Objective:

To evaluate the efficacy and safety of intranasal esketamine combined with an oral antidepressant in patients with treatment-resistant depression (TRD).

Approach:

• Study Selection: Included randomized controlled trials comparing intranasal esketamine plus an oral antidepressant versus placebo nasal spray plus the same oral antidepressant in TRD.
• Data Extraction: Two reviewers independently screened studies, extracted data, and assessed risk of bias using RoB 2.0.
• Outcome Assessment: Depression outcomes assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) and functional outcomes using the Sheehan Disability Scale (SDS).
• Statistical Analysis: Used random-effects models to pool mean differences for continuous outcomes, risk ratios for binary outcomes, and hazard ratios for relapse prevention.

Key Findings:

• Esketamine showed greater symptom reduction at day 28 (MADRS MD −2.99, 95% CI −5.10 to −0.89).
• Rapid improvement was evident by day 2 (MD −3.25, 95% CI −4.65 to −1.85).
• Esketamine increased day-28 response (RR 1.44, 95% CI 1.20–1.74) and remission (RR 1.52, 95% CI 1.20–1.92).
• Functioning improved (SDS MD −1.70, 95% CI −2.61 to −0.79).
• Esketamine reduced relapse risk during maintenance (HR 0.51, 95% CI 0.42–0.62).
• Increased treatment-emergent adverse events (TEAE) with esketamine (RR 1.37, 95% CI 1.25–1.50) and discontinuation due to adverse events (RR 2.68, 95% CI 1.35–5.29).

Interpretation:

Intranasal esketamine plus an oral antidepressant provides rapid, modest acute improvement and reduces relapse risk during maintenance among stabilized responders/remitters, but increases acute adverse events.

Limitations:

• Heterogeneity in TRD definitions and treatment pathways.
• Potential for functional unblinding in trial designs.

Conclusion:

Intranasal esketamine should be used within supervised care.