[Mechanisms of action of antidepressants: new data from Escitalopram].

A first improvement in the treatment of depression was achieved in 1970-80 with the development of selective serotonin reuptake inhibitors (SSRI) because these drugs, which are as potent antidepressants as the tricyclics, are devoid of most of the secondary effects of the latter drugs (orthostatic hypotension, weight gain, dry mouth, etc, mainly caused by their capacity to block alpha1-adrenergic, H1 histaminergic and muscarinic receptors). However, SSRI did not solve all the problems inherent to the treatment of depression because (i) approximately 30% of depressed patients do not respond to these drugs, and (ii) their antidepressant effect becomes really significant only after 3-4 weeks of treatment, like that observed with tricyclics. A further improvement in the development of antidepressant drugs has recently been made with the synthesis of the S enantiomer of citalopram, called Escitalopram. Indeed, this active enantiomer is the most selective among all SSRI available to date, including citalopram. In addition, the potency of Escitalopram to inhibit serotonin reuptake (K(i)=2,1 nM) and to induce antidepressant-like effects in relevant animal paradigms (forced swimming test; chronic mild stress; stress-induced ultrasonic vocalization) is markedly increased as compared with citalopram and other SSRI. In particular, in the forced swimming test, which is especially relevant for assessing the potential antidepressant properties of drugs, Escitalopram was shown to be at least 15 fold more potent than any other SSRI to delay helplessness-induced immobility of rats. Even more interestingly, under chronic treatment conditions, Escitalopram was found to be significantly more rapid than any other antidepressant (tricyclics such as imipramine, SSRI such as fluoxetine) to restore sucrose intake in rats subjected to chronic mild stress, suggesting a reduced delay in its antidepressant action. This was indeed fully confirmed in humans as only 1-2 weeks of treatment with Escitalopram was enough to significantly reduce MADRS score in depressed subjects, compared to 3-4 weeks with any other antidepressant drug. These unique properties led to further investigations of the pharmacological profile of Escitalopram. It thus appeared that, at equipotent doses, the S enantiomer was significantly more efficient than citalopram (racemate) to increase the extracellular levels of serotonin within the frontal cortex of freely moving rats bearing a locally implanted microdialysis probe. Further experiments showed that R-citalopram counteracted the capacity of Escitalopram to enhance extracellular 5-HT levels, thereby explaining why the racemate had only a limited action in this regard. In addition, behavioural studies (stress-induced ultrasonic vocalization test) also showed that R-citalopram exerts effects opposite to those (antidepressant--and anxiolytic--like effects) of Escitalopram. The reason for these differences between the two enantiomers might concern the secondary molecular targets at which citalopram acts, but with affinities at least two orders of magnitude less than for the serotonin transporter. Indeed, R-citalopram has a 7-10-fold higher affinity for H1 histaminergic (K(i)=180 nM) and alpha1-adrenergic (K(i)=560 nM) receptors than Escitalopram (respective K(is) > or = 2 000 nM), and this difference might contribute not only to the better selectivity of the latter enantiomer for its therapeutically relevant target (i.e. the serotonin transporter) but also to its improved capacity to enhance central 5-HT neurotransmission. On the other hand, the global affinity of Escitalopram (K(i)=200-430 nM) for both subtypes of sigma receptors (sigma1 and sigma2) is higher than that of R-citalopram (and of the racemate citalopram; K(i)=200-1 500 nM), and this might also strengthen the antidepressant and anxiolytic effects of the S enantiomer because behavioural studies showed that selective sigma1 and sigma2 agonists are endowed with both antidepressant--and anxiolytic-like properties in relevant animal models. However, to date, the exact nature (agonist or antagonist) of the action of Escitalopram at sigma receptors is not known yet, and this question has to be addressed in future investigations. Altogether, these data open novel perspectives for both a better treatment of depressive disorders and a better knowledge of the neurobiological mechanisms underlying antidepressant therapy, and, possibly, depression itself.