Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive–compulsive disorder responses

Abstract

Considerable evidence is now available to support the pivotal role of the serotonin (5-HT) system in exerting the antidepressant response in humans. Different types of antidepressant treatments enhance 5-HT neurotransmission via different pre- or postsynaptic mechanisms. The time course for the occurrence of these adaptive changes in the brain of laboratory animals is consistent with the delayed onset of the antidepressant response in humans. The drugs effective in obsessive–compulsive disorder (OCD) also enhance 5-HT neurotransmission in brain regions involved in mediating OCD symptoms but with a more prolonged delay, consistently with the longer time necessary to obtain an optimal therapeutic effect in OCD than in depression. The elucidation of these mechanisms of action lead to the development of new pharmacologic strategies to potentiate the therapeutic effect of the drugs currently available and to the identification of novel targets to accelerate and further improve treatment response in depression and OCD.

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.