Mechanism of action of serotonin selective reuptake inhibitors

Journal of Affective Disorders 51 (1998) 215–235

Research report

Mechanism of action of serotonin selective reuptake inhibitors Serotonin receptors and pathways mediate therapeutic effects and side effects 1, Stephen M. Stahl *

Clinical Neuroscience Research Center, 8899 University Center Lane, Suite 130, San Diego, San Diego, CA 92122, USA

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.  1998 Elsevier Science B.V. All rights reserved. Keywords: Fluoxetine; Fluvoxamine; Paroxetine; Sertraline; Citalopram; Depression; Panic; Obsessive–compulsive; Bulimia

*Tel.: 1 1-619-4529232; fax: 1 1-619-4523946. 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.

1. Introduction

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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

0165-0327 / 98 / $ – see front matter  1998 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 98 )00221-3

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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.

2. 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 Sambunaris, 1995; Kunovac and Stahl, 1995; Leonard, 1992; Risch and Nemeroff, 1992; Sandler et al., 1991; Shih et al., 1995). There may be 14 or more varieties of serotonin receptors (Fig. 1) including at least three major families (5HT1A, 5HT2A / C, and 5HT3) (Figs. 2–4) (Cowen, 1991; Harrington et al., 1992; Langer et al., 1992; Leonard, 1994; Lesch et al., 1993; Peroutka, 1993; TIPS, 1996). Only recently have drugs selective for serotonin receptor subtypes been discovered, but many of those are still not available for human testing. With the classification of multiple subtypes for serotonin receptors, research is attempting to clarify not only that serotonin is involved in these various physiological functions in a general sense, but also by which receptor subtype(s). Theories abound and proof is lacking, but on the basis of the existing data it certainly appears plausible that serotonin’s involvement in mediating different physiological actions likely involves different receptors for its different actions. Studies of serotonin receptor subtype selective agents have led to the hypothesis that post-synaptic 5HT1A receptors mediate such actions as mood,

Fig. 1. More than a dozen 5HT receptor subtypes are known including the presynaptic serotonin transporter, as well as 5HT1A, 5HT1D, 5HT2A, 5HT2C, 5HT3 and 5HT4. Additional receptors are also being clarified at a rapid pace (designated as 5HTx, 5HTy, 5HTz, etc.).

anxiety and temperature regulation, largely from studies of 5HT1A partial agonists such as the azapirones buspirone and ipsapirone (Fig. 2) (Carli et al., 1993; Cliffe and Fletcher, 1993; Deakin, 1988; DeVry et al., 1992; Dubovsky, 1994; Glitz and Pohl, 1991; Keppel Hesselink, 1992; Kurtz, 1992; Lesch, 1992; Sprouse and Wilkinson, 1995; Stahl, 1992,

Fig. 2. Functions of post-synaptic 5HT1A receptors include antidepressant, anxiolytic and temperature regulating actions.

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1996; Traber and Glaser, 1987). Similarly, postsynaptic 5HT2 receptors also appear to have a role in mood, anxiety and temperature regulation, but may also be key in the mediation of sexual function, sleep, obsessions and compulsions, eating behavior, hallucinations, psychosis, and panic attacks (Fig. 3) (Bersani et al., 1990; Dubovsky, 1994; Grigsnaschi et al., 1993; Hoch et al., 1952; Kunovac and Stahl, 1995; Leysen, 1992; Stahl, 1996; Stutzmann et al., 1991). Finally, 5HT3 receptors certainly are involved in nausea, vomiting, appetite and GI motility, and have less well documented effects on anxiety and cognition as well (Fig. 4) (Barnes et al., 1990; Bunce et al., 1991; Costall et al., 1990; Herrstedt et al., 1993; Kunovac and Stahl, 1995; Levitt et al., 1993; Trickelbank, 1989). Do different serotonin pathways mediate different physiological actions of serotonin? With the clarifi-

Fig. 3. Functions of post-synaptic 5HT2 receptors include long term antidepressant, short term anxiogenic, temperature regulating, sexual function regulating, sleep regulating, anti-obsessive compulsive disorder (OCD) actions, anti-bulimic actions, hallucinations, psychosis and short term worsening, long term improvements in panic.

Fig. 4. Functions of post-synaptic 5HT3 receptors include nausea, appetite and gastrointestinal motility.

