Serotonin/serotonergic system antidepressants

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

Additionally, COX-2 inhibitors influence—either directly or via CNS-immune mechanisms—the CNS serotonergic system. In a rat model, treatment with rofecoxib was followed by an increase of serotonin in the frontal and the temporo-parietal cortex (Sandrini et al., 2002). Since the lack of serotonin is one of the pinpoints in the pathophysiology of depression, a clinical antidepressant effect of COX-2 inhibitors would be expected due to this effect. A possible mechanism of the antidepressant action of COX-2 inhibitors is the inhibition of the release of IL-1 and IL-6. Moreover, COX-2 inhibitors also protect the CNS from effects of quinolinic acid (Salzberg-Brenhouse et al., 2003). 

Blier P, de Montigny C (1998) Possible serotonergic mechanisms underlying the antidepressant and anti-obsessive-compulsive disorder responses. Biol Psychiatry 44 313-323 Bonasera SJ, Tecott LH (2000) Mouse models of serotonin receptor function toward agenetic dissection of serotonin systems. Pharmacol Ther 88 133-142 Bonhoeffer T (1996) Neurotrophins and activity-dependent development of the neocortex. Curr Opin Nemobiol 6 119-126... 

SERTPR variants may also not be specifically associated with response to SSRIs but confer a more general predisposition to respond to any kind of antidepressant treatment targeting the serotonin system. The 1 allele of SERTP R has not only associated been associated with a better response to SSRIs but also a good response to total sleep deprivation (Benedetti et al. 1999). An enhancement of serotonergic transmission has been proposed as one possible mechanism of action of sleep deprivation (Gardner et al. 1997). 

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