Elsevier

Journal of Affective Disorders

Volume 51, Issue 3, 1 December 1998, Pages 215-235
Journal of Affective Disorders

Research report
Mechanism of action of serotonin selective reuptake inhibitors: Serotonin receptors and pathways mediate therapeutic effects and side effects

https://doi.org/10.1016/S0165-0327(98)00221-3Get rights and content

Abstract

Serotonin selective reuptake inhibitors (SSRIs) are currently among the most frequently prescribed therapeutic agents in all of medicine. Their therapeutic actions are diverse, ranging from efficacy in depression to obsessive–compulsive disorder, panic disorder, bulimia and other conditions as well. The plethora of biological substrates, receptors and pathways for serotonin are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. Specifically, the immediate actions of SSRIs are mostly side effects, and may be mediated by the initiating actions of SSRIs, namely negative allosteric modulation of the serotonin transporter. A leading hypothesis to explain these immediate side effects is that serotonin is increased at specific serotonin receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Desensitization of post-synaptic receptors in these same discrete brain regions may explain the development of tolerance to these same side effects. The explanation for therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. A leading hypothesis for this action is desensitization of somatodendritic serotonin 1A autoreceptors in the midbrain raphe. The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in those critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders. Understanding the topography of serotonin receptor subtypes in discrete anatomical pathways may enhance our understanding of both the therapeutic actions and side effects of these important pharmaceutical agents.

Introduction

This article will explore hypotheses to explain the diverse actions of serotonin selective reuptake inhibitors (SSRIs). Two main hypotheses will be explored here. Firstly, the wide variety of therapeutic actions and side effects of the SSRIs may be mediated by specific receptor subtypes and discrete pathways for serotonin throughout the central nervous system, and in the case of certain side effects, throughout the body. Secondly, the explanation for delayed therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. The explanation for the delayed development of tolerance to side effects of SSRIs also may be found in delayed neurochemical adaptations.

Section snippets

Topography for serotonin's actions: receptor subtypes and unique projection pathways

Do different post-synaptic serotonin receptor subtypes mediate different physiological actions of serotonin? Serotonin has long been known to mediate (probably with other neurotransmitters) such diverse behaviors as mood, anxiety, sleep, temperature, appetite, sexual behavior, eating behavior, movements, gastrointestinal (GI) motility, and many more (Aghajanian, 1995, Brown and van Praag, 1991, Cowen, 1991, Dubovsky, 1994, Glennon and Duckat, 1995, Jacobs and Fornal, 1995, Keppel Hesselink and

Initiating actions of SSRIs

Inhibition of the neuronal transporter for serotonin has long been established as one of the mechanisms of action of numerous antidepressants (Barker and Blakely, 1995, Feighner and Boyer, 1996, Leonard, 1996, Stahl, 1996). The introduction of several agents more selective for this action over any other pharmacologic effect has created a new and well known class of antidepressants called SSRIs (e.g., see Feighner and Boyer, 1996).

Hyman and Nestler (1996) have proposed that acute, short term

General overview

Since it generally takes time for the numerous therapeutic actions of the SSRIs to develop or for the side effects of the SSRIs to abate (Feighner and Boyer, 1996), this has led to a search for delayed neurobiological actions of the SSRIs which might explain their delayed pharmacological actions. One such delayed action of the SSRIs is the desensitization of 5HT1A and 5HT2A receptors (Charney et al., 1981, Charney et al., 1991, Leonard, 1995, Leonard, 1996, Stahl, 1992, Stahl, 1994, Stahl, 1996

Topography for SSRI therapeutic actions and side effects

Serotonin projections and pathways as mediators of specific therapeutic effects of SSRIs. The therapeutic actions demonstrated by SSRIs are of course not limited to antidepressant actions (Feighner and Boyer, 1996, Stahl, 1996), but also include therapeutic utility in panic disorder (Ballenger, 1996), obsessive–compulsive disorder (Stein and Hollander, 1996) and bulimia (Curzon, 1991, Pijl et al., 1991, Walsh and Devlin, 1995). The possible anatomic substrates for these actions are illustrated

Conclusions

A crude topography of serotonin functioning in its different pathways and at its various receptor subtypes is beginning to crystallize from ongoing experiments. To the extent that these findings comprise hypotheses, they may generate experiments to prove or refute them. To the extent that these are mere speculations, they will hopefully lead to cogent hypotheses better formulated for experimental testing as knowledge of the serotonin systems and receptors advances.

The plethora of well

Acknowledgements

Figures adapted and reproduced from S.M. Stahl, Essential Psychopharmacology, Cambridge University Press, New York, 1996, with permission. Grant support: this work was supported in part by NIMH research grant No. 5 RO1 MH45787-02 and by a VA Merit Review Award to Dr. Stahl. This work was also supported in part by Mental Health Clinical Research Center grant No. MH30914 and by General Clinical Research Center grant No. MO1-RR00827 to UCSD.

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    Dr. Stahl is a consultant, speaker and grant recipient of each company which manufactures SSRIs (Lilly, Pfizer, Smith Kline, Forest, Solvay) as well as many of their competitors (Janssen, Bayer, Yamanouchi, Glaxo–Wellcome, Wyeth-Ayerst, Bristol Myers Squibb, Roche, Ciba-Geigy, Pharmacia-Upjohn), but not a major stockholder in any. Dr. Stahl is also a consultant and recipient of stock options for a small biotechnology company in San Diego, Neurocrine Biosciences.

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