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Introduction: One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT2 receptor subtypes represent promising targets but their precise roles have yet to be determined. Areas covered: The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT2A and/or 5-HT2C receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT2 receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis. Expert opinion: Although studies support the hypothesis that the inactivation of 5-HT2A and/or 5-HT2C receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT2B receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.
Quesseveur et al. (Fri,) studied this question.