Targeting of glutamate receptors is a novel approach for the treatment of major depressive disorder (MDD). This study aimed to review the usefulness for esketamine nasal spray for the management of treatment-resistant depression (TRD) using the tools of evidence-based medicine: number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Data sources were four completed Phase 3 randomized, double-blind, placebo-controlled, studies, including two pivotal registration studies of esketamine nasal spray in TRD in non-elderly adults (acute flexible-dose study NCT02418585, maintenance study NCT02493868) Efficacy outcomes included acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12; and other thresholds using the MADRS and Clinical Global Impressions-Severity [CGI-S] scales), categorical shifts in MADRS and CGI-S scores, and avoidance of relapse/recurrence (observed relapse rates). NNT, NNH and LLH are calculated for combination of esketamine nasal spray and oral antidepressant (esketamine+AD) vs AD+placebo in patients with TRD.

In the acute flexible-dose study of esketamine nasal spray (56-84 mg twice-weekly for 4 weeks), MADRS response with esketamine+AD vs AD+placebo at endpoint (rates 63.4% vs 49.5%, respectively) yielded an NNT value of 8, and MADRS remission at endpoint (48.2% vs 30.3%) resulted in a NNT vs AD+placebo of 6. NNH values vs AD+placebo were <10 for the adverse events (AE) of 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%), the NNH values were 5, 5, 6, 7, and 9, respectively. Discontinuation rates due to AE (7.0% vs 0.9%) yielded a NNH of 17. LHH comparing MADRS remission vs discontinuation was 17/6, or approximately 3. The pattern of results was similar for the other acute studies and for the pooled data combining all 3 acute studies. Maintenance use of esketamine (dose 56-84 mg once-weekly or once-every-other-week) plus an oral AD demonstrated NNT values <10 for relapse and/or maintenance of remission in favor of esketamine+AD vs AD+placebo, a NNT of 4 was observed for outcome of relapse in patients with stable response at the time of randomization (relapse rates were 25.8% vs 57.6%, respectively). In the maintenance study, discontinuation rates due to an AE (2.6% vs 2.1%) yielded a non-significant NNH value of 178.

The low NNT values <10 for efficacy outcomes suggest potential benefits of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times more likely to result in acute remission vs discontinuation due to an AE.

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