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Fig. 5. Schematic representation of serotonin pathways in the central nervous system. Five pathways are indicated, including projections from midbrain raphe to prefrontal cortex (1); basal ganglia (2); hippocampus (3), hypothalamus (4), and spinal cord (5).

cation of multiple discrete projection pathways for serotonin in the central nervous system (shown semischematically in Fig. 5), research is attempting to map a topography of serotonin physiology by elucidating which function(s) any given pathway controls (Arzmitia and Whitaker-Arzmitia, 1995; Mansour et al., 1995; Marsden, 1996; Murphy, 1991; Pazos and Palacios, 1985a,b; Radja et al., 1992; Verge et al., 1985). It would not be surprising if the various CNS disorders mediated in part by serotonin involve various different pathways as well as various different receptor subtypes. Similarly, therapeutic actions of drugs affecting serotonin may also exhibit a topography with site specific actions necessary for each element of the therapeutic spectrum (e.g., see El Mansari et al., 1995). Also, side effects of drugs affecting serotonin may exhibit a topography with site specific actions for each physiological function. Unfortunately, it is not possible to readily study serotonin receptor subtypes in specific pathways, as these receptors are located in multiple places throughout the brain, and most experiments utilize systemic drug administration which would be expected to affect all receptors in all locations equally. Nevertheless, a crude topography of serotonin functioning is beginning to crystalize from ongoing experiments in rats. This is discussed in further detail below.

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3. 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 actions of psychotropic drugs should be termed ‘‘initiating’’ mechanisms because they start a molecular cascade resulting in ‘‘adaptations’’ to chronic administration of the drug. In the case of SSRIs, the acute short term action is to cause negative allosteric modulation of the presynaptic serotonin transporter (Barker and Blakely, 1995; Feighner and Boyer, 1996; Stahl, 1996). Since the presynaptic serotonin transporter differs from presynaptic norepinephrine or dopamine transporters (Barker and Blakely, 1995), SSRIs by definition are able to act selectively on serotonin transport with far less potency on the norepinephrine or dopamine transport. The serotonin transporter is organized as a component of a molecular complex which includes an enzyme and several binding sites (Barker and Blakely, 1995; Leonard, 1996; Stahl, 1996). The enzyme is energy-producing Na 1 / K 1 ATPase (sodium– potassium adenosine triphosphatase). Binding sites are for serotonin itself, for the sodium ion and for the SSRI. These binding sites serve either to increase serotonin binding (the sodium site) or to decrease serotonin binding (the SSRI site). The serotonin transporter in Fig. 6 shows binding sites for serotonin and for the SSRI. Sodium binding to its site on the molecule increases transporter affinity for serotonin (positive allosteric modulation), allowing serotonin to bind to the transporter (Fig. 7, sodium binding not shown). However, SSRI binding to its site on the molecule decreases transporter affinity for serotonin (called negative allosteric modulation), thus inhibiting serotonin binding to the transporter (Fig. 8). The fact that synthetic drugs bind to a natural receptor suggests that there is a naturallyoccurring ligand for this site (i.e., an endogenous

Fig. 6. Immediate (initiating) actions of SSRIs Part I. The transport carrier for serotonin reuptake is shown schematically as a boxcar with seats for serotonin. Fig. 7. Immediate (initiating) actions of SSRIs Part II. In the presence of serotonin and sodium, the transporter binds serotonin. Fig. 8. Immediate (initiating) actions of SSRIs Part III. In the presence of an SSRI, the serotonin transporter loses its affinity for binding serotonin.

SSRI) but the hunt for such a substance has so far failed to conclusively demonstrate such a ligand. The serotonin transporter is localized on presynaptic axon terminals of serotonin neurons (Fig. 9), as well as on the cell bodies of serotinin neurons (Figs. 11–15) (Barker and Blakely, 1995; Feighner and Boyer, 1996; Stahl, 1996). The well known physiologic function of this transporter comes to play when serotonin is released, when this transporter is utilized as a mechanism to remove serotonin from the synapse. This has two effects: firstly to terminate the actions of serotonin in the synaptic cleft, and secondly to allow the captured serotonin to be stored for

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4. Adaptative actions of SSRIs

4.1. General overview

Fig. 9. Physiological action of the transporter is to act like a shuttle for transporting serotonin which has been released into the synapse back into the presynaptic neuron for subsequent storage and reuse.

subsequent reuse. When an SSRI binds to the transporter, serotonin accumulates in the synapse, since its release is no longer accompanied by presynaptic transport back into the neuron (Fig. 10). These molecular events occur immediately after administration of an SSRI (Barker and Blakely, 1995).

