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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. I’d like to talk to you about brexanolone, a medication currently approved by the FDA for the treatment of postpartum depression.
One in 9 women struggles with postpartum depression, a condition which causes great suffering for new mothers just as they are faced with the responsibility of caring for their newborns. Women with this condition are deeply depressed. Afflicted mothers can’t care for themselves nor can they care for their babies and other children in their homes. At its worst, women with postpartum depression are at risk for suicide.
Given the prevalence of women affected and the severity and impact of the symptoms, it’s rather amazing that not until 2019 was a drug specifically approved for the treatment of postpartum depression. Following phase III studies that showed statistically significant improvement in HAM-D depression scores in women with postpartum depression, brexanolone was FDA approved specifically for the treatment of postpartum depression in adults. What’s so special about brexanolone?
Brexanolone is a synthetic form of allopregnanolone, a neurosteroid that appears to act like an antidepressant and a gamma-aminobutyric acid (GABA-A) receptor positive modulator. In this respect, it has been hypothesized that brexanolone may target symptoms of anxiety. It is unique also in that it works very quickly, in a couple of days. It’s important to note that unlike standard antidepressants, which are administered orally, brexanolone is administered via a continuous 60-hour infusion.
Because postpartum depression is so often accompanied by severe and incapacitating anxiety and pervasive insomnia, a recent study looked at the efficacy of brexanolone for these targeted symptoms. Let’s review the data from this randomized, double-blind, placebo-controlled study to address this issue. This study was authored by Neill Epperson and colleagues and included several authors employed by Sage Therapeutics, the maker of brexanolone. It employed posthoc pooled analyses from 3 pivotal phase III, double-blind, randomized, placebo-controlled trials called the HUMMINGBIRD Trials. Subjects were women aged 18–45 who had new-onset major depression in their third trimester or within the first 4 weeks following delivery. There were 2 groups of subjects. Group 1 included 109 women who received active drug, and group 2 included 107 women who received placebo. The primary endpoints of the study involved change from baseline in HAMD-17 and proportions of patients achieving Clinical Global Improvement (CGI-I) scores at 60 hours. Secondary endpoints included assessments of HAMD-17s and CGI-I scores at various endpoints up to 30 days after infusion. The posthoc analyses included analyses of HAM-D and CGI-I anxiety somatization as well as insomnia subscales of the HAMD-17 at points up to 30 days following administration of brexanolone. A further so-called exploratory analysis was employed to assess for 70% or greater reduction from baseline in insomnia scores.
Results showed a significant 81.4% improvement in overall HAM-D-17s for women in the active treatment arm at the 60-hour mark, just after infusion was completed, compared with 67.3% for women who received placebo. HAM-D score improvements were 88.2% vs 75.7% for treatment and placebo groups, respectively, 30 days after treatment. Assessing CGI-I scores at 60 hours and 30 days found achievement of very much or much improvement for 81.5% for the active group vs 61.7% for the placebo group.
Change from baseline in HAM-D-17 anxiety somatization scores were statistically significantly greater for the brexanolone vs placebo groups at hour 24 of the infusion through day 30. With regard to the insomnia, change from baseline was statistically significantly greater with brexanolone group as compared with placebo at all time points starting at hour 24 through day 7 and nonstatistically at day 30. In an exploratory analysis of the effect of brexanolone on insomnia, a statistically significantly greater proportion of brexanolone-treated patients achieved a 70% or better reduction from baseline in HAM-D-17 insomnia subscale scores as compared with placebo-treated subjects.
The authors concluded that brexanolone achieved a rapid—that is, by hour 24—and sustained—that is, through 30 days—reduction in core depressive symptoms. Also, brexanolone rapidly and persistently improved symptoms of both anxiety and insomnia in women with postpartum depression. They also concluded that the percent of responders in terms of anxiety, insomnia and depression and the degree of clinically meaningful improvement as assessed by the CGI-I also increased with brexanolone treatment. The authors justified their use of anxiety somatization and insomnia subscores of the HAMD-17 scales because, as they said, anxiety and insomnia are so prevalent in women with postpartum depression.
