SAGE-217 for Patients with Major Depressive Disorder

Published - Written by Ken Wu, MBBS, MRCPCH

Jackie is a 37-year-old woman who visits your clinic and asks for help with her mood. She reports that she had occasionally been feeling low and sad for a few months, but she has felt depressed almost every day in the past month. She feels like she is tired all the time and has no energy, even for things she enjoys, such as meeting friends or going to her weekly gym class. In the past few weeks, she has also had recurrent thoughts about hurting herself and committing suicide that have now become more vivid. You diagnose her with a major depressive disorder and explain the different antidepressant medications that are available.

Current antidepressant medications target a wide range of neurotransmitters and their effects are mainly aimed to enhance monoaminergic neurotransmission involving norepinephrine, dopamine, and serotonin. The treatment effects of these antidepressants are variable in patients and can take at least 4 weeks to emerge. The  inhibitory neurotransmitter γ-aminobutyric acid (GABA) has become a new target for antidepressants based on the hypothesis that a GABA deficit is involved in the etiology of depression.

SAGE-217 is an oral synthetic neurosteroid that is a positive allosteric modulator of GABA type A receptors. In a recent phase 2 trial published in the NEJM, treatment with SAGE-217 was associated with a reduction in depressive symptoms after 2 weeks, as compared with placebo. The relatively quick onset of therapeutic effects compared with most antidepressants makes SAGE-217 an appealing treatment choice. However, editorialist called for more time to assess the effect of SAGE-217 given that previous drugs targeting non-monoamine neurotransmitter systems have failed after promising phase 2 trial results.

The following NEJM Journal Watch summary explains the study and results in more detail.


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

Peter Roy-Byrne, MD reviewing Gunduz-Bruce H et al. N Engl J Med 2019 Sep 5 Coccaro EF. N Engl J Med 2019 Sep 5

An oral positive allosteric modulator of GABAA receptors showed rapid efficacy with a large effect size — but this small trial lacked participants with treatment-resistant depression.

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 GABAA 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 assessed for 2 more weeks.

At day 15, change from baseline in HRSD was significantly greater with SAGE-217 than placebo (−17.4 vs. −10.3), as were rates of response (HRSD reduction of >50% from baseline, 79% vs. 41%) and remission (attainment of HRSD score ≤7, 64% vs. 26%). At day 28, these outcomes no longer significantly differed between groups. The most common adverse events were headache, dizziness, nausea, and somnolence (53% and 45% of each group experienced at least 1 event). No serious adverse events occurred.

Comment: The rapid antidepressant onset and substantial effect size seen in this trial are not typically observed with most antidepressants; still, the lack of related studies, the small size of the sample, and the exclusion of treatment-resistant participants should temper enthusiasm — at least for now. But even if SAGE-217 is not effective in treatment-resistant patients, its tolerability and novel mechanism of action might make it a valuable addition to the antidepressant armamentarium.


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 Ken is a 2019-2020 NEJM Editorial Fellow and a paediatrician working in the National Health Service of the United Kingdom. He graduated from Imperial College School of Medicine and is training in general paediatrics in London.