APPROVED AND POTENTIAL TREATMENTS FOR PPD

SSRI antidepressants represent first-line treatment for perinatal depression during both pregnancy and postpartum. As with other major depressive episodes, about 50% of those treated with adequate doses for an adequate duration respond to treatment, with onset of response in 4-6 weeks, although higher doses may be needed later in pregnancy due to increased drug metabolism and volume of distribution. The first FDAapproved antidepressant for treatment of PPD is zuranolone, an oral neuroactive steroid (NAS) GABA-A receptor positive allosteric modulator (PAM), which is a synthetic allopregnanolone, demonstrated superiority of 50 mg/d dose vs. placebo x 14 days (timelimited treatment) with rapid onset and extended maintenance of effect in women with moderate to severe PPD. It may be used as an initial treatment in PPD for severe symptoms and/or suicide risk, or postpartum after failure of a monoamine antidepressant during pregnancy. Another potential treatment for PPD is RE104, the prodrug of 4-OH-DiPT, an analogue of psilosin, but with shorter (2-3 hour) duration of psychedelic effect. This serotonin receptor (5-HT2A) agonist may produce psychedelic effects, disrupt brain networks and reduce activity in the Default Mode Network, thus increasing connectivity. Positive topline results from the Reunion Neuroscience RECONNECT Phase 2 clinical trial evaluated a single 30 mg subcutaneous injection of RE104 vs active control arm using 1.5 mg dose, in adult female patients with moderate-to severe PPD. Primary endpoint was met with the 30mg dose demonstrating a statistically significant reduction from baseline on the MADRS total score of 23.0 points on Day 7, as compared to a reduction of 17.2 points in patients treated in the 1.5 mg active control arm (difference of 5.80; p=0.0094). Clinically meaningful reductions were observed for RE104 30mg on Day 1 following administration and maintained through Day 28. Safety and tolerability were reassuring. There is potential for drugs with new MOAs to expand therapeutic options in the treatment of PPD.

References

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of Postpartum Depression. Am J Psychiatry 2023;180(9):668-675. Clayton A, Hoffman MC, Hendricks P, et al. RE104: A Novel Serotonergic Psychedelic 4OH-DiPT Prodrug for the Treatment of Postpartum Depression. Presentation at the 64th Annual Meeting of the American College of Neuropsychopharmacology, January 12-15, 2026, Nassau, Bahamas