Pharmacotherapeutic approaches to treating postpartum depression: a focus on GABAA receptor positive allosteric modulators

Expert Opin Pharmacother. 2026 May 18. doi: 10.1080/14656566.2026.2675004. Online ahead of print.

ABSTRACT

INTRODUCTION: Postpartum depression (PPD) is a common psychiatric illness with significant consequences for both mother and infant. The approval of brexanolone in 2019 introduced a novel mechanism of antidepressant action targeting the gamma-aminobutyric acid type A receptor (GABA_AR) through neuroactive steroids (NASs), highlighting the role of GABAergic and stress-axis dysregulation in PPD.

AREAS COVERED: This review summarizes current understanding of NAS biology and GABA_AR modulation in the pathophysiology of PPD, including the GABAergic deficit hypothesis and the impact of peripartum hormonal fluctuations. We review clinical trial data supporting the efficacy, safety, and rapid onset of brexanolone and zuranolone, as well as their sustained antidepressant effects. In addition, we discuss emerging NAS-based therapeutics and preclinical models demonstrating the role of GABAergic plasticity and stress-axis regulation in PPD. Literature was identified through review of clinical, observational, and preclinical studies relevant to NAS signaling and GABAergic function.

EXPERT OPINION: Positive allosteric modulators of GABA_AR represent a novel and promising approach to the treatment of PPD, with rapid and sustained antidepressant effects. These agents may ultimately have broader applications across psychiatric disorders characterized by GABAergic dysfunction, although further research is needed to clarify their role and optimize their use.

PMID:42150157 | DOI:10.1080/14656566.2026.2675004