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Original Research

Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study

Anna Feeney, MDa,b,*; Bettina B. Hoeppner, PhDb,c; Marlene P. Freeman, MDa,b,d; Martina Flynn, BAa; Dan V. Iosifescu, MDe,f; Madhukar H. Trivedi, MDg; Gerard Sanacora, MDh; Sanjay J. Mathew, MDi,j; Charles DeBattista, MDk; Dawn F. Ionescu, MDl; Cristina Cusin, MDb,c; George I. Papakostas, MDa,b; Manish K. Jha, MDg; and Maurizio Fava, MDa,b

Published: November 14, 2022


Objective: Ketamine is a novel and rapidly acting treatment for major depressive disorder (MDD). Benzodiazepines are commonly coprescribed with antidepressants in MDD. This study sought to examine data from a randomized clinical trial that compared a single infusion of intravenous (IV) ketamine to midazolam placebo in treatment-resistant depression (DSM-IV-TR MDD) and to assess whether the use of concomitant oral benzodiazepines differentially affected treatment response to ketamine versus midazolam.

Methods: This trial ran from December 2015 to December 2016. Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). A significant treatment-by-benzodiazepine effect could be interpreted as a possible moderator of differential treatment response to ketamine versus midazolam. Benzodiazepine use was examined as both a binary and a continuous predictor, to assess the impact of dosage.

Results: Benzodiazepine users did not differ from non-users on the original study’s primary outcome measure, score on the 6-item Hamilton Depression Rating Scale (HDRS-6), at baseline, but the former had more severe anxiety. When oral benzodiazepine use was modeled as a binary predictor, benzodiazepine use did not impact differential treatment response. However, when benzodiazepine dosage was considered, there was a significant impact of benzodiazepine use on differential treatment response. Oral benzodiazepines significantly impacted HDRS-6 (P = .018) and Clinical Global Impressions–Severity of Illness scale (CGI-S; P = .008) scores at day 1 (24 hours post treatment); effects were nonsignificant for all day 3 outcomes. Among ketamine subjects, higher doses of benzodiazepines were associated with less improvement in depression scores at day 1.

Conclusions: Concomitant oral benzodiazepines at higher doses may attenuate the antidepressant effects of IV ketamine at day 1 but not day 3 post-infusion.

Trial Registration: identifier: NCT01920555.

Volume: 84

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