Zuranolone

Zuranolone

• 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