By Nicole Cirino, MD, CST, IF
Reproductive Psychiatrist, Professor of Psychiatry and OB/GYN, Oregon Health & Science University, Portland
SYNOPSIS: Zuranolone was approved by the Food and Drug Administration for the treatment of postpartum depression (PPD) in March 2019. One potential factor identified in PPD etiology is the dramatic perinatal changes in circulating levels of allopregnanolone, a neuroactive steroid with gamma-aminobutyric acid type A (GABAA) receptor positive allosteric modulator properties. In brain regions associated with emotion and self-perception, neural network connectivity supported by GABAergic signaling is positively correlated with plasma allopregnanolone concentrations in individuals with PPD vs. healthy postpartum female individuals.
SOURCE: Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of zuranolone vs placebo in postpartum depression: A randomized clinical trial. JAMA Psychiatry 2021;78:951-959.
This trial by Deligiannidis et al was a Phase III, double-blind, randomized, placebo-controlled clinical trial for postpartum depression (PPD) conducted between January 2017 and December 2018 in 27 enrolling U.S. sites. Participants were women 18 to 45 years of age, who delivered within six months, with PPD without psychosis. The major depressive episode (MDE) with perinatal onset being studied must have begun either in the third trimester or four or fewer weeks post-delivery with a baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher (severe depression).
Patients were randomized 1:1 to receive zuranolone 30 mg or matching placebo capsules daily, taken at night for two weeks. Time points were evaluated day 3 through day 45, four weeks after treatment was discontinued. Patients were not permitted to breastfeed for the 14 days of treatment and the seven-day period following treatment.
The primary endpoint was a change from baseline in HAMD-17 score for zuranolone vs. placebo at day 15. Secondary endpoints included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥ 50% score reduction), and remission (score ≤ 7) rates. The study population had a mean age of 29.3 years (standard deviation [SD] 5.4 years) in the zuranolone group and 27.4 years (SD 5.3 years) in the placebo group (range, 18 to 44 years). Most patients identified as white (placebo group, 54% vs. zuranolone group, 58%) or Black/African American (placebo group, 42% vs. zuranolone group, 41%). Twenty-four percent of the placebo group vs. 21% of the zuranolone group identified as Hispanic or Latina. At baseline, 21% vs. 18% of patients in the zuranolone and placebo groups, respectively, were taking stable doses of antidepressant medications.
Safety and tolerability were evaluated by adverse events (AEs), vital signs, clinical laboratory evaluations, electrocardiogram parameters, and the Columbia-Suicide Severity Rating Scale. Results showed that by day 3, women receiving zuranolone experienced a greater reduction in HAMD-17 scores than women receiving placebo (mean reduction, 12.5 vs. 9.8; P = 0.03). At day 3, a higher percentage of patients in the zuranolone group achieved HAMD-17 remission vs. the placebo group (19% vs. 5%, respectively; odds ratio [OR], 3.9; 95% confidence interval [CI], 1.2-12.2; P = 0.02). Remission, defined as a HAMD-17 score of 7 or less, also was more common in the zuranolone group at day 8 (32% vs. 19%; P = 0.020) and day 15 (45% vs. 23%; P = 0.011). At day 15, the primary endpoint and final day of treatment, there was a significantly greater reduction from baseline in HAMD-17 total score with zuranolone compared with placebo (-17.8 points vs. -13.6 points; 95% CI; P = 0.003; effect size, 0.53.)
Greater reductions from baseline in HAMD-17 score favoring zuranolone compared with placebo were observed at all measured time points from day 3 through day 45.
At day 45, four weeks after study drug cessation, HAMD-17 response was 75% in the zuranolone group vs. 57% in the placebo group (OR, 2.3; 95% CI, 1.1-4.6; P = 0.02) and HAMD-17 remission was 53% in the zuranolone group vs. 30% in the placebo group (OR, 2.5; 95% CI, 1.3-5.0; P = 0.009). Improvements in anxiety, a common PPD symptom/comorbidity, and in clinician-measured global functioning (CGI-I) also were sustained through day 45.
