Slow-wave activity (SWA) during early non-rapid eye movement sleep is lower in people with treatment-resistant depression (TRD) than in healthy volunteers. Ketamine, but not placebo, increases SWA in TRD patients, especially those who respond to treatment, while having no effect on SWA in healthy volunteers. Ketamine also improves overall sleep in TRD patients by increasing total sleep time and sleep efficiency and reducing sleep latency. The increase in SWA after ketamine lessens with age. The findings suggest that ketamine's antidepressant effects are closely tied to its modulation of early sleep SWA and its ability to improve sleep architecture in TRD.
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.