03. Zuranolone for the Treatment of Postpartum Depression

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Hello. I’m Dr. Vivien Burt, Professor Emeritus at UCLA and Founder and consultant of the UCLA Women’s Life Center. In a previous Quick Take, I reported on brexanolone, a neuroactive steroid administered intravenously for the treatment of postpartum depression. Today, I’m going to bring you hot-off-the-press news about zuranolone, the first oral agent approved to treat postpartum depression.

Postpartum depression is generally treated with psychotherapy and antidepressants often augmented with agents to address anxiety and insomnia. In the last few years, postpartum depression has been hypothesized to be due to hormonally driven dysregulated brain networks. Allopregnanolone, a metabolite of progesterone, increases in pregnancy and peaks in the third trimester and then steeply decreases following delivery. Like brexanolone, zuranolone is an allopregnanolone agonist, but unlike brexanolone, which is delivered over a 60-hour infusion, it is given orally over 14 days.

This study summarizes data supporting the use of zuranolone for the treatment of postpartum depression. This randomized, double-blind, placebo-controlled study comprised 196 patients, all with major depression with onset during the third trimester or within 4 weeks postpartum. Excluded were women with histories of bipolar disorder, psychosis, or suicidal ideation or behavior. Concomitant antidepressant use was permitted, and the patients agreed not to breastfeed from first study dose through 7 days following the last study dose. The subjects were randomized to 2 groups, half on zuranolone and half on placebo, which they took for 14 consecutive days after which treatment with active drug or placebo was discontinued. The patients were followed for a total of 45 days from study inception.

The primary outcome measure was change in HAM-D-17 scores at day 15. However, there were a number of important secondary outcomes, including changes in HAM-D at days 3, 28, and 45 and Clinical Global Improvement scores at day 15. Furthermore, HAM-D responses assessed as at least 50% reduction of baseline scores and actual remission assessed as achievement of HAM-D total scores of 7 or less were measured on day 15. Changes in anxiety were also assessed using the HAM-A instrument measured at day 15. Other self-ratings by the subjects were used to assess degree of concurrence with these clinical measurements and included the PHQ-9 and the Edinburgh Postnatal Depression scores. Montgomery-Asberg Depression Rating Scales were also done. Treatment-emergent adverse effects and emergence of suicidal ideation or behavior was detected by the Columbia Suicide Severity Rating Scale. Vital signs and clinical lab measurements as well as ECGs were also assessed. Importantly, the subjects were demographically balanced and included 21.9% African American and 38.4% Hispanic/Latino women. Most of the patients had baseline HAM-D scores of at least 26 on the 17-item scale, and most had moderate-to-severe anxiety as measured by their baseline HAM-A scores.

The results were quite impressive. First of all, there was a statistically significant reduction in depression at day 15 compared with placebo with a reduction of 15.6 points for the zuranolone group vs 11.6 points for the placebo group. Importantly, of those whose depression responded, zuranolone was better than placebo as early as day 3 and this trend continued at every subsequent study visit. By day 15, 57% of patients on zuranolone had achieved HAM-D response compared with 38.9% of the placebo group. This represents an odds ratio of 2.02. Improvement in all time points was sustained through day 45—that is well beyond the 14 days of zuranolone administration. At day 15, improvements in anxiety were also statistically significantly better in the zuranolone group than the placebo group. With regard to actual remission from depression, by day 15, HAM-D remission was numerically better than the placebo group and statistically significantly greater at day 45—that is 44% in the active group vs 29.4% in the placebo group. Patient-reported outcomes as measured by PHQ-9 and the Edinburgh Postnatal Depression Scale matched overall HAM-D measurements.

Zuranolone appeared to be safe and generally well-tolerated with most common treatment-emergent adverse effects of somnolence, dizziness, and sedation. There was no loss of consciousness and no significant changes in vital signs or ECG. There was no increase in suicidal ideation or withdrawal symptoms after discontinuation of zuranolone.

So, in summary, results of this study, which were the basis for FDA approval, indicate that zuranolone is a fast-acting medication that effectively treats postpartum depression with efficacy as early as day 3 of treatment and extending to day 45 of this study. In addition, zuranolone appears to be effective for anxiety, often a common component of postpartum depression. So, this appears to be a rigorous and well-done study with multiple instruments across multiple times from day 3 of the 14-day protocol for drug administration to day 45. Nevertheless, it should be noted that the study enrollees all had severe postpartum depression with HAM-Ds of 26 or greater. There was also a high placebo response, probably reflecting the fact that all subjects, placebo and actively treated subjects, had 8 visits in the 45 days of the study, which may not reflect the attention given typically to similar patients. Because subjects were not permitted to breastfeed their infants during the study, the effects of zuranolone on lactation and the extent of infant exposure through breastmilk is unknown. Finally, given that the study ended at day 45, more studies need to be done to determine long-term efficacy.

With all this said, zuranolone represents an exciting breakthrough treatment for postpartum depression. For the very first time, a medication targeted for postpartum depression that is easy to administer via a 14-day oral regimen and provides rapid and sustained, at least through 45 days of treatment, is available. Adjunctive antidepressants during and after treatment with zuranolone were permitted in this study and therefore would likely be advisable for patients with severe postpartum depression. Longer term studies do need to be done to determine sustained efficacy beyond the 45 days of this study. And studies are needed to determine efficacy of zuranolone in less severely depressed postpartum patients. Zuranolone clearly represents a much-needed treatment option for severely depressed postpartum women. We will look forward to more studies to assess its efficacy over the long term and in other clinical studies.

Abstract

Zuranolone for the Treatment of Postpartum Depression

Kristina M Deligiannidis, Samantha Meltzer-Brody, Bassem Maximos, E Quinn Peeper, Marlene Freeman, Robert Lasser, Amy Bullock, Mona Kotecha, Sigui Li, Fiona Forrestal, Nilanjana Rana, Manny Garcia, Bridgette Leclair, James Doherty

Objective: Postpartum depression (PPD) is a common perinatal complication with adverse maternal and infant outcomes. This study investigated the efficacy and safety of zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and neuroactive steroid, as an oral, once-daily, 14-day treatment course for patients with severe PPD.

Methods: In this double-blind phase 3 trial, women with severe PPD were randomized in a 1:1 ratio to receive zuranolone 50 mg/day or placebo for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15; key secondary endpoints were change from baseline in HAM-D score at days 3, 28, and 45 and change from baseline in Clinical Global Impressions severity (CGI-S) score at day 15. Adverse events were monitored.

Results: Among 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) completed the 45-day study. Treatment with zuranolone compared with placebo resulted in statistically significant improvement in depressive symptoms at day 15 (least squares mean [LSM] change from baseline in HAM-D score, -15.6 vs. -11.6; LSM difference, -4.0, 95% CI=-6.3, -1.7); significant improvement in depressive symptoms was also reported at days 3, 28, and 45. CGI-S score at day 15 significantly improved with zuranolone compared with placebo. The most common adverse events (≥10%) with zuranolone were somnolence, dizziness, and sedation. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed.

Conclusions: In this trial, zuranolone demonstrated significant improvements in depressive symptoms and was generally well tolerated, supporting the potential of zuranolone as a novel, rapid-acting oral treatment for PPD.

Reference

Deligiannidis, K. M., Meltzer-Brody, S., Maximos, B., Peeper, E. Q., Freeman, M., Lasser, R., Bullock, A., Kotecha, M., Li, S., Forrestal, F., Rana, N., Garcia, M., Leclair, B., & Doherty, J. (2023). Zuranolone for the treatment of postpartum depression. American Journal of Psychiatry.