A Decade of Serotonin Research: Role of Serotonin in Treatment of PsychosisSerotonergic basis of antipsychotic drug effects in schizophrenia
Introduction
Since the advent of chlorpromazine and elucidation of its mechanisms of action, there has been a focus on dopamine (DA) neurotransmission both in formulating pathophysiological theories of schizophrenia and in developing new therapeutic agents Randrup and Munkvad 1965, Carlsson 1974, Snyder et al 1974, Creese et al 1976, Seeman et al 1976, Davis et al 1991. Recently, considerable attention has been focused on the potential involvement of serotonin (5-HT) in both the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. One reason for this has been the tremendous success of the so-called “atypical” antipsychotic drugs that have as a common feature high affinity for one or more 5-HT receptor subtypes (e.g., 5-HT2A). In fact, it is now known that there is a large family of 5-HT receptors whose function and pharmacology are only beginning to be understood. The molecular biology of serotonin receptors, and the therapeutic implications of drugs acting at these receptors is reviewed in the article by Kroeze and Roth (this issue).
This paper will review evidence linking 5-HT systems to the mediation of antipsychotic drug effects, and also to the possible etiology of the disorder. We shall address the role of serotonin in neurodevelopment, and the functional interactions of DA and 5-HT systems. By examining the psychotomimetic and psychotogenic properties of hallucinogens, and changes in serotonergic function in schizophrenia, we hope to provide insight into how 5-HT systems may play a role in the clinical action of atypical antipsychotic drugs, and to highlight many of the remaining unanswered questions.
Section snippets
Functional interactions of DA and 5-HT systems
A major line of evidence supporting a potential role of serotonin in mediating antipsychotic drug effects involves the anatomical and functional interactions of DA and 5-HT. DA and 5-HT neurotransmission interact at different anatomical levels, are mediated by different 5-HT receptor subtypes, and affect different aspects of DA function. Generally speaking, the reduction of 5-HT activity is associated with an enhancement of DA. This interaction has been suggested to account for the beneficial
5-HT2a receptor antagonist properties of atypical antipsychotics
Meltzer et al (1989) formalized and popularized a concept that had been previously suggested in a report by Ceulemans et al (1985), to wit, that the ratio of 5-HT2A to D2 affinities was the key pharmacologic property of atypical antipsychotic drugs. Meltzer et al (1989) suggested that typical and atypical antipsychotics can be distinguished on the basis of lower D2 and higher 5-HT2A pKI values (a logarithmic measure of the affinity of a drug for its receptor), parameters derived from in vitro
Psychotomimetic and psychotogenic properties of hallucinogens
Another line of evidence linking serotonin to schizophrenia and, by extension, antipsychotic drug activity is the research on hallucinogenic drugs. Several terms are often used for such drugs, including hallucinogen and psychotomimetic. It should be recognized that both terms are misnomers, because not all such drugs reliably produce hallucinations, nor do they usually produce a state that mimics psychosis. As such, despite the differences between the effects of “hallucinogens” and the symptoms
Evidence for 5-HT dysfunction in schizophrenia
There is sparse evidence for 5-HT involvement in the pathophysiology of schizophrenia. Direct evidence for abnormal 5-HT2A-mediated neurotransmission in schizophrenia comes primarily from cerebral spinal fluid (CSF) studies of 5-HT metabolites and postmortem ligand binding studies of 5-HT, 5-HT metabolites, 5-HT transporters, and 5-HT receptors. Indirect evidence comes from pharmacologic challenges probing the 5-HT system, the observed effects of antipsychotic drugs with clinical efficacy in
Serotonin and neurodevelopment: implications for atypical antipsychotics
Serotonin plays a role in the development of multiple tissues and organs, including the fertilized ovum, the heart, the intestines, craniofacial structures, and the central nervous system from the earliest stages of gastrulation through adulthood (Lauder 1990). Within the brain, serotonin influences neuronal and glial morphology, connectivity, and function (Azmitia and Whitaker-Azmitia 1991). Some of these effects are direct, some are mediated by growth factors (the best characterized of which
Conclusions
In summary, a broad array of evidence (both direct and indirect) implicates 5-HT in the pathophysiology of schizophrenia, and as a key substrate mediating atypical antipsychotic drug effects Kapur and Remington 1996, Kapur 1996. Moreover, in view of the role of serotonin in neurodevelopment and neuronal plasticity, there is a strong rationale for the potential involvement of serotonin in the pathogenesis and neurodevelopmental diathesis of schizophrenia. This evidence, however suggestive of and
Acknowledgements
This work was supported, in part, by US Public Health Service research grants MH00537, MH-40537, and MH-42705, and Center grants MH33127 and HD03310.
This work was presented at the Neuroscience Discussion Forum “A Decade of Serotonin Research” held at Amelia Island, Florida in November, 1997. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Eli Lilly and Company.
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