A randomized, outpatient trial involving women aged 18 to 45 years, no more than six months postpartum, with postpartum depression and a baseline HAMD-17 score of 26 or higher. Participants were then randomized to either placebo or zuranolone [a neuroactive steroid (NAS) GABAA receptor (GABAAR)–positive allosteric modulator (PAM)] administered orally each evening for two weeks (76 and 77 participants, respectively). From day 3 through day 45, the researchers observed sustained differences in HAMD-17 scores that favoured zuranolon and noted sustained differences at day 15 that favored zuranolone in HAMD-17 response on the basis of HAMD-17 score remission, as well as change from baseline for Montgomery-Åsberg Depression Rating Scale score and Hamilton Rating Scale for Anxiety score. Investigators concluded that for women with postpartum depression, zuranolone improves symptoms of depression.
The pathophysiology of postpartum depression (PPD)
The pathophysiology of PPD is likely multifactorial, with evidence supporting a role for disruption of perinatal γ-aminobutyric acid (GABA) signaling, the major inhibitory signaling pathway of the central nervous system. One potential factor affecting GABAergic signaling and PPD development are dramatic perinatal changes in circulating levels of allopregnanolone, a neuroactive steroid (NAS) GABAA receptor (GABAAR)–positive allosteric modulator (PAM).In brain regions associated with emotion and self-perception, neural network connectivity, supported by GABAergic signaling, is positively correlated with plasma allopregnanolone concentrations in individuals with PPD vs healthy postpartum female individuals.The role of GABAergic signaling is further supported by animal model studies demonstrating PPD-like behaviors in mice lacking the extrasynaptic GABAAR δ subunit or potassium/chloride cotransporter KCC2, and these PPD models also functionally link GABA with the hypothalamic-pituitary axis, a stress pathway implicated in PPD.Administration of a preclinical NAS GABAAR PAM that targets both synaptic and extrasynaptic receptors (SAGE-516; Sage Therapeutics, Inc) in late pregnancy reduced PPD-like behaviors in these mouse models, supporting the development of NAS GABAAR PAMs in PPD treatment.
Clinical research in the treatment of PPD supports a role for NAS GABAAR PAMs. Brexanolone injection, a NAS GABAAR PAM, demonstrated reductions in depressive symptoms in 3 double-blind, randomized, placebo-controlled trials and was approved by the US Food and Drug Administration for treatment of adults with PPD.Zuranolone (SAGE-217; Sage Therapeutics, Inc) is an investigational NAS GABAAR PAM with a similar mechanism of action and a pharmacokinetic profile suitable for once-daily oral dosing.NAS GABAAR PAMs have pharmacological profiles and binding sites distinct from benzodiazepines,with the ability to modulate the activity of both synaptic and extrasynaptic GABAARs.Therefore, we performed a phase 3, double-blind, randomized, placebo-controlled clinical trial comparing the efficacy and safety of zuranolone vs placebo in the outpatient treatment of adult women with PPD.
See the article
Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2021;78(9):951–959. doi:10.1001/jamapsychiatry.2021.1559.