Do Benzodiazepines Attenuate the Antidepressant Effects of Ketamine?

Ketamine is an N–methyl-d-aspartate (NMDA) receptor antagonist and has emerged as a novel and rapidly acting treatment for major depressive disorder (MDD).  Although it  has not been approved as an antidepressant by the US Food and Drug Administration, intravenous (IV) ketamine is increasingly being used in individuals with treatment-resistant depression (TRD).  In this population, anxiety and insomnia are common, and benzodiazepines are frequently prescribed in conjunction with antidepressants.  Some studies have raised concerns about the concurrent use of benzodiazepines and ketamine, observing that benzodiazepines may attenuate or slow the antidepressant effects of ketamine.

In a study published in the Journal of Clinical Psychiatry, Anna Feeney, MD and colleagues from the Clinical Trials Network and Institute and the Department of Psychiatry at Mass General examined the impact of concurrent benzodiazepine use on treatment response in patients receiving IV ketamine.  This study analyzed data from a multisite, randomized, double-blind, placebo-controlled trial examining the efficacy of a single infusion of IV ketamine added to ongoing antidepressant treatment in adults with TRD.  Subjects who were taking oral benzodiazepines (n = 44) were compared to those who were not (n = 55). 

At baseline, benzodiazepine users did not differ from non-users in terms of depression severity, although benzodiazepine users did report more severe anxiety symptoms.  When oral benzodiazepine use was assessed as a binary predictor of response, benzodiazepine use did not impact treatment response. 

However, when benzodiazepine dosage was considered, the researchers observed that higher doses of benzodiazepines did affect treatment response.   On Day 1 (24 hours after ketamine infusion), individuals treated with higher doses of benzodiazepines (above the median diazepam equivalent dosage of 8 mg) experienced a smaller reduction in depressive symptoms compared to those using a lower dose of benzodiazepines and non-users, as measured using the 6-item Hamilton Depression Rating Scale and Clinical Global Impressions–Severity of Illness scale (CGI-S).  At Day 3, this difference was no longer significant.

Questions Remain

This study extends previous research by examining the impact of benzodiazepine dosage.  When benzodiazepine dosage was considered, individuals reporting concurrent use of higher doses of benzodiazepines had a less robust response to ketamine. This finding may suggest that oral benzodiazepines affect the antidepressant effects of ketamine; however, the effect is more evident early on and only with higher doses of  benzodiazepines. 

There are, however, alternative explanations for the findings.  At baseline, the participants using benzodiazepines had more severe anxiety, and in this group it is possible that higher doses of benzodiazepines were used in those participants with the most severe anxiety. Thus, the attenuated or delayed response with ketamine may reflect treatment response in individuals with more severe illness, rather than  benzodiazepines’ reducing the effects of ketamine. Future studies designed specifically to measure the effects of benzodiazepines on response to ketamine will help to clarify this question.

Feeney A, Hoeppner BB, Freeman MP, Flynn M, Iosifescu DV, Trivedi MH, Sanacora G, Mathew SJ, DeBattista C, Ionescu DF, Cusin C, Papakostas GI, Jha MK, Fava M. Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine: Findings From the RAPID Intravenous Ketamine Study. J Clin Psychiatry. 2022 Nov 14;84(1):22m14491.