Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression.
Pharmaceuticals (Basel, Switzerland) November 7, 2023 Courtney M Vecera, Alan C Courtes, Gregory Jones et al.
Treatment-resistant depression (TRD) lacks a consensus definition, with studies requiring between 1 and 4 failed antidepressant therapies. An imbalance between the neurotransmitters L-glutamate and GABA is emerging as key in TRD. Among glutamatergic targets, NMDA receptor antagonism, particularly with ketamine and esketamine (Spravato), has shown robust responses. NMDA-glycine site modulators D-cycloserine and apimostinel show promising safety and efficacy. Dextromethorphan-bupropion (Auvelity) demonstrates positive results, especially in subpopulations with cognitive dysfunction. The most promising GABA modulators are synthetic neurosteroid analogs like brexanolone. Three compounds are FDA-approved: esketamine for TRD, Auvelity for MDD, and brexanolone for postpartum depression, though concerns exist with esketamine and brexanolone.