Review ArticlesPossible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses
Introduction
Several classes of drugs with various effects on monoaminergic systems exert a clear antidepressant effect. For instance, some tricyclic antidepressant (TCA) drugs block the reuptake of serotonin (5-HT), of norepinephrine (NE), or both, and some like trimipramine and iprindole, do not affect the reuptake of either of these two neurotransmitters (Hyttel 1982). Monoamine oxidase inhibitors (MAOIs) prevent the catabolism of 5-HT, NE, and dopamine. Electroconvulsive shock treatment probably results in the release of virtually every neurotransmitter following the delivery of the electrical stimuli; however, the observation that selective 5-HT reuptake inhibitors (SSRIs) exert an antidepressant effect that is similar to that of other agents without any degree of selectivity for monoaminergic systems clearly indicates that the 5-HT system can be pivotal in the antidepressant response.
In the case of the obsessive–compulsive disorder (OCD), only the potent 5-HT reuptake inhibitors (SRIs) are effective in groups of patients (Jenike 1993). Namely, fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram have been demonstrated to significantly attenuate OCD in placebo-controlled trials. Furthermore, the TCA chlomipramine, which is a potent 5-HT reuptake inhibitor, also produces an anti-OCD effect, but a relapse takes place when patients are switched in a double-blind fashion to the TCA desipramine, which is a selective NE reuptake inhibitor (Leonard et al 1991). In addition, it was recently reported that desipramine addition to the regimen of SSRI-resistant OCD patients does not produce a therapeutic effect (Barr et al 1997). Clearly then, the anti-OCD effect, unlike the antidepressant response, rests largely on the inhibition of the 5-HT reuptake process (Goodman et al 1989).
The present review will concentrate on the putative mechanism of action of drugs effective in the treatment of major depression and OCD. The emphasis will be on the characteristics of the clinical response obtained with these agents in relation to the modifications of 5-HT neurotransmission. Specifically, the criteria for the extrapolation of data obtained in animal experiments to human therapeutics will be reviewed. These include: the community and specificity of the effects with respect to drug classes, brain region selectivity for the manifestation of the changes, and time course as well as dose range to obtain the alterations. Some clinical verifications of the putative mechanism of action of the antidepressant and anti-OCD treatments will then be presented. The article will be concluded with the identification of novel targets to improve the antidepressant and anti-OCD response.
Section snippets
The antidepressant response
Extensive electrophysiological investigations carried out in our laboratory have documented that several types of antidepressant treatments enhance 5-HT neurotransmission in the rat hippocampus (see Blier and de Montigny 1994). This net effect that is common to the major types of antidepressant treatments is, however, mediated via different mechanisms (see Figure 1, Table 1). All TCA drugs, independently of their capacity to inhibit the reuptake of 5-HT and/or NE, progressively enhance the
The antiobsessional response
To elucidate the mechanism of action of SSRIs, in OCD, efforts were concentrated on the modification of the 5-HT neuronal element that is produced solely by these drugs. From Table 1, it is clear that this property is the desensitization of terminal 5-HT autoreceptors. Such results were, however, obtained in the rat hippocampus and, subsequently, in the rat hypothalamus after 2–3-week treatments Chaput et al 1986, Moret and Briley 1990. It is thus difficult to extrapolate such results to the
Novel targets to improve the antidepressant and the anti-OCD responses
The selective activation of postsynaptic 5-HT1A receptors, using the combination of buspirone and pindolol, appears to be sufficient to produce an antidepressant effect in some depressed patients (Blier et al 1997). Consequently, an agonist selective for such receptors should produce a rapid antidepressant effect, because it would not initially suppress the firing activity of 5-HT neurons. Flibanserin (BIMT 17) is a 5-HT1A agonist with a preferential activity for postsynaptic 5-HT1A receptors
Conclusions
The investigation of the possible mechanisms of action of antidepressant drugs on the 5-HT system in the brain of laboratory animals has provided useful information to improve the pharmacotherapy of affective and anxiety disorders. Because of such research endeavors, there are now more rapid and effective treatments for these disorders. Furthermore, new therapeutic approaches are being devised on the basis of such information. With such approaches, it is hoped that further insights will be
Acknowledgements
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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