Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis - Report - MDSpire

Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis

  • By

  • Jingqiang Xie

  • Chunying Pu

  • Mingyue Sun

  • July 3, 2026

  • 0 min

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Clinical Report: Combination of Intranasal Esketamine and Oral Antidepressant for TRD

Overview

This systematic review and meta-analysis evaluated the efficacy and safety of intranasal esketamine combined with oral antidepressants for treatment-resistant depression (TRD). The findings indicate that this combination is associated with increased adverse events during acute treatment.

Background

Treatment-resistant depression (TRD) poses significant challenges in clinical practice, affecting a substantial proportion of patients with major depressive disorder (MDD). Current treatment options often yield inadequate responses.

Data Highlights

OutcomeEffect95% CI
Symptom Reduction (MADRS)MD -2.99-5.10 to -0.89
Response RateRR 1.441.20–1.74
Remission RateRR 1.521.20–1.92
Functioning Improvement (SDS)MD -1.70-2.61 to -0.79
Relapse Risk (Maintenance)HR 0.510.42–0.62
Any TEAE (Acute)RR 1.371.25–1.50

Key Findings

  • Intranasal esketamine plus oral antidepressant showed greater symptom reduction at day 28 compared to placebo.
  • Rapid improvement in depressive symptoms was observed as early as day 2.
  • Esketamine increased response and remission rates significantly compared to placebo.
  • Continued use of esketamine during maintenance reduced the risk of relapse.
  • Increased rates of treatment-emergent adverse events were noted during acute induction.
  • Notable increases in dissociation and blood pressure events were reported with esketamine use.

Clinical Implications

Clinicians should be aware of the potential for increased adverse events and consider supervised administration.

Conclusion

Intranasal esketamine combined with oral antidepressants requires careful monitoring for adverse effects.

Related Resources & Content

  1. JAMA Network Open, 2023 -- Oral Ketamine for Treatment-Resistant Depression—Not Yet Time?
  2. Frontiers in Psychiatry, 2023 -- Case Report: Intranasal esketamine and accelerated intermittent theta-burst stimulation for severe treatment-resistant depression with suicidal ideation
  3. Drugs - Real World Outcomes, 2024 -- Healthcare Utilization, Cost Implications, and Treatment Approaches for Patients with Treatment-Resistant Depression Undergoing Esketamine Induction in the United States
  4. SPRAVATO (esketamine) nasal spray, CIII -- Highlights of Prescribing Information
  5. Frontiers in Psychiatry — Rapid reduction of suicidal ideation with transient dissociative and “drunken gait” symptoms after intranasal esketamine, with music intervention: a case report
  6. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression
  7. Long-term safety and maintenance of response with esketamine nasal spray in participants with treatment-resistant depression: interim results of the SUSTAIN-3 study
  8. Intranasal esketamine for patients with major depressive disorder: A systematic review and meta-analysis
  9. SPRAVATO (esketamine) nasal spray, CIII — Highlights of Prescribing Information

Original Source(s)

Intranasal esketamine plus oral antidepressant for treatment-resistant depression: acute induction and maintenance relapse-prevention outcomes in a systematic review and meta-analysis

  • by Jingqiang Xie, Chunying Pu, Mingyue Sun

  • July 3, 2026

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