Fig. 10. When the serotonin transporter is blocked by an SSRI, serotonin no longer is transported out of the synapse, so accumulates there to prolong and increase its interactions at all the various serotonin receptor subtypes in the synapse.

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, 1991; Leonard, 1995, 1996; Stahl, 1992, 1994, 1996). Although it is tempting to conceptualize receptor desensitization as the mechanism of therapeutic action of SSRIs, it might be better to conceptualize such desensitization merely as a marker of adaptation (Hyman and Nestler, 1996). Adaptations might explain the onset of therapeutic actions, or the development of tolerance to side effects, or both. Adaptations may also be epiphenomena which occur in parallel to the delayed therapeutic actions, but are not de facto therapeutic actions. Most adaptations are studied in experimental animals, especially male rats who are presumably not depressed and who presumably do not have abnormalities in their serotonergic regulation prior to antidepressant treatment. It may be very difficult to extrapolate such results to adaptive effects which occur in depressed humans, many of whom are female (Robins and Regier, 1991; Wells et al., 1989), a subset of whom may have dysfunction in their serotonergic regulation even prior to SSRI treatment, and only about 2 / 3 of whom improve with SSRI treatment (Brown et al., 1991; Deakin et al., 1991; Feighner and Boyer, 1996; Maes and Meltzer, 1995; Mann et al., 1996; Stahl, 1992, 1994, 1996). Recent attempts to document serotonergic functioning in depressed patients themselves prior to and following effective or ineffective treatment with SSRIs are beginning to clarify which adaptations in serotonergic functioning are linked to untreated depression, which adaptations are caused by SSRI treatment, and which adaptations are linked to response or nonresponse to SSRI treatment (Brown and van Praag, 1991; Charney et al., 1981; Heninger, 1995; Sandler et al., 1991; Stahl, 1992, 1994, 1996). Unfortunately, proof of which adaptations might be

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key for SSRI treatment response is yet lacking, so all studies of chronic SSRI effects in experimental animals should be considered hypotheses, not conclusions.

4.2. Desensitization of somatodendritic serotonin 1 A autoreceptors: a leading hypothesis for SSRI delayed therapeutic actions In order to explain the delayed onset of clinical efficacy of SSRIs, many investigators have evaluated delayed onset receptor adaptations as potential mediators of therapeutic actions, reasoning that events which are temporally correlated with clinical effects may possibly mediate the simultaneous therapeutic effects. One hypothesis which has been proposed in order to explain the delayed onset of clinical efficacy is to express this action in terms of delayed serotonin receptor adaptations (see Charney et al., 1981, 1991; Stahl, 1994, 1996 for reviews). To understand this hypothesis, one must recognize that presynaptic serotonin receptors are located not only on the axon terminal, but also on the cell body and neighboring dendrites. Such receptors include not only the serotonin transporter itself (which has already been discussed), but also autoreceptors, which act to reduce serotonin neuronal firing and serotonin release. In the presynaptic axonal area they are called terminal autoreceptors and display 5HT1D pharmacologic properties (Fig. 11) (Glennon and Duckat, 1995; Hoyer and Middlemiss, 1989; Hoyer et al., 1990; Stahl, 1996). In the cell body (soma) area, they are called somatodendritic autoreceptors, and display 5HT1A pharmacologic properties (Fig. 12) (Aghajanian, 1995; Glennon and Duckat, 1995; Sprouse and Aghajanian, 1987, 1988; Sprouse and Wilkinson, 1995; Stahl, 1996; Weissman-Nanopoulos et al., 1985). Normally, stimulation of 5HT1A somatodendritic autoreceptors located in the midbrain raphe decreases neuronal firing rates and thus reduces 5HT in projection sites (more about projection sites later) (Fig. 12, bottom) (Aghajanian, 1995; Glennon and Duckat, 1995; Sprouse and Aghajanian, 1987, 1988; Sprouse and Wilkinson, 1995; Stahl, 1996; Weissman-Nanopoulos et al., 1985). This is what happens both under normal physiological conditions, and by the acute initiating actions of an SSRI (Fig.

