Reference: Am J Psychiatry. 2023 Jul 26 early online
Practice Point: Consider zuranolone 50 mg po daily for 14 days for severe postpartum depression.
EBM Pearl: Statistically significant differences between scores on a rating scale may not always translate to clinically meaningful outcomes.
Postpartum depression (PPD) significantly impacts maternal health and the transformation into motherhood, causing a nearly 20% increased risk of maternal death from suicide as well as negatively impacting breastfeeding, mother-infant bonding, and childhood development. Despite the fact that PPD involves hormonal shifts from pregnancy to postpartum, it is typically treated like major depression. Zuranolone, a new medication approved for PPD, works as an analogue of allopregnanolone, a progesterone metabolite which modulates GABAA receptors and has antidepressant and anxiolytic effects. Allopregnanolone’s fluctuation during pregnancy and rapid decline after delivery are thought to contribute to PPD. In a recent phase 3 trial published in the American Journal of Psychiatry, Zuranolone was found to be effective in the treatment of PPD.
Investigators randomized 200 adults with severe PPD diagnosed ≤ 12 months after delivery to zuranolone 50 mg/day in the evening with a fatty meal vs. placebo for 14 days. In cases of intolerance, zuranolone was reduced to 40 mg daily. Participants were followed for a total of 8 visits over 45 days. Concomitant use of antidepressants and therapy was permitted as long as participants were on a stable dose of medication and participating in therapy regularly 30 days prior to the start of the trial. Contraception was required and the mothers stopped breastfeeding during treatment and for 7 days following. The primary outcome was change from baseline score at day 15 on the 17-item Hamilton Depression Rating Scale (HAM-D) although additional scales including the PHQ-9 and Edinburgh postpartum depression scale were also used. The HAM-D ranges from 0-52 points, with a reduction of 3-5 points generally accepted as a clinically meaningful improvement.
One hundred ninety-five patients (98%) were included in the analysis, with 175 (85%) completing the trial. At the end of the treatment (on day 15), the zuranolone group exhibited fewer depressive symptoms compared with control. The least squares mean difference in HAM-D scores from baseline was -15.6 points with zuranolone, compared with -11.6 points with placebo, with a mean difference between both groups of -4 points (95% CI -6.3 to -1.7 points) in favor of zuranolone. Similar results were obtained two weeks and one month later. The most common side effects with zuranolone were somnolence, dizziness, and sedation, and no increases in suicidal ideation were reported. Sixteen participants (16%) in the zuranolone group reduced their dose to 40 mg per day compared to one in the placebo group.
Given these results, zuranolone appears to be a worthwhile intervention for PPD. Still, there are limitations. The generalizability was limited as patients with the most severe symptoms (those with suicidality or psychotic features) were excluded. And although the trial was technically double-blinded, investigators and participants may have been able to determine group assignment due to side effects, which we know favors the intervention. While a difference of 4 points on the HAM-D scale is generally considered clinically important, the net benefit remains uncertain. While no provider is going to deny this treatment due to the risk to breastfeeding, if the magnitude of benefit is small, the net benefit is less clear. There are some strengths to the trial – the population studied was diverse, the antidepressive effects came on quickly, and the dropout rate was low. Looking ahead, it would be interesting to see how zuranolone impacts outcomes such as maternal-infant bonding, breastfeeding, childhood development, and suicide risk. Given the current evidence, zuranolone holds promise as a valuable intervention for mothers grappling with severe PPD.
For more information, see the topic Postpartum Depression in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Senior Associate Editor at DynaMed.