REVIEW OF: Deligiannidis KM et al, JAMA Psychiatry 2021;78(9):951–959

STUDY TYPE: Randomized controlled trial

DSM-5 defines postpartum depression (PPD) as any major depressive episode that begins during pregnancy or within four weeks after giving birth. Traditional antidepressants have long been used during this period, but only small studies supporting their efficacy exist and none have received FDA approval for this use. Brexanolone (Zulresso) is a neuroactive steroid that was approved by the FDA for PPD in 2019. However, this steroid requires 60 hours of continuous intravenous infusion as well as around-the-clock monitoring due to concerns for potential serious adverse effects such as loss of consciousness.

Zuranolone is an investigational medicine that is structurally similar to brexanolone but can be given orally. Both drugs work on the gabaergic system in a way that is distinct from benzodiazepines, and both are structural analogs of allopregnanolone (just as levothyroxine is a synthetic analog of the naturally occurring hormone thyroxine). This was a Phase 3 study testing the safety and efficacy of zuranolone for PPD.

In this trial, 151 women who developed new-onset depression either during their third trimester of pregnancy or within four weeks after giving birth were enrolled. Patients were randomized to receive either zuranolone 30 mg or placebo over the course of two weeks. The primary outcome measure was improvement on the Hamilton Depression Rating Scale, and assessments were made on days three, six, nine, 15, and 45.

On day 15, which was the primary date of interest, depression scores were significantly lower in the zuranolone cohort compared to placebo (-17.8 points vs -13.6 points; p = 0.003; effect size 0.53). Statistically significant effects were apparent as early as day three and were maintained through day 45, which was a full four weeks after treatment had been completed. Significant improvements were also seen in anxiety and global functioning, as well as maternal functioning. Zuranolone was well tolerated with the most common side effects being somnolence (15%), headaches (9%), and dizziness (8%), although none of these rates differed much from placebo.

The major limitation of this study is that breastfeeding women were not included, so zuranolone cannot yet be recommended for these patients. Furthermore, it remains to be seen whether the benefits of zuranolone are sustained beyond four weeks post-treatment.

TCPR’S TAKE
Zuranolone appears to be a safe and effective option for PPD. Encouragingly, its benefits appear to occur rapidly, and a two-week course of treatment may be all that is needed. The manufacturer plans to file for FDA approval in 2022. If it comes to market, it will offer a much more pragmatic option than brexanolone.