The effects of ketamine and esketamine on functional outcomes in major depressive disorder and treatment-resistant depression: A systematic review

Introduction: Functional impairment is commonly reported amongst individuals with major depressive disorder (MDD) or treatment-resistant depression (TRD). Extant evidence suggests that ketamine and esketamine, N-methyl-D-aspartate (NMDA) receptor antagonists and glutamatergic modulators, have shown efficacy in treating MDD/TRD. While symptom reduction remains central to treatment, many individuals with TRD continue to experience work, social and family difficulties even when mood symptoms remit. Hence, this review synthesizes evidence on the effect of es/ketamine on functional outcomes, as measured by workplace productivity and psychosocial function.

Methods: A systematic search was conducted in PubMed, OVID (Embase) and PsychInfo through February 1, 2025. Eligible studies were randomized controlled trials (RCTs) or post hoc RCT analyses in adults (≥18 years) with MDD or TRD, examining ketamine (R- or S-enantiomer, intravenous) or intranasal esketamine. Comparators included placebo, standard care, antidepressants or other active agents. Primary outcomes were functional impairment, workplace performance and related domains.

Results: No controlled studies were identified for ketamine, emphasizing a considerable gap in literature. Nine studies investigated esketamine and functional impairment. Significant mean [sd] reduction in Sheehan Disability Scale (SDS) scores were observed with esketamine (-13.6, [8.31]) versus placebo (-9.4, [8.43]). Workplace productivity also significantly improved; notably, reduced productivity loss (p = 0.0045), presenteeism (p = 0.0098), and activity impairment (p = 0.0172) relative to controls.

Conclusion: Esketamine alleviates depressive symptoms and improves functioning, notably in workplace domains. Future studies should include functional outcomes as key secondary or co-primary outcomes, reflecting the ultimate goal of recovery in TRD/MDD.