Progress in Treating Postpartum Depression

Postpartum depression involves function-impairing depressive symptoms with onset during the last trimester of pregnancy and/or the first month after delivery. Symptoms are often severe and impact the mother as well as her family. Treatments, including typical antidepressants and/or psychotherapy, are often of limited help.

A new way to treat postpartum depression

In April 2019, the FDA approved brexanolone for the treatment of postpartum depression. As discussed in an earlier post, brexanolone is a formulation of the naturally occurring neurosteroid allopregnanolone. This compound powerfully influences the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Although brexanolone is highly effective in treating severe postpartum depression, it is administered as a 60-hour intravenous infusion. For individuals so ill that they need psychiatric hospitalization, such a protocol is appropriate, but administering this drug on an outpatient basis is more difficult.

Investigators have synthesized a number of steroids based on the structure of allopregnanolone. Their goal was to find a drug that had actions similar to allopregnanolone on the GABA neurotransmitter system but that had pharmacologic properties that allowed it to be taken orally. Such pharmacologic properties include absorption of the intact drug from the gut into the bloodstream and the ability to enter brain tissue while maintaining high activity at GABA-A receptors. Eventually, a steroid called zuranolone was synthesized that demonstrated these properties.

Zuranolone has been carefully examined in a small number of people in phase 1 and phase 2 testing. Such trials test for safety in healthy individuals and then in persons with the underlying condition. To answer the question of whether zuranolone is effective in women with severe symptoms of postpartum depression, a large phase 3 study was conducted. The results of this study were recently reported by Kristina Deligiannidis and colleagues in JAMA Psychiatry. The results are impressive.

In this multi-site, double-blind, placebo-controlled study, 153 women were randomized to take either placebo or 30 mg zuranolone orally once a day for two weeks. The women were between the ages of 18 and 45, were less than six months postpartum, and had been experiencing a major nonpsychotic depressive episode diagnosed no earlier than the third trimester of their pregnancy and no later than four weeks postpartum. Depressive symptoms were assessed with the 17-item Hamilton Rating Scale for Depression (HAMD-17), a standardized depression inventory. The zuranolone and placebo groups were well matched for age, race, ethnicity, duration of depressive symptoms, baseline use of antidepressants, and baseline depression scores.

The main outcome measure was the change from baseline HAMD-17 scores on day 15. In addition to this primary outcome measure, HAMD-17 scores were measured on days 3, 8, 21, and 45, along with assessments of anxiety symptoms and overall functioning. Day 45 was a month after the last dose of zuranolone had been administered.

The results were clear. About 72 percent of women taking zuranolone versus 48 percent on placebo showed a response, defined as a 50 percent decrease in HAMD-17 scores from baseline. About 45 percent of women taking zuranolone versus 23 percent on placebo reported so few symptoms that they were considered to be in remission.

The benefit of the active drug over placebo was seen as early as day 3. In addition, a month after the last dose of the drug was taken, 53 percent of the women were in remission compared to 30 percent of those who took the placebo.

In addition to improvement in depression scores, symptoms of anxiety improved substantially. There was also a significant improvement in the ability to function in the women taking zuranolone.

Implications for the future

The FDA usually requires two phase 3 studies showing efficacy to approve a new medicine. If a second study confirms the results of this initial phase 3 study, it is likely that this oral medicine will be available for clinical use and possibly replace the 60-hour intravenous infusion of brexanolone for the treatment of postpartum depression. This advance will make treatment much more accessible to those who would benefit from it.

Synthesizing this new drug, demonstrating that it has a powerful influence on the GABAergic system, showing that it has pharmacologic properties allowing it to be taken in pill form, and then testing it in a phase 3 clinical trial takes the skills of a large number of pre-clinical and clinical investigators working towards a common goal.

As we learn more about the role of the GABAergic system in depressive disorders, it is likely that more medicines will be developed. We also note that clinical trials are underway examining zuranolone for the treatment of women and men with major depression.

This post was written by Eugene Rubin M.D., Ph.D., and Charles Zorumski, M.D. We also disclose that Zorumski serves on the Scientific Advisory Board of Sage Therapeutics, the company developing zuranolone for clinical use, and has equity in the company. He was not involved in the study described in this post.