Efficacy of 5HT2C Antagonists Alone and in Combination with SSRIs in Clinical Treatment of Depression

Several compounds that are clinically effective antidepressants are potent 5-HT2C antagonists (Millan 2006). Nefazodone, trazodone, and remeron all block 5-HT2C receptors; however, their pharmacological profile also encompasses blockade of 5-HT2A receptors as well as histamine 1 and alpha 2 receptors (Hyttel 1982). Agomelatonine is a potent 5-HT2C antagonist that has been shown to be effective in treatment of major depression. However, this compound also activates melatonin receptors, which prevents concluding that the clinical effectiveness is merely due to blockade of 5-HT2C receptors (Goodwin et al. 2009).

Depression is characterized by a high degree of comorbidity with closely related dysfunctions like anxiety and insomnia (van Mill et al. 2010). Although the efficacy of treatment of depression with selective 5-HT2C antagonists remains to be elucidated, it has been shown that blockade of 5-HT2C receptors alleviates anxiety and improves quality of sleep (Stahl et al. 2010). Reversing these comorbid dysfunctions adds to the overall treatment of depression.

The current first choice in the treatment of depression is SSRIs. Although safe in their clinical use, their effectiveness and side-effect profile urges the development of newer powerful antidepressants (Dremencov 2009). The onset and sustained efficacy of SSRIs has been a matter of debate for decades. The combination of SSRIs with autoreceptor antagonists like 5-HT1B and HT1A would relieve the autorestraining properties of the serotonergic system in response to SSRI administration and push the clinical efficacy (Mongeau et al. 1997; Blier et al. 1998). In addition, 5-HT2C antagonists have been shown to be able to augment the biochemical effectiveness of SSRIs in preclinical studies (Cremers et al. 2004; Cremers et al. 2007). Thus, systemic administration of ketanserin potentiated fluoxetine-induced increase in cortical and hippocampal 5-HT levels (Cremers et al. 2004). Either systemic or local (into the hippocampus) administration of SB 242084 enhanced citalopram-induced increase in hippocampal 5-HT levels (Cremers et al. 2007).

Given the possible clinical effectiveness of 5-HT2C antagonists and their activity in treating comorbid dysfunctions, this approach is appealing. In addition, 5-HT2C antagonists have also been shown to reverse several SSRI-induced side effects, e.g., anxiogenesis and sexual dysfunction, further adding to the attractiveness of synthesizing combined serotonin uptake inhibitors/5-HT2C antagonists. Lu 24530 is a compound with combined 5-HT reuptake inhibition and 5-HT2C antagonistic properties that is currently in phase II of clinical evaluations (see http://clinicaltrials.gov/ct2/ show/NCT00599911?term=trial+NCT00599911&rank = 1).

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