The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication
Veronika Andrashko, Tomáš Novák, Martin Brunovský, Monika Klírová, Peter Šóš, Jiřı́ Horáček
Frontiers in Psychiatry August 28, 2020 DOI: 10.3389/fpsyt.2020.00844 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Post-hoc analysis of data from two previous studies Peer reviewed |
|---|---|
| Sample size | 47 |
| Population | Patients with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) |
| Interventions | Ketamine Benzodiazepines |
| Dose | 0.54 mg per kg (ketamine); >8 mg diazepam equivalent (benzodiazepine threshold) |
| Duration | One week |
| Measures | MADRS |
| Topics | Anxiety Depression Ketamine Esketamine |
| Keywords | Antidepressant Benzodiazepine Concomitant Diazepam Depression economics Anesthesia Pharmacology Electroconvulsive therapy studies |
| Citations | 46 |
| Key points | Concomitant benzodiazepine treatment at doses greater than 8 mg diazepam equivalent was associated with a significantly worse antidepressant response to ketamine on days 3 and 7. |
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.