Novel Oral GABA Modulator Promising for Major Depressive Disorder

depressed woman sitting head in hands in the dark bedroom
The tolerability and novel mechanism of action of SAGE-217, an oral positive allosteric modulator of γ-aminobutyric acid type A receptors, might make it a valuable addition to the antidepressant armamentarium.

SAGE-217, an oral allosteric modulator of γ-aminobutyric acid (GABA) type A receptors, was found to be safe and effective for the treatment of major depressive disorder, as reported in a study published in the New England Journal of Medicine.

In this phase 2, double-blind trial ( Identifier: NCT03000530), 89 patients were randomly assigned to receive either SAGE-217 30 mg (n=45) or placebo (n=44) once daily. The study was conducted from April 2017 through October 2017 at 8 sites in the United States. Patients underwent assessment at baseline, at days 2 through 8, and on days 15, 21, 28, 35, and 42. The primary outcome measure was the change in Hamilton Depression Rating Scale (HAM-D) score from baseline to day 15. As secondary end point measures, the investigators also captured the following variables at each assessment: change from baseline on additional depression and anxiety scales, the proportion of patients achieving a >50% reduction from baseline HAM-D score, the proportion of patients achieving a HAM-D score ≤7, and the proportion of patients achieving a Clinical Global Impression of Improvement score of 1 (“very much improved”) or 2 (“much improved”).

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Safety was assessed by measuring the frequency and severity of adverse events. Mixed-effects models were used to calculate the least-squares mean change from baseline in HAM-D scores.

Demographic characteristics were similar between the SAGE-217 and placebo groups. Mean patient age (± standard deviation) was 49.1±13.6 years in the SAGE-217 group and 38.3±12.2 years in the placebo group. Fewer women were enrolled in the SAGE-217 group compared with the placebo group (56% vs 68%). The majority of trial participants were black, comprising 80% and 64% of the SAGE-217 and placebo groups, respectively. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group.

On day 15, the least-squares mean (±standard error) change in HAM-D score from baseline was −17.4±1.3 points in the SAGE-217 group and −10.3±1.3 points in the placebo group, for a least-squares mean difference in change of −7.0 points (95% CI, −10.2 to −3.9; P <.001). Compared with the placebo group, patients in the SAGE-217 group were more likely to achieve a >50% reduction from baseline in HAM-D score (OR, 9.6; 95% CI, 2.9-31.6), a HAM-D score ≤7 (OR, 5.3; 95% CI, 2.1-13.3), and a Clinical Global Impression of Improvement score of 1 or 2 (OR, 8.6; 95% CI, 2.5-29.5). Results for additional measures of depression and anxiety were similar, favoring SAGE-217 over placebo.

No serious adverse events were detected over the study course. The proportion of patients who had at least 1 adverse event was 53% in the SAGE-217 group and 45% in the placebo group. In patients taking SAGE-217, the most commonly reported adverse events were headache (18%), dizziness (11%), nausea (11%), and somnolence (7%).

These data indicate that daily administration of SAGE-217 may reduce depression symptoms by day 15. Although adverse events were more common in patients receiving SAGE-217 than in patients receiving placebo, no serious treatment-emergent adverse events occurred.

Additional research is necessary to investigate the long-term efficacy of SAGE-217 and to compare SAGE-217 with existing pharmacotherapies for depression.

Disclosure: Sage Therapeutics designed the trial, provided the SAGE-217 and placebo, collected and analyzed the data, and paid for professional writing assistance.


Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019;381(10):903-911.