The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication

Abstract

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD− (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.

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

“…(ie, taken between day −2 and day 2) did not augment or diminish the rapid, robust antidepressant effect observed after the first dose of esketamine in these patients (primary efficacy endpoint), which is specifically relevant in the setting of psychiatric emergencies. The findings from the ASPIRE studies do not support prior studies in which benzodiazepines were shown to attenuate the acute antidepressant effect of ketamine (Ford et al 17 [case study, n=1]; Frye et al 18 [post-hoc analysis, n=10]; Albott et al 19 [post-hoc analysis, n=14]; Andrashko et al 29 [n=47, excluded patients with suicidal risk assessed by clinical examination]). The disparity may be explained, at least in part, by the small sample size and uncontrolled methods of the ketamine studies and, perhaps, that the ketamine studies included patients who had TRD but were not in acute crisis.…”

“…In a post-hoc analysis of 10 patients with TRD given ketamine infusions twice weekly for up to 2 weeks, Frye et al 18 reported that non-responders received significantly higher mean daily doses of benzodiazepines than responders (≥50% decrease from baseline MADRS total score). Likewise, in a study of 47 patients with MDD and without suicidal risk who received a single ketamine infusion as an add-on to ongoing antidepressant treatment, Andrashko et al 29 reported a significantly lower response rate among those taking high-dose benzodiazepines (defined as >8 mg diazepam equivalent, n=13). And, in a post hoc analysis of 13 patients with TRD who received a ketamine infusion 3 times weekly for 2 weeks, Albott et al 19 reported no significant differences between benzodiazepine and non-benzodiazepine users in response or remission rates, or depression relapse rate over 4-week follow-up, but those taking benzodiazepine took significantly longer time to reach these outcomes and experienced significantly shorter therapeutic effect.…”

Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action

“…These findings were supported by reports of prolonged time to remission and shortened time to relapse in 13 patients with MDD receiving BZD compared to patients not concurrently receiving BZDs. 33 A recently published study 34 analyzing data from 2 previously conducted randomized, controlled trials reported that concurrent BZD use was a predictor of nonresponse in 47 patients with MDD to ketamine in a dose-dependent manner. Responders were receiving significantly lower doses of BZDs (7.7 ± 4.5 mg vs 32.1 ± 24.9 mg, diazepam equivalents) when compared to nonresponders.…”

“…As ketamine use increases, it is important to identify clinically significant pharmacodynamic drug-drug interactions. BZDs have been reported [31][32][33][34] to attenuate the effect of ketamine in MDD. While not all studies have reported evidence of this interaction, 35 given the persistence of this effect in the setting of heterogeneous data and proposed mechanism of ketamine in MDD, it seems likely that BZDs pose a pharmacodynamic interaction in a dose-dependent manner.…”

“…Responders were receiving significantly lower doses of BZDs (7.7 6 4.5 mg vs 32.1 6 24.9 mg, diazepam equivalents) when compared to nonresponders. 34 Interestingly, all of these reports [31][32][33][34] describe attenuation of both acute and sustained effects of ketamine in MDD. While a recent study 35 did not replicate these findings, BZD doses were not reported.…”