Novel Agent Promising for Major Depression: Phase 3 Data

Pauline Anderson

June 09, 2023


Patients who received zuranolone 50 mg/d demonstrated significantly greater improvement in depressive symptoms than those who received placebo, with a rapid onset of effect.


The US Food and Drug Administration has accepted filing of a new drug application for zuranolone, a neuroactive steroid that targets g-aminobutyric acid type A receptors (GABAAR), for the treatment of major depressive disorder (MDD) and postpartum depression.

The study included 543 mostly White female patients with MDD. The mean age of the patients was about 40 years. Participants were randomly assigned to receive oral zuranolone 50 mg or placebo once daily for 14 days.

About 30% of patients were taking an antidepressant.

The primary endpoint was change in Hamilton Depression Rating Scale (HAM-D) score at day 15.


The zuranolone group showed significantly greater improvement in depressive symptoms at 15 days compared with the placebo group (least square mean [LSM] change on HAM-D, -14.1, vs -12.3; P = .01; Cohen's d = 0.23).

Improvements were observed on day 3, the earliest assessment, and were sustained at all subsequent visits during the treatment and follow-up period (through day 42).

Results favored zuranolone regardless of the use of antidepressant therapies.

Patients with anxiety who received the active drug experienced improvement in anxiety symptoms compared to the patients who received placebo.

The drug was well tolerated, and there were no new safety findings. The most common treatment-emergent adverse events were somnolence and headache. There was no weight gain, sexual dysfunction, withdrawal symptoms, or increased suicidal ideation or behavior.


The study adds to evidence suggesting zuranolone is a promising novel therapy for treating MDD, the authors note.


The study was conducted by Anita H. Clayton, MD, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine, Charlottesville, and colleagues. It was published online May 3 in The American Journal of Psychiatry.


The study was short term, and the patient population was severely depressed at study entry, which may limit application to those with mild or moderate symptoms. There was a robust placebo response, possibly partly due to the COVID-19 pandemic, when there was an increase in depressive symptoms in the US population, and so frequent in-person visits may have led to an improvement in symptoms even if the patient was receiving placebo.


The study was funded by Sage Therapeutics and Biogen. Author disclosures can be accessed in the original article.

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