- 6. Perinatal and Postnatal Toxicity.- III. Human Subject.- 1. Acute Toxicity.- 2. Teratology.- 3. Perinatal and Postnatal Toxicity.- IV. Mutagenic Activity.- V. Discussion of Side-Effects.- C. Phenothiazines.- I. General.- II. Animal.- 1. Acute Toxicity.- 2. Subchronic Toxicity.- 3. Chronic Toxicity.- 4. Fertility.- 5. Teratology.- 6. Perinatal and Postnatal Toxicity.- III. Man.- 1. Acute Toxicity.- 2. Fertility.- 3. Teratology.- 4. Perinatal and Postnatal Toxicity.- IV. Mutagenic Activities.- V. Carcinogenicity.- VI. Physical Dependence.- VII. Discussion of Side-Effects.- D. Reserpine.- I. General.- II. Animals.- 1. Acute Toxicity.- 2. Subchronic Toxicity.- 3. Chronic Toxicity.- 4. Fertility.- 5. Teratology.- 6. Perinatal and Postnatal Toxicity.- III. Man.- 1. Acute Toxicity.- 2. Teratology.- 3. Perinatal and Postnatal Toxicity.- IV. Carcinogenicity.- V. Discussion of Side-Effects.- References.- 12 Clinical Pharmacology (Pharmacokinetics).- A. Introduction.- B. Phenothiazines and Thioxanthenes.- I. Chlorpromazine, Levomepromazine.- 1. Methods for Assessment of Chlorpromazine Concentration in Biological Fluids.- 2. Pharmacokinetics of CPZ in Man.- II. Phenothiazines with Piperidine Side-Chain (Thioridazine, Mesoridazine).- 1. Methods for Assessment of Thioridazine Concentration in Biological Fluids.- 2. Pharmacokinetics of Thioridazine and Mesoridazine in Man.- III. Phenothiazines with Piperazine Side-Chain (Perazine, Butaperazine, Perphenazine, Fluphenazine).- 1. Methods for Assessment of Plasma Concentrations.- 2. Pharmacokinetics of Piperazine Side-Chain Phenothiazines in Man.- IV. Pharmacokinetics of Thioxanthenes in Man.- C. Pharmacokinetics of Clozapine and Loxapine in Man.- D. Pharmacokinetics of Butyrophenones in Man.- References.- 13 Metabolism and Kinetics.- A. Introduction.- B. Phenothiazines and Thioxanthenes.- I. Kinetics in Animals.- 1. Absorption.- 2. Distribution.- 3. Elimination.- II. Extent of Biotransformation in Vivo.- III. Metabolic Pathways.- 1. Reactions at the Ring System.- 2. Reactions at the C-2 Substituent.- 3. Reactions at the N-10 Side Chain.- 4. Combinations of Reactions.- C. Clozapine.- I. Kinetics in Animals.- II. Metabolism.- D. Butyrophenones and Diphenylbutylpiperidine Derivatives.- I. Kinetics in Animals.- II. Metabolism.- E. Reserpine.- References.- 14 Psychometric and Psychophysiological Actions of Antipsychotics in Men.- A. Introduction.- I. Aims of the Review.- B. Methodological Problems in Measuring the Effects of Antipsychotic Drugs on Behavioral and Psychophysiological Parameters.- I. Selection of Indicators.- II. Selection of Situational Conditions.- III. Selection of Subjects.- IV. Time Course of Action.- C. Review of Antipsychotic Drugs on Different Areas of Psychological Functioning.- I. Effects of Antipsychotic Drugs on Perception.- 1. Assessment Approaches.- 2. Determination of Thresholds.- II. Effects of Antipsychotic Drugs on Thinking and Intelligence (Cognitive Processes).- 1. Assessment Approaches.- 2. General Intelligence Tests.- 3. Reasoning.- 4. Word Fluency.- 5. Verbal Thinking.- 6. Conclusions on the Effects of Antipsychotic Drugs on Cognitive Processes.- III. Learning.- 1. Assessment Aproaches.- 2. Verbal Learning.- 3. Classical Conditioning.- 4. Operant Conditioning.- 5. Conclusions Concerning the Effects of Antipsychotic Drugs on Learning.- IV. Memory Processes.- V. Effects of Antipsychotic Drugs on Psychomotor Performance.- 1. Assessment Approaches.- 2. Psychomotor Speed.- 3. Sensorimotor Speed.- 4. Complex Psychomotor and Sensory Coordination.- 5. Finger, Hand, and Arm Dexterity.- 6. Finger and Hand Steadiness.- 7. Precision of Small Movements of Fingers, Hands, and Arms.- 8. Other Types of Psychomotor Abilities.- 9. Conclusions About the Effects of Antipsychotic Drugs on Psychomotor Abilities.- VI. Concentration and Vigilance.- 1. Assessment Approaches.- 2. Vigilance.- 3. Concentration as Measured by Coding Tests (Digit Symbol Test).- 4. Concentration Measured by Continuous Arithmetic Calculations.- 5. Concentration Measured by Cancellation Tests.- 6. Conclusions Concerning the Effects of Antipsychotic Drugs on Concentration and Vigilance.- VII. Effects of Antipsychotic Drugs on Psychophysiological Parameters.- 1. Problems of Psychophysiological Measures.