pathophysiology of PPD (postpartum depression) is likely to be multifactorial (1)
evidence supports a role for disruption of perinatal gamma-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
Zuranolone is an NAS GABAAR PAM with a similar mechanism of action and a pharmacokinetic profile suitable for once-daily oral dosing (1)
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
Deligiannidis et al showed that
zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD
Clayton et al stated that
completed studies in the zuranolone clinical trial program, patients receiving zuranolone consistently experienced improvement in depressive symptoms following a 2-week treatment course
treatment with zuranolone was generally well tolerated with a consistent safety and tolerability profile
Reference:
(1) Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, Sankoh AJ, Silber C, Campbell AD, Werneburg B, Kanes SJ, Lasser R. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2021 Sep 1;78(9):951-959. doi: 10.1001/jamapsychiatry.2021.1559. Erratum in: JAMA Psychiatry. 2022 Jul 1;79(7):740. Erratum in: JAMA Psychiatry. 2023 Feb 1;80(2):191. PMID: 34190962; PMCID: PMC8246337.
Clayton A, Cutler AJ, Deligiannidis KM, Lasser R, Sankoh AJ, Doherty J, Kotecha M. Clinical Efficacy of a 2-Week Treatment Course of Zuranolone for the Treatment of Major Depressive Disorder and Postpartum Depression: Outcomes From the Clinical Development Program. Eur Psychiatry. 2022 Sep 1;65(Suppl 1):S97-8. doi: 10.1192/j.eurpsy.2022.282. PMCID: PMC9567193
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