Rapid-acting NMDA and GABAergic Modulators in Mood Disorders: From Synaptic Mechanisms to Clinical Practice

Depression is increasingly conceptualized as a disorder of impaired synaptic plasticity and excitation-inhibition imbalance within corticolimbic circuits. Two rapid-acting therapeutic classes, NMDA receptor modulators (ketamine, esketamine) and neuroactive-steroid GABA-A positive allosteric modulators (brexanolone, zuranolone), offer complementary approaches to restore circuit function. Clinically, intravenous ketamine and intranasal esketamine show superiority over placebo and active comparators in treatment-resistant depression (TRD), with esketamine supported for continuation-phase relapse prevention and, in the United States, is approved both as adjunctive therapy and as monotherapy in adults with TRD. Evidence of efficacy extends to bipolar depression with careful mood-stabilizer coverage. Both agents reduce suicidal ideation within hours to days, although effects on suicidal behavior have not been demonstrated. Safety profiles include dissociation and hemodynamic changes; concerns with prolonged or high-cumulative exposure include cystitis and misuse liability. Neurosteroid GABA-A modulators are effective in post partum depression with some preliminary evidence in major depression, particularly in combination with antidepressants, while adverse events are mainly dose-dependent sedation. Brexanolone requires monitored infusion, whereas zuranolone enables a 14-day outpatient course. Patient selection should integrate diagnosis, comorbidity, concomitant medications (e.g. benzodiazepines), logistics, and perinatal goals. Robust efficacy/tolerability predictors remain limited, though early symptomatic change is clinically informative. In conclusion, NMDA receptor modulators and neuroactive-steroid GABA-A positive allosteric modulators have improved the treatment for mood disorders and accelerated a transition to mechanism-driven care.