GABA-A Agent SAGE-217: A New Antidepressant?

Peter ForsterMajor Depression, Treatments of Depression Leave a Comment

Psychiatrists and patients alike are hungry for new antidepressants.

Few new medications have been developed in the last 10 years that are effective antidepressants, and those that have come to the market have all been variants of existing medications.

The only really novel treatments for depression in the last 15 years in psychiatry are ketamine and TMS, both of which are expensive and time-consuming.

This may explain why a short trial of a GABA-A agent in a small sample of people with depression was published in the prestigious New England Journal of Medicine.

Peter Roy-Byrne, in a summary in Journal Watch, asked the rhetorical question, “At Last, an Effective Oral Antidepressant with a Novel Mechanism of Action?”

And, indeed, there is reason for excitement, since this study found a relatively large effect size by day 15 of treatment.

Nearly two thirds of the patients achieved remission (Hamilton Depression Rating Scale score of less than 7) by day 15.

Neurosteroids for Depression

This is the second GABA-A agent from Sage Therapeutics that has been in the news in the last year. Earlier this year, Sage obtained “breakthrough” approval by the FDA for brexanolone injection (Zulresso) for the treatment of postpartum depression.

Both of these agents belong to a class of neurosteroids that are related to progesterone and that appear to work as positive allosteric modulators of GABA-A.

This is very exciting stuff. But with both of these agents, we have no information at this point about long term effects.

Other Positive Allosteric Modulators of GABA-A

Other positive allosteric modulators of GABA-A include the benzodiazepines and barbiturates, both of which have short term studies showing effectiveness in treating depression.

Alprazolam was at one point heralded in JAMA as a medication that was as effective as imipramine in the treatment of depression but seemed to work faster.

But adverse effects and a lack of long term effectiveness ended up limiting the usefulness of these medications.


Gunduz-Bruce H et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med 2019 Sep 5; 381:903. (

Coccaro EF. New hope for patients with major depressive disorder? N Engl J Med 2019 Sep 5; 381:980. (

Feighner JP, Aden GC, Fabre LF, Rickels K, Smith WT. Comparison of Alprazolam, Imipramine, and Placebo in the Treatment of Depression. JAMA. 1983;249(22):3057–3064. doi:10.1001/jama.1983.03330460039029