Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine
Anna Feeney, Bettina B. Hoeppner, Marlene P. Freeman, Martina Flynn, Dan V. Iosifescu, Madhukar H. Trivedi, Gerard Sanacora, Sanjay J. Mathew, Charles DeBattista, Dawn F. Ionescu, Cristina Cusin, George I. Papakostas, Manish K. Jha, Maurizio Fava
The Journal of Clinical Psychiatry November 14, 2022 DOI: 10.4088/jcp.22m14491 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 99 |
| Population | Adults with treatment-resistant major depressive disorder (DSM-IV-TR MDD) |
| Intervention | Midazolam |
| Duration | Single infusion, assessed at day 1 (24 hours) and day 3 post-infusion |
| Topics | Anxiety Depression Ketamine Esketamine |
| Keywords | Benzodiazepine Placebo Midazolam Clinical global impression Antidepressant Major depressive episode Anesthesia Concomitant |
| Citations | 9 |
| Registration | NCT01920555 |
| Key findings | Higher doses of concomitant oral benzodiazepines were associated with less improvement in depression scores at day 1 after a single infusion of intravenous ketamine, but not at day 3. |
Abstract
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: ClinicalTrials.gov identifier: NCT01920555.
Comparable studies
Other randomized controlled trials on ketamine for anxiety, most cited first.