Fig. 11. 5HT1D receptors located on the axon terminals act as autoreceptors (top). When the receptor in the bottom figure detects 5HT, it stops the release of more 5HT (gate closed).

12bottom and Figs. 13 and 14). (Adell and Artigas, 1991; Bel and Artigas, 1992; Blier et al., 1987; Chaput et al., 1986; Frankfurt et al., 1994; Fuller, 1994; Invernizzi et al., 1992; Rutter et al., 1994; Wong et al., 1995) However, during chronic treatment with an SSRI, the 5HT1A receptors become desensitized (Fig. 15), thereby disinhibiting neuronal firing (Fig. 16) (Blier and de Montigney, 1983; de Montigney et al., 1992; Stahl, 1996; Wong et al., 1995). Thus, serotonergic neurotransmission is increased, and in the continuous presence of an SSRI, enhanced extracellular 5HT levels are observed in terminal regions (Fig. 17) (Bel and Artigas, 1993; Perry and Fuller, 1992; Rutter et al., 1994; Stahl, 1996; Wong et al., 1995), although not all investigators agree (Hjorth and Auerbach, 1994). The mechanism of the 5HT1A receptor’s desensitization may be due to a decrease in the G proteins which link this receptor to its second messenger system (Li et al., 1996).

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Fig. 12. Presynaptic 5HT1A receptors are located on the cell body and dendrites (top) and are therefore called somatodendritic autoreceptors. When this receptor detects 5HT, it shuts down 5HT neuronal impulse flow (electric bolt) and stops 5HT release.

Continuing to enhance 5HT release in the terminals of the various serotonin pathways as they project throughout the central nervous system may

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lead in turn to even further adaptations there. Thus, the terminal 5HT1D autoreceptors may desensitize, leading to even more serotonin release (Chaput et al., 1991; Fuller, 1994; Stahl, 1996). Also, the postsynaptic 5HT receptors may desensitize any of the 14 or more varieties of serotonin receptors (Fig. 17) (Charney et al., 1981, 1991; Stahl, 1994, 1996). Experiments supporting this hypothesis of delayed adaptations of somoatodendritic 5HT1A autoreceptors as the mediators of delayed therapeutic effects of SSRIs have been performed by measuring serotonin released by SSRIs both in the midbrain raphe nuclei and in various projection areas in the brain, utilizing microdialysis probes in normal male rats (e.g., Adell and Artigas, 1991; Fuller, 1994). Other experiments have measured neuronal firing rates with electrodes in these same areas, and largely come to the same conclusions (e.g., Chaput et al., 1986). There are, however, differences in pre- versus post-synaptic serotonin receptors in how they adapt to chronic drug treatments (Blier et al., 1993a,b; Chaput et al., 1991; Cox et al., 1993; Invernizzi et al., 1992; Kreiss and Lucki, 1994; Radja et al., 1992; Sprouse and Wilkinson, 1995; Yocca et al., 1992; Wong et al., 1995). Also, serotonin release from the terminals of some pathways projecting to one part of the brain may not be representative of serotonin release from the terminals of other pathways in other parts of the brain (Adell and Artigas, 1991; Artigas, 1993; Bel and Artigas, 1992; Frankfurt et al., 1994; Fuller, 1994; Invernizzi et al., 1992). This has led to the

Fig. 13. Adaptive actions of SSRIs, Part I. In depression, the 5HT neuron may not be functioning normally. Theories suggest a possible deficiency of 5HT itself, with a compensatory up-regulation of 5HT receptors, particularly postsynaptic 5HT2 receptors. Despite their increased number, the functioning of these receptors may in fact be diminished, perhaps reflecting dysregulation in converting receptor occupancy by 5HT into nerve inpulses and physiological effects.

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Fig. 14. Adaptive actions of SSRIs, Part II. When an SSRI is given acutely, it blocks the 5HT transporter immediately, and increases 5HT, especially at midbrain raphe cell bodies, and to a lesser extent, at axon terminals, especially in certain projection pathways in the brain. The increased 5HT and the presence of SSRI are shown in the inset.

hypothesis that the various physiological effects of SSRIs, both desired and unwanted, may be mediated by different receptors and different pathways.

