In 2019, the Food and Drug Administration (FDA) approved brexanolone, marketed by Sage Therapeutics as Zulresso, as a treatment for postpartum depression (PPD).  As a neurosteroid, brexanolone represents a novel approach to the treatment of postpartum mood disorders.  One of the most exciting things about brexanolone is the rapidity of the response, with the initial studies indicating remission of depression within 24 to 48 hours.  Because antidepressants typically take 2-4 weeks to kick in, an antidepressant agent with rapid onset of action would be particularly appealing to women with severe PPD.  

Zulresso must be administered intravenously over 60 hours, which means that patients must be hospitalized for about three days. While some psychiatric hospitals are able to handle medical issues (including the administration of IV drugs and monitoring for side effects), many psychiatric hospitals do not have this capacity.  

In addition, Zulresso may have potentially serious side effects, including excessive sedation and sudden loss of consciousness; thus the FDA requires a REMS (Risk Evaluation and Mitigation Strategy) for healthcare facilities seeking to administer Zulresso.  According to the REMS, patients must be under 24-hour supervision with monitoring by an on-site medical professional and continuous pulse oximetry to detect excessive sedation.  

Given these constraints, the rollout of Zulresso has been slow.  While very exciting to have a new option for the treatment of PPD, we have not been able to offer Zulresso to many women seeking treatment with this novel agent.  We have been eagerly awaiting the arrival of zuranolone – an oral version of brexanolone.  

Like brexanolone, zuranolone is a neurosteroid, an analogue of allopregnanolone which is a positive allosteric modulator of the GABA-A receptor. What distinguishes zuranolone from brexanolone is that it has much better oral bioavailability and thus does not have to be administered intravenously. It can be taken as an oral medication, similar to conventional antidepressants.  

Results of Phase 3 Clinical Trials 

Last week, Deligiannidis and colleagues published data from the phase 3 clinical trial of zuranolone for postpartum depression.  This double-blind, randomized, placebo-controlled clinical trial was conducted between January 2017 and December 2018 at 27 sites within the United States. 

Women with PPD (between the ages of 18 and 45) were eligible for the study if they were less than six months postpartum and had a major depressive episode beginning during the third trimester or before 4 weeks postpartum.  This study included only women with severe PPD, defined as a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Participants were randomized to receive either placebo or zuranolone (30 mg) administered orally each evening for 2 weeks.

A total of 153 patients were randomized patients, with analyzable data from 150 patients. By day 3, women receiving zuranolone experienced a greater reduction in HAM-D scores than women receiving placebo (mean reduction, 12.5 vs 9.8; P = .03).  The difference in mean HAM-D scores steadily increased up to day 15. At day 15, the mean reduction in HAM-D scores was 17.8 in women receiving SAGE-217 vs. 13.6 in the placebo group (difference -4.2; P = .003).  

At day 45, women treated with zuranolone continued to show a greater reduction in HAM-D scores than women receiving placebo (19.2 vs 15.1, P = .003).  Zuranolone treatment was also associated with a significant reduction in Hamilton Anxiety Rating Scale compared with placebo, 16.6 vs 12.7 (P = .006).

Zuranolone was well-tolerated. Among women receiving zuranolone, 58% reported adverse events, compared to 51% of the women in the placebo group.  One patient in each group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event versus none for placebo.  The most common adverse events in the SAGE-217 group included somnolence (12.8%), headache (9.0%), dizziness (7.7%), upper respiratory tract infection (7.7%), diarrhea (6.4%), sedation (5.1%), and nausea (3.8%).

There was no indication of an increase in suicidal ideation or suicidal behavior over baseline, as measured with the Columbia Suicide Severity Rating Scale (C-SSRS).

Looking Forward

The current study indicates that zuranolone has antidepressant effects in women with severe PPD.  Improvements in depression were observed at day 3 and continued to improve over the 15 days of the study.  While this may not be as robust as the response observed with brexanolone, it does appear that zuranolone acts more quickly than conventional antidepressants.  

Also important is the finding that there was only one patient (out of 77) who reported a serious adverse event.  Because of concerns about  serious adverse events in women receiving brexanolone (suicidal ideation after the infusion in one subject and syncope/altered consciousness in another patient), Zulresso was approved with a Risk Evaluation and Mitigation Strategy (REMS).  It seems unlikely that zuranolone will require a REMS.

Ruta Nonacs, MD PhD

Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, Sankoh AJ, Silber C, Campbell AD, Werneburg B, Kanes SJ, Lasser R.  Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial.  JAMA Psychiatry. 2021 Jun 30. 



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