- 2. Measures of Central Nervous System.- 3. Autonomic Nervous System Measures.- VIII. Emotional Processes.- 1. Assessment Approaches.- 2. Emotional Stability.- 3. Anxiety.- IX. Motivational Processes.- 1. Assessment Approaches.- 2. Activation.- 3. Other Motivational Aspects.- References.- 15 Endocrine Effects of Neuroleptics.- A. History.- B. Psychotherapeutic Drugs Affecting the Endocrine System.- I. Phenothiazines.- II. Butyrophenones.- III. Rauwolfia Derivatives.- IV. Benzodiazepines.- V. Barbiturates.- VI. Lithium.- VII. Thalidomide.- VIII. Antidepressants.- IX. Hydroxyzine.- X. Ergot Derivatives.- C. Mechanisms of Endocrine Effects.- I. The Mediator Theory.- II. The Tropin Balance Theory.- III. The Steroid Receptor Theory.- D. Conclusions.- References.- Antidepressants: Chemistry (Structure and Effectiveness).- 16 Chemistry (Structure and Activity).- A. Thymoleptics.- I. Imipramine.- II. Imipramine Analogs.- III. Search for the “Active” Conformation of Imipramine and Its Analogs.- IV. Further Exploration of Structure-Activity Relationships.- V. Compounds Found in Screening.- VI. Search for Compounds with Greater Specificity.- VII. Compounds with a Mechanism of Action Different From that of Imipramine and Its Analogs.- B. Conclusion.- References.- 17 Monoamine Oxidase Inhibitors as Antidepressants.- A. Introduction.- B. Pharmacology — Background.- I. Pharmacology of MAOIs.- II. Function.- III. Structure and Biologic Action.- IV. Mode of Action.- V. MAOIs Used Clinically.- VI. Biochemical Markers — Usefulness in Practice.- VII. Acetylation Phenotype.- C. Evaluation of MAOI Antidepressant Efficacy.- I. Experimental Design Problem.- 1. Spontaneous Remission.- II. Controlled and Open Studies.- III. Time Lapse before Response.- D. Practicum for Clinical Use.- I. How to Select Patients for a MAOI.- II. Patient Compliance.- III. When to Use a Monoamine Oxidase Inhibitor.- IV. Secondary Causes of Depression.- V. Indications for the Monoamine Oxidase Inhibitors.- E. Use in Phobic Anxiety.- F. Achievers’ Depression.- I. Posology.- II. Toxicity and Side Effects.- III. Interactions.- 1. With Tricyclic Antidepressants.- 2. With Narcotic Analgesics.- 3. With Insulin.- 4. With Other Prescription Medications.- 5. With Over-the-Counter Medications.- G. Potential for Drug Abuse.- I. Behavioral Toxicity.- H. Management of Overdosage and Side Effects.- I. Summary.- References.- 18 Tricyclic Antidepressants: General Pharmacology.- A. Introduction.- B. Behavioral Effects.- C. Interaction with Other Drugs.- D. Interaction with Biogenic Amines.- E. Amine Uptake Inhibition.- F. Cardiovascular Effects.- G. Concluding Remarks.- References.- 19 Neurophysiological Properties (in Animals).- A. Tricyclic Antidepressants (ADs).- I. Effects of ADs on the Electrical Activity of the Brain.- II. Actions of ADs on the Excitability of the CNS.- III. Action of ADs on the EEG Arousal Response.- IV. Drug-Interaction Studies on ADs.- V. Additional Neurophysiological Studies on the Effects of ADs.- B. Monoamine Oxidase Inhibitors (MAOIs).- I. Effects of MAOIs on the Electric Activity of the Brain.- II. Additional Neurophysiological Results on the Effects of MAOIs.- C. Concluding Remarks.- References.- Supplementary References.- 20 Clinical Neurophysiological Properties of Antidepressants.- A. Introduction.- B. EEG Classification of Psychotropic Drugs.- C. Method of EEG Analysis.- D. EEG Findings in Depression.- E. EEG Findings with Antidepressants.- I. Drugs Commonly Used as Antidepressants.- 1. Tricyclic Antidepressants.- 2. MAO Inhibitors.- 3. Inorganic Salts.- 4. Miscellaneous Antidepressants.- II. Drugs Belonging to Other Classes but Having Some Antidepressant Properties.- 1. Neuroleptics with Antidepressant Properties.- 2. Psychostimulants.- III. Drugs Predicted as Antidepressant Based on their CEEG Profiles.- 1. Drugs Predicted by Animal Pharmacology as Antidepressants, and Confirmed Based on CEEG Profiles.- 2. Drugs Predicted to be Antidepressants by CEEG Alone, But Not by Animal Pharmacology.- F. Summary and Conclusion.- References.- 21a Biochemical Effects of Antidepressants in Animals.- A. Introduction.- B. Monoamine Oxidase Inhibitors.- I. Multiple Forms of MAO and Selective MAO Inhibitors.- II. Physiologic Consequences of MAO Inhibition.