Serotonin 2C receptor antagonists induce fast-onset antidepressant effects

Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) inmice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swimtest (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classicalmarkers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derivedneurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatmentwith citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventraltegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked theantidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR)and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2Cantagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induceantidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that theseeffects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onsetantidepressants, which act through enhancement of mesocortical dopaminergic signaling.Molecular Psychiatry advance online publication, 29 October 2013; doi:10.1038/mp.2013.144Keywords: antidepressant; BDNF; eEF; mTOR; neuronal remodelingINTRODUCTIONMajor depression is among the leading causes of disabilityworldwide and affects roughly 17% of the population.