Peripartum Depression Pharmacotherapies Targeting GABA–Glutamate Neurotransmission

Peripartum depression (PPD) represents a significant public health concern, affecting 10–17% of women globally. Traditional monoaminergic treatments demonstrate limited efficacy and delayed onset of action. The glutamate–GABA imbalance hypothesis provides a novel theoretical framework for understanding depression pathophysiology and developing targeted therapeutic interventions. This review examines emerging pharmacotherapeutic approaches targeting glutamatergic and GABAergic neurotransmitter systems for PPD treatment. Search criteria targeted randomized clinical trials investigating GABA-A-positive allosteric modulators (brexanolone, zuranolone, and ganaxolone) and NMDA receptor antagonists (ketamine and esketamine) in PPD patients. Brexanolone was the first neurosteroid to receive FDA approval for PPD, while zuranolone also shows promise. Ketamine and esketamine are also associated with reduced PPD risk, particularly with perioperative administration during cesarean delivery, though benefits are predominantly short-term. These glutamate–GABA pathway modulators represent novel therapeutic alternatives with rapid onset profiles. Further investigation and research are needed to optimize dosing protocols and patient selection criteria and to establish long-term efficacy before PPD treatment guidelines can be drafted.