- C. Tricyclic Antidepressants and Other Drugs Which Affect Monoaminergic Systems in Brain.- I. Effects of Tricyclic Antidepressants on MAO Activity.- II. Blockade by Tricyclic Antidepressants of the Uptake of Biogenic Amines.- III. Interaction of Tricyclic Antidepressants with Other Drugs.- IV. Effect of Tricyclic Antidepressants Following Their Prolonged Administration on Adaptive Presynaptic Regulation.- V. Miscellaneous Biochemical Effects of Antidepressant Drugs.- D. Effect of Antidepressant Drugs on the Sensitivity of the NE-Receptor-Coupled Cyclic AMP Generating System in the Limbic Forebrain and in Other Structures of the Brain.- References.- 21b Biochemical Effects of Antidepressants in Man.- A. General Introduction.- B. Biochemical Effects of Antidepressants as Reflected in the Urine.- I. Introduction.- II. Effects of Tricyclics and MAO Inhibitors.- III. Discussion.- C. Biochemical Effects of Antidepressants as Reflected in the Blood.- I. Introduction.- II. Effects of Tricyclics and MAO Inhibitors.- III. Discussion.- D. Biochemical Effects of Antidepressants as Reflected in the CSF.- I. Introduction.- II. Effects of Tricyclics, MAO Inhibitors, and Precursors of Biogenic Amines.- III. Discussion.- E. General Discussion.- References.- 21c Drug-Induced Alterations in Animal Behavior as a Tool for the Evaluation of Antidepressants: Correlation with Biochemical Effects.- A. Introduction.- B. Amine-Depleted Animals as a Model for the Study of Antidepressants, Correlations with Biochemical Effects.- I. Parameters Used for the Determination of Antidepressant Effects in Amine-Depleted Animals.- C. Drug-Induced Behaviors Implicating Aminergic Stimulation in the Evaluation of Antidepressants.- I. Behavioral Responses Induced by Indirect Stimulation of Catecholaminergic Receptors.- II. Behavioral Responses Induced by Direct Stimulation of Monoaminergic Receptors.- III. Behavioral Response Related to Serotoninergic Stimulation.- D. Final Conclusion and Remarks.- References.- 22 Toxicology of Antidepressant Drugs.- A. Introduction.- B. Monoamine Oxidase Inhibitor.- I. Animal Toxicity.- 1. General Toxicology.- 2. Interaction Experiments.- II. Intoxication in Man.- 1. Effects of Acute Overdose.- 2. Treatment of Acute MAO Inhibitor Overdose.- 3. Chronic Toxicity of MAO Inhibitors.- C. Tricyclic Antidepressants.- I. Animal Toxicity.- 1. General Toxicology.- 2. Interaction Experiments.- 3. Cardiovascular Effects.- 4. Induction of Myeloid Body Formation.- II. Teratology.- III. Intoxication in Man.- 1. Effects of Acute Overdose.- 2. Treatment of Tricyclic Antidepressant Overdose.- D. Conclusions.- References.- 23 Metabolism of Antidepressants.- A. Introduction.- B. Dibenzazepines.- I. Imipramine and Its Therapeutically Used Metabolites.- II. Derivatives of Imipramine.- 1. Chlorimipramine.- 2. Trimepramine.- 3. Lofepramine.- 4. Ketipramine.- C. Dibenzocycloheptadienes (Amitriptyline, Nortriptyline).- D. Other Antidepressants.- 1. Noxiptiline.- 2. Opipramol.- 3. Protriptyline.- 4. Proheptatriene.- 5. Intriptyline.- 6. Doxepine.- 7. Prothiadene.- 8. Melitracene.- 9. Dimethacrine.- 10. Maprotiline.- 11. Dibenzepine.- 12. Miscellaneous Antidepressants.- References.- 24 Physiological and Psychological Effects of Antidepressants in Man.- A. Introduction.- B. Central Physiological Effects.- C. Peripheral Physiological Effects.- I. Skin Conductance.- II. Finger Tremor.- III. Pupil Diameter.- IV. Cardiovascular Changes.- V. Salivation Rate.- D. Psychological Effects.- E. Conclusions.- References.- 25 Pharmacology and Toxicology of Lithium.- A. Human Data, Animal Data, in Vitro Data.- B. Pharmacokinetics.- C. Renal Elimination and Mechanism of Poisoning.- D. Adverse Effects.- I. Neuromuscular System.- II. Mind.- III. Heart.- IV. Thyroid.- V. Kidneys.- VI. Skin.- VII. Body Weight.- VIII. Edema.- E. Teratogenicity.- F. Lactation.- G. Interaction with Other Drugs.- H. Literature.- References.- 26 Antipsychotics and Experimental Seizure Models.- A. Introduction.- B. Neuroleptics.- I. Tricyclic Compounds.- 1. Clorpromazine.- 2. Other Tricyclic Neuroleptics.- II. Butyrophenos and Diphenylbutylpiperidines.- C. Reserpine.- D. Influence of Neuroleptics and Reserpine on the Effects of Anticonvulsant Drugs.- E. Conclusions.- References.- Author Index.