Now, there were limitations to this study. These include the fact that the HAMD-17 anxiety somatization subscale is not validated to diagnose symptoms of anxiety. Furthermore, the study was not powered to assess secondary and exploratory outcomes—thus, for example, the assessment of greater than or equal to 70% improvement in insomnia. Additionally, the placebo-treated subjects achieved relatively high rates of response, which may have contributed to nonstatistic treatment differences. In this study, both drug-treated and placebo-treated subjects were hospitalized and therefore were given close attention and care that may well have contributed to the reported results.
So, what can we, the readers, conclude from this study? Well, although the data on the efficacy of brexanolone on anxiety and insomnia are promising, further studies looking at rigorous analyses of these symptoms are needed. Is brexanolone an exciting and attractive option for women with postpartum depression? Possibly. But there are certainly some caveats that ought to be considered. One disadvantage is that it has to be administered via a lengthy infusion, about 60 hours, in a healthcare setting. Because rare but potentially severe side effects have been reported, including sedation and sudden loss of consciousness, this medication must be given under 24-hour supervision with monitoring by an on-site medical professional as part of a special Risk Evaluation and Mitigation Strategy program. Furthermore, women must forgo breastfeeding during treatment and for the posttreatment monitoring while in a healthcare setting. Finally, the cost of the medication is about $34,000 before discounts and insurance.
So, where are we in targeted treatment of postpartum depression? Well, for the first time, we’ve got a drug specifically approved for the treatment of this relatively common and often devastating disorder that affects not just new mothers but their children, their partners, and other family members. Brexanolone is likely a first step in this armamentarium, but it is certainly an important first step. We’re now awaiting other milestone treatments for postpartum depression, and the exciting news is that these new treatments employ mechanisms that are different than our tried-and-true antidepressants, treatments that are at least comparably efficacious but seem to be different because they jumpstart responses.
Abstract
Effect of Brexanolone on Depressive Symptoms, Anxiety, and Insomnia in Women With Postpartum Depression
C Neill Epperson, David R Rubinow, Samantha Meltzer-Brody, Kristina M Deligiannidis, Robert Riesenberg, Andrew D Krystal, Kemi Bankole, Ming-Yi Huang, Haihong Li, Colville Brown, Stephen J Kanes, Robert Lasser
Background: Brexanolone is currently the only treatment specifically approved for postpartum depression (PPD) in the United States, based on the results from one Phase 2 and two Phase 3 double-blind, randomized, controlled trials in the HUMMINGBIRD program.
Methods: Adults with PPD randomized to a 60-h infusion of brexanolone 90 μg/kg/h (BRX90) or placebo from the 3 trials were included in these post hoc analyses. Data on change from baseline (CFB) in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score, HAMD-17 Anxiety/Somatization and Insomnia subscales, and Clinical Global Impression of Improvement (CGI-I) scale were pooled. Response rates for HAMD-17 (≥50 % reduction from baseline) and CGI-I (score of 1 or 2) scales and time to response were analyzed.
Results: Patients receiving BRX90 (n = 102) versus placebo (n = 107) achieved a more rapid HAMD-17 response (median, 24 vs 36 h; p = 0.0265), with an Hour-60 cumulative response rate of 81.4 % versus 67.3 %; results were similar for time to CGI-I response (median, 24 vs 36 h; p = 0.0058), with an Hour-60 cumulative response rate of 81.4 % versus 61.7 %. CFB in HAMD-17 Anxiety/Somatization and Insomnia subscales also favored BRX90 versus placebo, starting at Hour 24 through Day 30 (all p < 0.05), and response rates for both subscales were higher with BRX90.
Limitations: The study was not powered to assess exploratory outcomes.
Conclusions: Brexanolone was associated with rapid improvement in depressive symptoms and symptoms of anxiety and insomnia compared with placebo in women with PPD. These data continue to support the use of brexanolone to treat adults with PPD.
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Reference
Epperson, C. N., Rubinow, D. R., Meltzer-Brody, S., Deligiannidis, K. M., Riesenberg, R., Krystal, A. D., Bankole, K., Huang, M., Li, H., Brown, C., Kanes, S. J., & Lasser, R. (2023).
Journal of Affective Disorders, 320
, 353-359.
