SAGE-217 reduces depressive symptoms in patients with major depression within 2 weeks

1. Patients with major depression randomized to receive SAGE-217, a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors, experienced fewer depressive symptoms after 2 weeks of treatment compared to patients receiving placebo.

2. Dizziness, nausea, and somnolence were more commonly experienced in the SAGE-217 group.

Evidence Rating Level: 1 (Excellent)  

Study Rundown: Treatment with antidepressants often takes over 4 weeks to become clinically notable. Most antidepressants work though alteration of serotonin or norepinephrine levels, though a lack of GABAergic activity may be an upstream cause of neurotransmitter imbalance leading to depressive symptoms. Increased levels of positive allosteric modulators of GABA type A receptors have been associated resolution of depression, leading some to believe increasing GABA type A receptor function with modulators such as SAGE-217 may treat depression. This phase 2 randomized study showed patients with major depression treated for 2 weeks experienced improved depressive symptoms compared to placebo treated patients. Other secondary outcomes of treatment efficacy also suggested reduced depression symptoms with SAGE-217 treatment. Adverse events were generally similar between placebo and SAGE-217 cohorts, though patients in the treatment group experienced more minor episodes of dizziness, nausea, and somnolence.

This study provides early clinical evidence to suggest GABA type A receptor positive modulation can result in successful treatment of depression with a rapid onset compared to traditional treatment options. Strengths of the study include evaluation of a therapy with a novel mechanism of action and its randomized design. The study is limited by the short length of follow-up out to just 42 days.

Click to read the study in NEJM

Relevant Reading: Cortical GABAergic dysfunction in stress and depression: new insights for therapeutic interventions

In-Depth [randomized controlled trial]: This phase 2, randomized controlled trial enrolled patients in the United States during 2017. Eligible adult patients had a diagnosis of major depressive disorder, a score on the Hamilton Depression Rating Scale (HAM-D) indicating active depressive symptoms and were either on stable doses of antidepressants or not taking antidepressant medications. Patients were randomized to receive SAGE-217 at 30mg daily (n=45) or a placebo (n=44) for 14 days. Patients were admitted for the first week of the study and followed as outpatients the second week. The primary study outcome was change from baseline to day 15 of the HAM-D score which was on average 17.4 points lower in the treatment group and 10.3 points lower in the placebo group (mean difference in change, −7.0; 95% confidence interval [CI], -10.2 to -3.9; P<0.001). Secondary outcomes of the percentage of patients with a >50% reduction in their HAM-D score, with a low (≤7) HAM-D score at 15 days, or with other significantly lowered depressive symptom scales all suggested greater treatment efficacy in the SAGE-217 group compared to the placebo group. No serious adverse events occurred in either treatment group. Adverse events were experienced by 53% and 45% of SAGE-217 and placebo patients, respectfully. Nausea and dizziness both occurred in 11% (5/45) of treated patients and 2% of placebo patients (1/44). Headache was the most common adverse event and occurred in 18% and 16% of treatment and placebo patients, respectfully.

Image: PD

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