5. 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 here in simplified icons. A prominent role of prefrontal serotonergic projections may factor in the antidepressant actions of the

SSRIs (Fig. 18) (Adell and Artigas, 1991, 1991; Artigas, 1993; Baxter et al., 1989; Foote and Morrison, 1987; Frankfurt et al., 1994; Fuller, 1994; Invernizzi et al., 1992; Jordan et al., 1994; Lewis et al., 1986; Morrison and Foote, 1986; Morrison et al., 1988; Rutter and Auerbach, 1993). Many basic science studies of this pathway have emphasized the adaptive actions of both adrenergic and serotonergic systems, particularly postsynaptically (Banerjee et al., 1979; Beer et al., 1987; Byerly et al., 1988; Charney et al., 1981; Peroutka and Snyder, 1980; Stahl, 1992; Tang et al., 1981). Also, recent studies of regional glucose utilization after fenfluramine challenges show alterations in prefrontal and temoroparietal cortex (Mann et al., 1996). An important role of raphe projections to basal ganglia may be signalled in OCD (Fig. 19), since PET (positron emission tomography) scans demonstrate abnormalities in orbital frontal projections to basal ganglia, and other clinical evidence links OCD to dysfunction in the basal ganglia (Baxter et al.,

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Fig. 15. Adaptive actions of SSRIs, Part III. The consequence of increased 5HT in the somatodendritic area is for the 5HT1A receptors there to desensitize / down regulate. Down regulated 5HT1A autoreceptors are indicated in the inset.

1990, 1992). Other evidence implicating the orbitofrontal cortex in OCD comes from preclinical studies demonstrating that an SSRI takes longer to desensitize serotonin receptors there than it does to desensitize serotonin receptors in other cortical regions (El Mansari et al., 1995). This fits with clinical observations that SSRIs take longer to work in OCD than they do in depression (see Feighner and Boyer, 1996; Stein and Hollander, 1996.) These preclinical studies clearly show that differences in adaptive properties of serotonin receptors in different brain regions may underlie different onsets of therapeutic actions of the SSRIs in various psychiatric disorders. The hippocampus may be involved in the rough equivalent to a limbic ictal event in panic disorder as suggested by PET scans. Perhaps this is a reasonable pathway to explore for the therapeutic actions of SSRIs in panic disorder (Fig. 20) (Gorman et al., 1989; Nordahl et al., 1990). Finally, the more recently demonstrated efficacy

of SSRIs in bulimia suggests that the control of appetite, feeding and satiety in the hypothalamus may be a reasonable hypothetical mediator of these therapeutic actions (Fig. 21) (Casper, 1995). The hypothetical biological substrates for the therapeutic actions of the SSRIs are summarized in Table 1. The argument for different pathways mediating different therapeutic actions is supported by observations that SSRIs, although therapeutic for several disorders, nevertheless have widely divergent actions in the various disorders. Thus, in depression, the SSRIs generally cause a complete remission of symptoms more often than a partial remission, do it at a relatively low dose of drug, and do so in about 2 to 8 weeks (Feighner and Boyer, 1996; Montgomery, 1996; Tollefson, 1995). On the other hand, the SSRIs generally cause only about 35% reduction in symptoms of OCD, may require higher doses and, as mentioned earlier, exhibit a very long delay in onset of action, often 12 to 20 or more weeks (Feighner and Boyer, 1996; Stein and Hollander, 1996). Fur-

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Fig. 16. Adaptive actions of SSRIs, Part IV. When autoreceptors are down regulated, this disinhibits the 5HT neuron, thus increasing neuronal impulse flow and serotonin release in axon terminals. This occurs with a delay since it takes time for the autoreceptors to down regulate. The increased delivery of 5HT in the axon terminals is indicated in the inset.

thermore, in panic disorder, SSRIs often induce an exacerbation as an acute effect, and symptom improvement only with a delay, with the need to start dosing even lower than used for depression (Ballenger, 1996; Feighner and Boyer, 1996). While such observations do not point to the specific pathway or receptor which can account for such clinically observable differences, it underscores the plausibility of the notion that there are different pathways functioning as the substrates for the different therapeutic actions of the SSRIs (Table 1).

