At Last, an Effective Oral Antidepressant with a Novel Mechanism of Action?

The effects of current antidepressants are variable and generally emerge within 4 to 8 weeks; thus, the search continues for antidepressants with novel mechanisms of action. In this manufacturer-supported, phase 2 trial, researchers assessed the efficacy and safety of the non–FDA-approved drug SAGE-217, an oral positive allosteric modulator of GABA_A receptors similar to brexanolone, a rapidly acting intravenous agent for postpartum depression (NEJM JW Psychiatry Nov 2018 and Lancet 2018; 392:1058). In all, 89 patients with moderate to severe major depression (mean Hamilton Rating Scale for Depression [HRSD] score, 25; none with treatment resistance), were randomized to a 30-mg daily dose of SAGE-217 or placebo for 2 weeks; outcomes were ass…