Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials

Bettina Diekamp; Stephane Borentain; Dong-Jing Fu; Robert Murray; Kristin Heerlein; Qiaoyi Zhang; Cornelius Schüle; Maju Mathews

doi:10.2147/NDT.S314874

Effect of Concomitant Benzodiazepine Use on Efficacy and Safety of Esketamine Nasal Spray in Patients with Major Depressive Disorder and Acute Suicidal Ideation or Behavior: Pooled Randomized, Controlled Trials

Neuropsychiatr Dis Treat. 2021 Jul 15:17:2347-2357. doi: 10.2147/NDT.S314874. eCollection 2021.

Authors

Bettina Diekamp¹, Stephane Borentain², Dong-Jing Fu³, Robert Murray⁴, Kristin Heerlein¹, Qiaoyi Zhang⁵, Cornelius Schüle⁶, Maju Mathews²

Affiliations

¹ Department of Medical and Scientific Affairs, Janssen-Cilag GmbH, Neuss, Germany.
² Department of Global Medical Affairs, Janssen Research & Development LLC, Titusville, NJ, USA.
³ Department of Neuroscience Clinical Development, Janssen Research & Development LLC, Titusville, NJ, USA.
⁴ Neuroscience Clinical Biostatistics, Janssen Research & Development LLC, Titusville, NJ, USA.
⁵ Global Market Access, Neuroscience, Janssen Global Services, LLC, Titusville, NJ, USA.
⁶ Ludwig-Maximilians-University Munich, Clinic for Psychiatry and Psychotherapy, Munich, Germany.

Abstract

Purpose: The impact of benzodiazepines on the efficacy and safety of esketamine as a rapid-acting antidepressant remains unclear.

Materials and methods: Data from two identically designed, randomized double-blind studies were pooled and analyzed on a post-hoc basis. In both studies, adults with major depressive disorder with acute suicidal ideation or behavior were randomized to placebo or esketamine 84 mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly initiated or optimized oral antidepressant[s]). Efficacy and safety were analyzed in two groups based on whether patients used concomitant benzodiazepines, which were prohibited within 8 hours before and 4 hours after the first dose of esketamine and within 8 hours of the primary efficacy assessment at 24 hours. The primary efficacy endpoint - change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score - was analyzed using ANCOVA.

Results: Most patients (309/451, 68.5%) used concomitant benzodiazepines. Greater decrease in MADRS total score was observed with esketamine (mean [SD]: -16.1 [11.73]) versus placebo (-12.6 [10.56]) at 24 hours (least-squares mean difference: -3.7, 95% CI: -5.76, -1.59). The differences between the esketamine and placebo groups were clinically meaningful, irrespective of benzodiazepine use (benzodiazepine: -4.3 [-6.63, -1.89]; no benzodiazepine: -3.1 [-6.62, 0.45]). Among patients taking esketamine, change in MADRS total score was not significantly different between patients taking benzodiazepines (-15.8 [11.27]) versus those not taking benzodiazepines (-16.8 [12.82]) (least-squares mean difference: 1.1, [-2.24, 4.45]). Among esketamine-treated patients, the incidence of sedation was higher with benzodiazepine use, whereas dissociation was similar.

Conclusion: Benzodiazepines do not meaningfully affect the rapid-acting antidepressant effect of esketamine at 24 hours post-first dose among patients with MDD and acute suicidal ideation or behavior.

Keywords: benzodiazepine; depression; esketamine; rapid-acting; suicidal ideation.

Grants and funding

The ASPIRE I and ASPIRE II studies were funded by Janssen Research & Development, LLC, Titusville, NJ, USA. Employees of the Sponsor, as noted in Author Contributions, were involved in data analysis or interpretation and/or other aspects pertinent to the studies. Authors had full access to all of the data in the study, were involved in writing and/or revising the manuscript, and had final responsibility for the decision to submit for publication.