5.1. Serotonin projections and pathways as mediators of specific side effects of SSRIs Although inhibition of serotonin reuptake occurs immediately after administration of an SSRI, it is generally only the side effects of these agents which are manifest immediately (Feighner and Boyer, 1996; Montgomery, 1996; Tollefson, 1995). Furthermore, whereas there is little evidence for tolerance to

the therapeutic effects of SSRIs, it is commonly observed that tolerance develops to various side effects (Feighner and Boyer, 1996; Montgomery, 1996; Tollefson, 1995). Shown in Figs. 22–28 are whimsical diagrams to simply illustrate hypothetical sites of action for various side effects of SSRIs. Such sites might also be expected to show adaptations if the side effect experienced at initiation of treatment shows tolerance over time. As the basal ganglia mediates movements and is implicated in movement disorders including akathisia caused by neuroleptics, this may be a good place to search for the actions of SSRIs in causing akathisia and even agitation (Fig. 22) (Marder and van Putten, 1995; Stanilla and Simpson, 1995; Wirsching et al., 1995). Central control of nausea and vomiting is known to be mediated both in the hypothalamus and in the brainstem (vomiting center of the chemoreceptor trigger zone) (Fig. 23) (Bunce et al., 1991; Herrstedt

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Fig. 17. After 5HT increases in the synaptic regions of axon terminals, it may cause some postsynaptic 5HT receptors to desensitize. This is indicated in the inset.

Fig. 18. Substrates for therapeutic actions of SSRIs. Part I, antidepressant actions. Raphe projections to prefrontal cortex (1) are hypothesized to mediate in part possible antidepressant actions of SSRIs. Other pathways which are implicated in the antidepressant actions of SSRIs but which are not shown include those from raphe to hippocampus, facial motor nucleus and amygdala.

et al., 1993; Kunovac and Stahl, 1995; Levitt et al., 1993). Perhaps the acute rise of serotonin in such areas causes these side effects. Alternatively, nausea

might arise from signals coming from the periphery (see Fig. 27 and Miller and Nonaka, 1992). Blockade of 5HT3 receptors is hypothesized to underlie the

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Fig. 19. Substrates for therapeutic actions of SSRIs; Part II, anti-OCD actions. Raphe projections to basal ganglia (2) are hypothesized to mediate possible anti-obsessive compulsive disorder therapeutic effects of the SSRIs.

Fig. 20. Substrates for therapeutic actions of SSRIs; Part III, anti-panic actions. Raphe projections to hippocampus and limbic cortex (3) are hypothesized to mediate possible long term anti-panic effects of the SSRIs.

therapeutic potential of 5HT3 antagonists such as ondansetron to block the nausea and vomiting associated with the administration of cancer chemotherapies (Bunce et al., 1991; Herrstedt et al., 1993; Levitt et al., 1993). Not surprisingly, antagonism of 5HT3 receptors blocks the nausea produced by SSRIs (Bergeron and Blier, 1994; Bailey et al., 1995; Pederson and Klysner, 1997.) The anxiogenic initiating actions of SSRIs may be mediated by the same pathways which mediate the anti-panic adaptive actions of SSRIs, thus implicating the hypothalamus and limbic cortex (Fig. 24) (Ballenger, 1996; Gorman et al., 1989; Nordahl et al., 1990).

Brainstem sleep centers are controlled by serotonergic input. Increased serotonin in these areas may be responsible for the insomnia and sleep disruption seen with SSRIs (Fig. 25) (Gillin et al., 1994, 1996; Seifritz et al., 1996). Sexual function is probably mediated by a multitude of neuronal pathways. However, orgasm and ejaculation are mediated in part by sympathetic and parasympathetic pathways and are spinal reflexes as part of the human sexual arousal cycle (Stein and Hollander, 1994; Kunovac and Stahl, 1995). Serotonergic pathways which descend down the spinal cord and synapse upon 5HT2 receptors may thus mediate some of the observed sexual dysfunc-

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Fig. 21. Substrates for therapeutic actions of SSRIs. Part IV, Anti-bulimic actions. Raphe projections to hypothalamus (4) are hypothesized to mediate possible anti-bulimic actions of the SSRIs.

