Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials

Adjunctive esketamine nasal spray improves short- and long-term depressive outcomes (including rapid effects in suicidal ideation) with higher, manageable adverse events and no increase in on-treatment suicidal ideation.

Background

Major depressive disorder (MDD) and treatment-resistant depression (TRD) carry high morbidity, relapse risk, and suicide risk. Intranasal esketamine, an NMDA-receptor antagonist, is FDA/EMA-approved as an adjunct to oral antidepressants, but trial results have been inconsistent for short-term efficacy and limited for long-term outcomes. This meta-analysis sought to clarify esketamine’s rapid, short-term, and maintenance benefits and safety across MDD populations with and without suicidal ideation.

Patients

• Adults with MDD, including TRD, with or without active suicidal ideation.
• Short-term efficacy: 7 RCTs (4 TRD without suicidal ideation; 3 MDD with suicidal ideation); n ≈ 1,421 for Day 28 remission analysis.
• Long-term relapse prevention: 2 RCTs among patients achieving stable remission after induction.

Intervention

• Esketamine nasal spray (28 mg, 56 mg, or 84 mg) administered twice weekly during induction, adjunctive to an oral antidepressant.
• Maintenance esketamine in long-term relapse prevention among remitters.

Control

• Placebo nasal spray plus oral antidepressant for acute/short-term comparisons.
• Placebo or quetiapine XR for long-term relapse prevention.

Outcome

• Primary efficacy:
  • TRD without suicidal ideation: Change in MADRS from baseline to Day 28.
  • MDD with suicidal ideation: Change in MADRS from baseline to Day 2 (rapid effect).
• Long-term efficacy: Relapse among patients with stable remission after induction.
• Secondary efficacy: Day 28 remission and clinical response; change in SDS and PHQ-9 (TRD without suicidal ideation); Day 2 remission (suicidal ideation subgroup).
• Safety: Sedation (MOAA/S ≤3), discontinuation due to adverse events (AEs), suicidality during treatment, and common AEs (e.g., nausea, dissociation, dizziness, BP increase).

Study Design

Systematic review and meta-analysis of randomized controlled trials (9 RCTs total; 7 for short-term efficacy and safety; 2 for long-term relapse prevention), conducted per PRISMA; protocol registered (PROSPERO 2024: CRD42024578635). Risk of bias assessed with Cochrane ROB2. Certainty appraised with GRADE.

Level of Evidence

Level I (systematic review and meta-analysis of RCTs).

Follow up period

• Rapid outcome: Day 2 (suicidal ideation subgroup).
• Short-term induction: 4 weeks.
• Maintenance/relapse prevention: approximately 16–32 weeks post-remission (across included trials).

Results

Primary outcomes

• TRD without suicidal ideation (Day 28, MADRS): Esketamine superior to placebo (SMD −0.24; 95% CI −0.38 to −0.09).
• MDD with suicidal ideation (Day 2, MADRS): Esketamine superior to placebo (SMD −0.30; 95% CI −0.47 to −0.12).
• Long-term relapse among remitters: Lower relapse with esketamine vs placebo/quetiapine (RR 0.60; 95% CI 0.45–0.80).
  • NNT (benefit): ≈ 6 (based on pooled control risks in included trials).

Secondary outcomes

• Day 28 remission (whole population): Higher with esketamine (RR 1.36; 95% CI 1.18–1.57).
  • Approximate pooled risks suggest control ≈ 30% vs esketamine ≈ 40% (absolute increase ≈ 9.5%).
  • NNT (benefit): ≈ 11.
• Day 28 clinical response: Overall non-significant (RR 1.20; 95% CI 0.99–1.46), but significant in TRD without suicidal ideation (RR 1.31; 95% CI 1.12–1.54).
• Function and symptom scales (TRD, Day 28):
  • SDS improvement: SMD −0.44 (95% CI −0.60 to −0.29).
  • PHQ-9 improvement: SMD −0.33 (95% CI −0.49 to −0.17).
• Day 2 remission (suicidal ideation subgroup): Higher with esketamine (RR 1.87; 95% CI 1.11–3.15). NNT varies by baseline risk; pooled data suggest a clinically meaningful absolute benefit consistent with rapid symptom control.

Safety

• Sedation (MOAA/S ≤3 during treatment): More frequent with esketamine (RR 10.09; 95% CI 4.21–24.23).
• Study drug discontinuation due to AEs: Higher with esketamine (RR 2.20; 95% CI 1.27–3.80).
• Suicidal ideation during treatment: No difference (RR 0.83; 95% CI 0.55–1.24); similar in subgroups with and without baseline suicidal ideation.
• Common AEs increased with esketamine: Nausea, dissociation, dizziness/vertigo, dysgeusia, headache, postural dizziness, blurred vision, vomiting; somnolence (RR 1.81; 95% CI 1.36–2.39). BP increases and mental impairment were numerically higher but with imprecise estimates.

Limitations

• Limited data to compare efficacy across esketamine dose levels (28/56/84 mg).
• Small number of trials for some outcomes limits heterogeneity and publication bias assessments; publication bias detected for MOAA/S ≤3.
• Day 2 efficacy could not be synthesized for the entire non-suicidal population due to reporting constraints.
• Some included trials had “some concerns” risk of bias; most had low risk. Certainty generally moderate-to-high by GRADE.

Funding

• Natural Science Foundation of Liaoning Province (No. 2021-MS-157)
• Basic Scientific Research Project of Liaoning Provincial Department of Education (No. LJKMZ20221159)
• Natural Science Foundation of Liaoning Province, China (No. 2023-MS-178)

Citation

Wang Z, Jiang L, Ma W, Li X, Gao Q, Lian S, Yu W. Esketamine Nasal Spray in Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials. Clinical Pharmacology & Therapeutics. 2025;117(6):1637–1649. doi:10.1002/cpt.3555.