John M. Kane - Serotonin in antipsychotic treatment: mechanisms and clinical practice

Cover

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Serotonin inAntipsychoticTreatment

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Medical Psychiatry

Series Editor

William A. Frosch, M.D.

Cornell University Medical College

New York, New York

1. Handbook of Depression and Anxiety: A Biological Approach ,edited by Johan A. den Boer and J. M. Ad Sitsen

2. Anticonvulsants in Mood Disorders , edited by Russell T. Joffeand Joseph R. Calabrese

3. Serotonin in Antipsychotic Treatment: Mechanisms and ClinicalPractice , edited by John M. Kane, H.-J. Mller, and FransAwouters

4. Handbook of Functional Gastrointestinal Disorders, edited byKevin W. Olden

ADDITIONAL VOLUMES IN PREPARATION

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Mechanisms and Clinical Practice

edited by

John M. Kane

Albert Einstein College of Medicine

Bronx, New York

Hillside Hospital

Long Island Jewish Medical Center

Glen Oaks, New York

H.-J. Mller

Psychiatric Hospital

University of Munich

Munich, Germany

Frans Awouters

Janssen Research Foundation

Beerse, Belgium

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ISBN: 0-8247-9302-1

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The history of psychiatry is fraught with enthusiasm followed by disillusionment. The linkage by Broca and Wernicke of certain aphasias with specificareas of the brain was heralded by many, including Freud (as witnessed by hisProject for a Scientific Psychology), as evidence that brain physiology and pathology would soon help us understand and treat psychiatric pathology. Psychoanalytical theory and practice played a similar role.

Loewi's proof that nerve impulses were indeed transmitted by a chemical(then dubbed vagus stuff, and later characterized and named acetylcholine) was the harbinger of multiple neurotransmitters to be discovered, characterized, named, and have something of their anatomical and physiologicalroles described. The discovery of the endorphins was thought to be the forerunner to conquering addiction, and dopamine was thought to explain schizophrenia. Many of these discoveries have elicited the same initially enthusiastic,somewhat naive, response, We have the answer. Perhaps in part, but certainly not yet. While each of these contributions contains at least a kernel oftruth, they each continue to require revision, refinement, and integration withother viewpoints of the complexity of mind-brain function.

Serotonin in Antipsychotic Treatment. Mechanisms and Clinical Practice modifies our naivet as well as stimulates our enthusiasm. The editors andcontributors provide us with a balanced view of the shortcomings of a purely

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dopaminergic view of Bleuler's group of schizophrenias, as well as expandour horizons as we grope toward understanding. Unfortunately, when we studyschizophrenia, we are studying a dirty disease in the sense that it is undoubtedlythe final common expression of many pathologies. In addition, the drugs weuse for treatment are dirty drugs; they have multiple effects on multiple systems. The observation that chlorpromazine and other early neuroleptics allproduced extrapyramidal side effects led people to think that these were necessarily linked to the therapeutic response, and they were used in part in thescreening for new compounds. This all reinforced the central role of dopaminein our theories of schizophrenia.

The discovery of clozapine, as noted in Chapter 2 of this volume, has forever altered the conventional wisdom that held all antipsychotics to be equallyefficacious and uniformly neurotoxic. The discovery of agents that are effective in the treatment of schizophrenia and that also have important effects onneurotransmitters other than dopamine has further widened both our understanding of the complexities of and our search for more effective and lessdamaging treatments. Risperidone is one of a now rapidly expanding group ofnovel and effective neuroleptics that can be characterized by their significanteffect on serotonergic mechanisms. In this volume it serves as a model for theexpansion of our understanding of the pathophysiology and treatment of schizophrenia. We must, however, guard against premature and simplistic explanations; we are merely on the road toward understanding.

William A. Frosch

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In the four decades since the introduction of chlorpromazine into clinical practice, antipsychotic medications have been the mainstay in both the acute andlong-term treatment of schizophrenia. Enormous research efforts have focused on understanding the mechanism of action of antipsychotic drugs inorder to develop more effective and less toxic agents, as well as to shed furtherlight on the etiology and pathophysiology of schizophrenia and other psychoticdisorders.

The dopamine receptor antagonist effects of effective antipsychotic agentsfocused attention primarily on dopaminergic systems. However, there havelong been strong currents of data implicating other neurotransmitter systemsin psychotic disorders and antipsychotic drug effects. A number of events inrecent years have helped to further efforts to explore other systems, particularly advances in molecular biology, which have helped to identify receptorsubtypes in a variety of familiesdopamine, serotonin, etc. In addition, thereintroduction of clozapine and the introduction of risperidone have helpedto stimulate new research on combined receptor effects.