Table 1 Hypothetical biological substrates for serotonergic efficacy of SSRIs 5HT1A agonism and subsequent desensitization in midbrain raphe may be the primary receptor action Depression: adaptive actions in prefrontal cortex? OCD: adaptive actions in basal ganglia / orbitofrontal cortex? Panic: adaptive actions in hippocampus / limbic cortex? Bulimia: adaptive actions in hypothalamus?

tions associated with SSRI administration (Fig. 26), although other 5HT receptors may also be involved (Boyer and Feighner, 1996a,b; Stein and Hollander, 1994). GI cramps and diarrhea, a side effect seen with SSRIs, may arise from increased amounts of serotonin at 5HT3 receptors in the gut (Fig. 27) (Bunce et al., 1991; Costall et al., 1990; Fozard, 1992; Kunovac and Stahl, 1995).

Fig. 22. Substrates for side effects of SSRIs. Part I, anxiety. Raphe projections to hippocampus and limbic cortex (3) are hypothesized to underlie the possible short term exacerbation or induction of anxiety caused by SSRIs.

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Fig. 23. Substrates for side effects of SSRIs. Part II, insomnia. Serotonin actions at brainstem sleep centers (5) are hypothesized to underlie the possible insomnia caused by the SSRIs.

Fig. 24. Substrates for side effects of SSRIs. Part III, Raphe projections to basal ganglia (2) are hypothesized to mediate the possible agitation and restlessness (akathisia) caused by the SSRIs.

Headache can both be provoked and prevented by SSRIs, presumably from interactions with serotonin receptors on cerebral vasculature, especially 5HT1D and 5HT2 receptor subtypes (Fig. 28) (Pearce, 1992; Kunovac and Stahl, 1995). The hypothetical biological substrates for the numerous different side effects observed with SSRI administration are summarized in Table 2.

6. Conclusions A crude topography of serotonin functioning in its different pathways and at its various receptor sub-

types 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 documented biological substrates, receptors and pathways for serotonin are candidates to mediate the plethora of therapeutic actions and side effects of SSRIs since SSRIs raise serotonin levels at multiple sites and at multiple receptors throughout the brain and in fact the entire

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Fig. 25. Substrates for side effects of SSRIs. Part IV, nausea and vomiting. Raphe projections to hypothalamus (4) are hypothesized to mediate the possible nausea caused by the SSRIs, whereas brainstem vomiting center (asterisk) may mediate possible vomiting caused by the SSRIs.

Fig. 26. Substrates for side effects of SSRIs. Part V, sexual dysfunction. Raphe projections to spinal cord sympathetic and parasympathetic neurons (5) may mediate possible sexual dysfunction caused by the SSRIs.

body. It seems reasonable to suggest that the diverse actions of SSRIs are mediated by serotonin, either due to the initiating actions of SSRIs (if the effects are immediate) or to the adaptive actions of SSRIs (if the effects are delayed). Those actions of serotonin which are immediate are possibly those which mediate the side effects. As tolerance to side effects develops, it seems reasonable to hypothesize that adaptations are occurring in the biological substrate mediating that side effect. On the other hand, adaptations in different serotonin projections may be mediating the various therapeutic actions of the SSRIs ranging from antidepressant, to

anti-obsessive compulsive to anti-panic to antibulimia.

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

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Fig. 27. Substrates for side effects of SSRIs. Part VI, GI cramps and diarrhea. Serotonin 3 receptors located directly on the gut wall may mediate the possible gastroinestinal cramps and diarrhea caused by the SSRIs.

Fig. 28. Substrates for side effects of SSRIs. Part VII, headache. Serotonin 1D and two receptors located on cerebral and cranial vasculature may mediate both the possible relief as well as the exacerbation of headache caused by the SSRIs.

Table 2 Hypothetical biological substrates for serotonergic side effects of SSRIs Anxiety / panicogenic Insomnia Agitation / akathisia Sexual dysfunction Nausea GI cramps / diarrhea Headache a

5HT2 a agonism in limbic cortex / hippocampus? 5HT2 agonism in brainstem sleep centers (raphe or lateral dorsal tegmentum)? 5HT2 agonism in basal ganglia? 5HT2 agonism at descending spinal cord synapses on sympathetic / parasympathetic neurons? 5HT3 agonism in chemoreceptor trigger zone? 5HT3 agonism in gut? 5HT1D or 5HT2 receptors in cerebral or cranial vasculature?

5HT2 receptors are heterogeneous and include 5HT2A, 5HT2B, and 5HT2C subtypes.

S.M. Stahl / Journal of Affective Disorders 51 (1998) 215 – 235

Research Center grant No. MH30914 and by General Clinical Research Center grant No. MO1-RR00827 to UCSD.

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