Treatment Response of Add-On Esketamine Nasal Spray in Resistant Major Depression in Relation to Add-On Second-Generation Antipsychotic Treatment

Abstract

In this meta-analysis, we aimed to estimate and compare the efficacy of add-on treatment of antidepressants with esketamine nasal spray and second-generation antipsychotics in patients with nonpsychotic major depressive disorder and inadequate response to antidepressants. Searching for acute-phase, double-blind, placebo-controlled, randomized trials, we found 22 second-generation antipsychotic (n = 8363) and 3 intranasal esketamine (n = 641) studies. Mean change in the Montgomery Åsberg Depression Rating Scale total score served as outcome. We determined a higher mean difference (vs placebo) for the pooled esketamine nasal spray trials (mean difference = 4.09, 95% confidence interval: 2.01 to 6.17) than for the pooled second-generation antipsychotic augmentation trials (mean difference = 2.05, 95% confidence interval: 1.51 to 2.59). Thus, the effect size for intranasal esketamine was nearly twice as high as those for the second-generation antipsychotics. This indicates high efficacy of add-on esketamine nasal spray in treatment-resistant major depressive disorder compared with other well-established, evidence-based pharmacological options such as augmentation with second-generation antipsychotics.

Keywords: add-on treatment; esketamine nasal spray; major depressive disorder; second-generation antipsychotics; treatment resistance.

Figure 1.

Effect sizes (mean differences) for the outcome mean change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to study endpoint. Comparison: pooled esketamine nasal spray group vs placebo nasal spray group and pooled second-generation antipsychotic (SGA) group vs placebo group. Data synthesis: random-effects model. The forest plot illustrates the mean differences with the associated 95% confidence intervals (CIs). Numerical values greater than 0 indicate a larger MADRS total score reduction in the esketamine/SGA group than in the placebo group. Statistical significance can be assumed if the 95% CI does not comprise the numerical value of 0, and/or if the P-value of the comparison is <.05.

Figure 2.

Effect sizes (mean differences) for the outcome mean change in Montgomery Åsberg Depression Rating Scale (MADRS) total score from baseline to study endpoint. Comparison: esketamine nasal spray vs placebo nasal spray and second-generation antipsychotic (SGA) vs placebo. Data synthesis: random-effects model. The forest plot illustrates the mean differences with the associated 95% confidence intervals (CIs). Numerical values greater than 0 indicate a larger MADRS total score reduction in the esketamine/SGA group than in the placebo group. Statistical significance can be assumed if the 95% CI does not comprise the numerical value of 0.