In a pair of phase 3 trials, the investigational antidepressant zuranolone was effective in treating postpartum depression and major depressive disorder in adults. An editorialist describes this agent as a mechanism-based treatment, one that combines knowledge of GABA signaling in mood disorders and observations about allopregnanolone, a hormone that is an endogenous modulator of GABAA receptors.
Among 196 women with severe postpartum depression, zuranolone 50 mg/day for 14 days significantly improved depressive symptoms by day 15 compared with placebo, researchers report. The agent was well tolerated, with adverse events of somnolence, dizziness, and sedation occurring in 10% or more of participants, and no patients with loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior.
In a study of 543 patients aged 18-64 years with severe major depressive disorder, zuranolone 50 mg/day had a rapid time to effect of 3 days and was significantly more effective than placebo for improving depressive symptoms by day 15. Two patients in each group had serious adverse events, and 9 patients in the zuranolone group and 4 patients in the placebo group discontinued treatment because of adverse events. The authors conclude, “Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder.”
Editorial: “Strong clinical response to zuranolone in postpartum depression may provide clues about mood disorder subtypes,” writes the editorialist. “One subtype might manifest a unique profile on clinical presentation, pathophysiology markers related to allopregnanolone, and therapeutic response to positive allosteric modulation of GABAA receptors. Confirmation of this possibility would require new data linking changes on clinical and pathophysiology indices induced by GABAA modulation. For example, if changes in depression with zuranolone consistently relate to changes in allopregnanolone or similar chemicals, a unique patient subtype could be identified involving pathophysiology sensitive to GABAA allosteric modulators.”