Patients with major depressive disorder who received SAGE-217 for fourteen days showed improvement in symptoms on day fifteen in a phase 2 safety and efficacy trial.
Handan Gunduz-Bruce, MD, with Sage Therapeutics, Cambridge, Massachusetts, and colleagues reported their findings in the September 5, 2019 issue of The New England Journal of Medicine.
Major depression is a complex mental disorder involving genetic and environmental factors, as well as multiple neurotransmitters. Gamma-aminobutyric acid (GABA) has been shown to play a major role in neural regulation as the primary inhibitory neurotransmitter of the central nervous system. Studies have shown decreased GABA levels in the plasma, cerebrospinal fluid, and brain tissue of patients with major depressive disorder.
Several medications show positive allosteric modulator activity on the GABA receptor, including benzodiazepines, barbiturates, muscle relaxants, alcohol, propofol, and etomidate, and thus are used as anxiolytics, sedatives, anticonvulsants, antispasmodics, and anesthetics. Neurosteroids are naturally occurring modulators of GABA receptors with pharmacologic activity that differs from that of glucocorticoids. Allopregnanolone, one such neurosteroid, acts as a positive allosteric modulator of the GABAA receptor. In studies of patients with post-partum depression (PPD), administration of intravenous brexanolone, the synthetic analog of allopregnanolone, resulted in significant reductions (improvement) in the Hamilton Rating Scale for Depression (HAM-D) score at sixty hours. This is consistent with the hypothesis that normalization of GABA function is clinically useful in the treatment of depression, and led to the approval of brexanolone by the U.S. Food and Drug Administration (FDA) on March 19, 2019.
This trial is a phase 2, randomized, double-blind, placebo-controlled study of the oral formulation of synthetic allopregnanolone, SAGE-217, in patients with major depressive disorder. Study investigators enrolled 89 adults with major depression with a HAM-D score of 22 or higher (moderate-to-severe depression), who were on stable doses of antidepressants for at least thirty days, or not taking any antidepressants. 45 patients were randomly assigned to receive SAGE-217 30 mg once daily for fourteen days, and 44 patients to placebo. The mean change in the baseline HAM-D scores on day fifteen was compared between groups.
The mean HAM-D score at baseline was 25.2 in the SAGE-217 group and 25.7 in the placebo group. On day 15, the mean change in the HAM-D score was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (between-group difference -7.1; 95% confidence interval [CI], -10.2 to -3.9; P<0.001).
Adverse events were reported by 53% in the SAGE-217 group and 45% in the placebo group. The most common adverse events reported in the SAGE-217 group were headache, nausea, and somnolence. No serious adverse events and no deaths were reported during the trial.
The study was funded by Sage Therapeutics.
Gunduz-Bruce, H, et al. Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med. 2019; 381:903-11.
Comments
- this trial further supports the hypothesis that GABAA receptors play an important role in major depression
- the effect of SAGE-217 was similar for patients taking conventional antidepressants during the trial and those not previously on antidepressant medication
- although the results of this trial show promise for patients suffering major depression, it is limited by being a short phase 2 trial with a small sample size (as designed); larger studies are needed with longer-term outcomes to better define efficacy and safety