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

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-ofcare (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.

Neurological Adverse Events Associated With Esketamine: A Disproportionality Analysis for Signal Detection Leveraging the FDA Adverse Event Reporting System

“…However, the concomitant use of benzodiazepines increased the risk of developing severe neurological AEs (χ2 = 4.10, p = 0.043). This finding is consistent with those of previous studies, which suggested that concomitant esketamine use with central nervous system depressants (e.g., benzodiazepines, opioids, alcohol) may worsen sedation (U.S. Food and Drug Administration, 2019; Diekamp et al, 2021). Given the frequent need for coprescriptions of hypnotics with esketamine, we recommend that non-benzodiazepines (e.g., zolpidem, zopiclone, zaleplon and eszopiclone) should be administered to mitigate the risk of severe neurological events.…”

The Patient’s Perspective on the Effects of Intranasal Esketamine in Treatment-Resistant Depression

“…Additionally, the use of benzodiazepine compounds (as for almost half of the sample in this study) has been recently listed among predictors of delayed response to ESK-NS, arguing that the former could slow esketamine action due to the contrasting effects on the glutamatergic system [2]. However, no significant interactions or negative impact on the effectiveness of ESK-NS had been previously reported for the concomitant assumption of sedative-hypnotics/anxiolytics [41], and growing evidence shows ketamine and esketamine's anxiolytic effects in both unipolar and bipolar TRD, with a positive impact of anxious symptoms on response to ESK-NS [2]. Here, we detected significant levels of anxiety at baseline and their rapid improvement seems in line with most recent findings.…”

Influence of β‐catenin signaling on neurogenesis in neuropsychiatric disorders: Anxiety and depression

“…Concurrent BDZ treatment at higher doses with ketamine may dampen ketamine's antidepressant effect (Choi & Kim, 2018). BDZs exhibit a minimal effect on ketamine's rapid antidepressant effect; however, sedation was prevalent (Diekamp et al, 2021). Older Asian adults who combined BDZs with antidepressants like SSRIs and tricyclic antidepressants suffered from BDZ side effects (Zhong et al, 2019).…”