Neuropsychiatric Disease and Treatment (Jul 2021)
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
Abstract
Bettina Diekamp,1 Stephane Borentain,2 Dong-Jing Fu,3 Robert Murray,4 Kristin Heerlein,1 Qiaoyi Zhang,5 Cornelius Schüle,6 Maju Mathews2 1Department of Medical and Scientific Affairs, Janssen-Cilag GmbH, Neuss, Germany; 2Department of Global Medical Affairs, Janssen Research & Development LLC, Titusville, NJ, USA; 3Department of Neuroscience Clinical Development, Janssen Research & Development LLC, Titusville, NJ, USA; 4Neuroscience Clinical Biostatistics, Janssen Research & Development LLC, Titusville, NJ, USA; 5Global Market Access, Neuroscience, Janssen Global Services, LLC, Titusville, NJ, USA; 6Ludwig-Maximilians-University Munich, Clinic for Psychiatry and Psychotherapy, Munich, GermanyCorrespondence: Bettina DiekampDepartment of Medical and Scientific Affairs, Janssen-Cilag GmbH, Johnson & Johnson Platz 1, Neuss, 41470, GermanyTel +49-21379556179Email [email protected]: 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: esketamine, benzodiazepine, depression, suicidal ideation, rapid-acting