Generally, zuranolone was well tolerated. The most common treatment-emergent AEs in the zuranolone group vs. placebo group were somnolence (15% vs. 11%), headache (9% vs. 12%), dizziness (8% vs. 6%), and sedation (5% vs. 0%), respectively. Three patients in the zuranolone group experienced severe treatment-emergent AEs (sedation, n = 1; confusional state, n = 1; migraine, n = 1), and three patients in the placebo group experienced severe treatment-emergent AEs (back pain/muscle spasms, n = 1; headache/oropharyngeal pain, n = 1; menorrhagia, n = 1). The patient in the zuranolone group experienced a confusional state on day 3, involving the inability to remember the exact sequence of the day’s events, along with sedation, which resolved within seven hours. 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) in either group.
COMMENTARY
Currently, none of the monoaminergic antidepressants (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants) have specific indications for PPD, despite being used widely, largely because of the lack of specific data in the PPD population.
I have written previously about brexanolone, which was the first drug to be approved by the U.S. Food and Drug Administration (FDA) specifically for the treatment of postpartum depression in adults. Brexanolone, a 60-hour infusion, demonstrated reductions in depressive symptoms in three double-blind, randomized, placebo-controlled trials.1 The same company, Sage Therapeutics, Inc., funded this trial, and zuranolone has been nicknamed the “little sister” of brexanolone.
This is not the first randomized controlled trial looking at the effectiveness of zuranolone. In 2019, zuranolone failed to meet its primary endpoint in a double-blind, placebo-controlled, pivotal Phase III study for adults with major depressive disorder (MDD). In that study, 581 patients were randomized to receive zuranolone or placebo once nightly for two weeks. The primary endpoint of the study was the same as the earlier study — change from baseline in the HAMD-17 total score at day 15.2
The use of brexanolone has been limited because of the need for a 60-hour infusion in a monitored setting requiring relatively high cost. In addition, brexanolone had some potentially serious side effects, including excessive sedation and sudden loss of consciousness. Thus, the FDA required a Risk Evaluation and Mitigation Strategy (REMS) for healthcare facilities seeking to administer it. It seems unlikely that zuranolone will require a REMS.
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, just like conventional antidepressants. However, the onset of action of oral zuranolone does not compare to the rapid onset of the brexanolone infusion. In the integrated brexanolone data, the rapid response rate was significant compared to placebo at hours 24, 48, 60, and 72 and at days 7 and 30.1 Studies now are underway to look at the safety of home infusion of brexanolone, but it has not yet been established as a viable modality of treatment.3
In summary, this trial expands our current research and continues to focus on the new approach to the treatment of PPD using neuroactive steroid agents. Some potential advantages over traditional antidepressants are the shorter duration of treatment (two weeks, compared to antidepressants, which can require months of treatment), minimal adverse effects shown thus far, and the targeted treatment specifically for PPD vs. general adult MDD. Thus far, the disadvantages of neuroactive steroids over antidepressants include a lack of data in lactation (in this trial, breastfeeding was halted for three weeks as a safety measure), unclear efficacy for anxiety as compared to traditional antidepressants, cost, and accessibility. We still have a way to go to establish whether either brexanolone infusion or oral zuranolone will be as accessible or as effective as traditional antidepressants for the treatment of PPD, but having a neuroactive steroid agent as an alternative or adjunct to treatment of PPD is promising.
REFERENCES
- Cirino N. Brexanolone for postpartum depression: Promising, but will it deliver? OB/GYN Clinical Alert 2019;35:81-84.
- Sage Therapeutics. Sage Therapeutics reports topline results from pivotal Phase 3 MOUNTAIN Study of SAGE-217 in major depressive
- disorder. Published Dec. 5, 2019. https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-reports-topline-results-pivotal-phase-3
- ClinicalTrials.gov. A study to assess the safe-use conditions for administration of ZULRESSO® in a home setting. Updated Sept. 28, 2021. https://clinicaltrials.gov/ct2/show/NCT05059600
