A single 60-hour infusion of brexanolone dramatically and rapidly improves severe postpartum depression with minimal adverse effects, a small manufacturer-conducted phase II trial suggests.

Brexanolone is a proprietary formulation of allopregnanolone, the major metabolite of progesterone and a potent modulator of synaptic and extrasynaptic gamma-aminobutyric acid type A (GABAA) receptors that has demonstrated profound benefits for anxiety and depression symptoms in animal models. Plasma levels of allopregnanolone rise to a peak during the third trimester of pregnancy, then abruptly fall after childbirth. “Failure of GABAA receptors to adapt to these changes at parturition has been postulated to have a role in triggering postpartum depression,” said Stephen Kanes, MD, of Sage Therapeutics, Cambridge, Mass., and his associates.

They assessed the drug’s effects in 21 women hospitalized for severe postpartum depression at 11 U.S. medical centers during a 5-month period. The study participants, who had Hamilton Rating Scale for Depression ( HAM-D ) scores of 26 or higher at baseline, randomized to receive a 60-hour infusion of brexanolone (10 patients) or a matching placebo (11 patients) in a double-blind fashion.

The primary outcome measure – mean reduction in HAM-D score at the end of the 60-hour infusion – was 21.0 points with brexanolone, significantly greater than the 8.8 point reduction seen with placebo. Women in the active-treatment group began showing a marked improvement within 24 hours of beginning the infusion, which was maintained throughout the week of treatment, as well as for the succeeding 30 days of follow-up.

Of the 10 patients, 7 receiving brexanolone (70%), compared with only 1 of those receiving placebo (9%), achieved remission of depression (HAM-D score of 7 or less) by the end of treatment. That remission occurred within 24 hours of beginning the infusion in six of the women in the brexanolone group. Moreover, improvement extended beyond the core depressive symptoms, with women in the active-treatment group also showing rapid and marked improvement on Clinical Global Impression–Improvement Scale scores , the investigators said (Lancet. 2017 Jun 12. doi: 10.1016/S0140-67369(17)31264-3 ).

Two women who received brexanolone admitted that, at baseline, they’d had active suicidal ideation with a specific plan and intent. Neither was suicidal after treatment.

Brexanolone was well-tolerated, with no serious adverse events or treatment discontinuations. Fewer patients who received active treatment (4) than placebo (8) reported mild adverse events. The most frequently reported adverse effects of brexanolone were dizziness and somnolence.

Among the limitations cited by the investigators was the use of a “very strict definition of postpartum depression” (HAM-D scores greater than or equal to 26).

Dr. Kanes and his associates reported that a phase III study currently underway is looking into the possible use of brexanolone in women with “varying degrees of severity.”

“Our findings provide the first placebo-controlled clinical support for the role of extrasynaptic GABAA receptors in the modulation of mood and affective states in any clinical population. The large effect size seen in this trial contrasts with that observed in studies of currently available and widely used antidepressants, including [selective serotonin reuptake inhibitors], [selective norepinephrine reuptake inhibitors], and tricyclics,” Dr. Kanes and his associates noted.