We’ve got been talking about zuranolone for some time and are eagerly awaiting its arrival.  If you’ve not heard about it yet, zuranolone is comparable to brexanolone, which was approved in 2019 by the FDA for the treatment of PPD.  Like brexanolone, zuranolone is a neuroactive steroid with antidepressant activity and a novel mechanism of motion as positive allosteric modulators of GABA-A receptors.  The massive difference between the 2 is that zuranolone is on the market as a pill, while brexanolone is run as an intravenous infusion.  This can be a huge advantage on the subject of ease of use and accessibility.  

One other Study Yields Positive Result

Up to now there have been several randomized controlled trials supporting the efficacy of zuranolone for the treatment of postpartum depression (PPD).  In essentially the most recent study, a double-blind phase 3 trial published int the American Journal of Psychiatry, women with severe PPD were randomized to receive zuranolone (50 mg/day) or placebo for 14 days. Depressive symptoms were assessed at baseline and on days 3, 28, and 45 the 17-item Hamilton Depression Rating Scale (HAM-D).

Among the many 196 patients randomized (zuranolone, N=98; placebo, N=98), 170 (86.7%) accomplished the 45-day study. Treatment with zuranolone resulted in statistically significant reductions in depressive symptoms at day 15 in comparison with placebo (change from baseline in HAM-D rating, -15.6 vs. -11.6).   Taking a look at the proportion of patients achieving HAM-D response, zuranolone was superior to placebo starting at day 3, and this trend was observed at every subsequent study visit.  The proportion of patients achieving HAM-D response at day 15 was significantly higher within the zuranolone group in comparison with the placebo group (57.0% vs. 38.9%; odds ratio=2.02, 95% CI=1.11, 3.67).

Zuranolone was generally well-tolerated.  Probably the most common hostile events (?10%) with zuranolone were somnolence, dizziness, and sedation. No lack of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed.

Looking Forward

This may be very exciting. Zuranolone would represent a brand new option for the treatment of PPD, a rapidly acting antidepressant with a very good safety profile.  In clinical trials, zuranolone has generally been well-tolerated; essentially the most common hostile events included headache, dizziness, and sedation.  As well as, individuals treated with zuranolone experience reductions in anxiety and insomnia, symptoms commonly related to PPD.

There are still some questions.  Women participating in zuranolone clinical trials were asked to forgo breastfeeding while taking zuranolone.  At this point we’ve got no information regarding the secretion of zuranolone into the breast milk or the results of zuranolone within the breast milk on the nursing infant.  Nor can we know if zuranolone affects breast milk production.   For many ladies, having to interrupt or avoid breastfeeding while receiving treatment for PPD could also be a big deterrent.

One other big query is expounded to the duration of the response.  Women taking zuranolone continued to experience a discount in depressive symptoms 30 days after taking the last dose of medication.  With traditional antidepressants, we generally recommend that ladies proceed treatment with an antidepressant for 6-12 months, or longer in women with recurrent depression, in an effort to minimize the danger for relapse.  Will women experience recurrent symptoms in some unspecified time in the future after a 15-day course of zuranolone? Will they need some form of maintenance antidepressant therapy? Will they need zuranolone boosters? We don’t yet know, but information regarding long-term outcomes shall be collected as we gain expertise regarding this recent medication.

Although further study is required and zuranolone may not represent a first-line treatment for all women with PPD, there are various women who will profit from having one other treatment option, including women with severe symptoms and people unable to access long-term psychiatric care.

The FDA is anticipated to make a choice on zuranolone by August fifth.

Ruta Nonacs, MD PhD

Deligiannidis KM, Meltzer-Brody S, Maximos B, Peeper EQ, Freeman M, Lasser R, Bullock A, Kotecha M, Li S, Forrestal F, Rana N, Garcia M, Leclair B, Doherty J. Zuranolone for the Treatment of Postpartum Depression. Am J Psychiatry. 2023 Jul 26.