Appraising esketamine nasal spray for the management of treatment-resistant depression in adults: Number needed to treat, number needed to harm, and likelihood to be helped or harmed

J Affect Disord. 2020 Jun 15:271:228-238. doi: 10.1016/j.jad.2020.03.106. Epub 2020 Apr 3.


Introduction: This post hoc study assessed the evidence-base for esketamine nasal spray for management of treatment-resistant depression (TRD) using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Methods: Data sources were four phase III randomized, double-blind studies including two positive studies (acute flexible-dose; maintenance) in patients with TRD. Key efficacy study outcomes: acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12). NNT, NNH were calculated for esketamine nasal spray+newly initiated oral antidepressant (esketamine+AD) vs. placebo+AD.

Results: In the pivotal acute flexible-dose study, MADRS response (63.4% vs. 49.5%) and remission (48.2% vs. 30.3%) at 4 weeks resulted in NNT of 8 and 6 for esketamine+AD vs. placebo+AD. NNH values <10 included dissociation (26.1% vs. 3.7%), vertigo (26.1% vs. 2.8%), nausea (26.1% vs. 6.4%), dizziness (20.9% vs. 4.6%), and dysgeusia (24.3% vs. 11.9%). Discontinuation rates due to adverse events (AE) (7.0% vs. 0.9%) yielded NNH=17. LHH comparing MADRS remission vs. discontinuation due to AE was 17 vs. 6. Maintenance use of esketamine+AD demonstrated NNT values<10 for relapse and/or maintenance of remission. In maintenance study, discontinuation due to AE (2.6% vs. 2.1%) yielded NNH=178 (non-significant).

Limitations: Only dichotomous outcomes were included.

Conclusion: NNT<10 for efficacy outcomes suggests potential benefit of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times likely to result in acute remission vs. discontinuations due to AE.

Keywords: Esketamine nasal spray; Number needed to harm (NNH); Number needed to treat (NNT); Treatment-resistant depression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Depression
  • Humans
  • Ketamine* / adverse effects
  • Nasal Sprays*
  • Treatment Outcome


  • Nasal Sprays
  • Esketamine
  • Ketamine