TY - JOUR
T1 - Effect of Concomitant Benzodiazepines on the Antidepressant Effects of Ketamine
T2 - Findings From the RAPID Intravenous Ketamine Study
AU - Feeney, Anna
AU - Hoeppner, Bettina B.
AU - Freeman, Marlene P.
AU - Flynn, Martina
AU - Iosifescu, Dan V.
AU - Trivedi, Madhukar H.
AU - Sanacora, Gerard
AU - Mathew, Sanjay J.
AU - DeBattista, Charles
AU - Ionescu, Dawn F.
AU - Cusin, Cristina
AU - Papakostas, George I.
AU - Jha, Manish K.
AU - Fava, Maurizio
N1 - Funding Information:
International, Bristol-Myers Squibb, Cowen, EMA Wellness, Engrail Therapeutics, Clexio, Denovo Biopharma, Gilgamesh, Hoffman–La Roche, IntraCellular Therapies, Janssen, Levo, Lundbeck, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, Vistagen Therapeutics, and XW Laboratories, and he received research contracts from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Naurex, and Usona over the past 36 months. Dr Sanacora holds equity in BioHaven Pharmaceuticals and is a co-inventor on a US patent (#8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application No. 047162-7177P1 (00754) filed on August 20, 2018, by Yale University Office of Cooperative Research. Yale University has a financial relationship with Janssen Pharmaceuticals and may in the future receive financial benefits from this relationship. The University has put multiple measures in place to mitigate this institutional conflict of interest. Questions about the details of these measures should be directed to Yale University’s Conflict of Interest office. Dr Mathew is supported through the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, Texas, and receives support from The Menninger Clinic. Dr Mathew has served as a consultant to Alkermes, Allergan, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Neurocrine, Perception Neuroscience, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, and Signant Health. He has received research support from Biohaven Pharmaceuticals, Merck, Sage Therapeutics, and VistaGen Therapeutics. Dr DeBattista: Grant support: Biolite, Compass, Sage, Relmada, and Janssen. Consultant: Corcept Therapeutics, Sage, Alkermes, Therapeutics; she has been involved in research studies sponsored by Livanova, Atai, Otsuka and Clexio Biosciences; and she has received research funding from NIMH, National Institutes of Health– National Institute of Neurological Disorders and Stroke (NIH-NINDS), as well as the American Foundation for Suicide Prevention. Dr Papakostas: Consulting: Orexo US, Alfasigma USA, Eleusis Health Solutions Limited, Merck, Praxis Precision Medicines, Otsuka, and Boehringer Ingelheim. Honoraria: Otsuka, Boehringer Ingelheim, and Lundbeck. Research support: Johnson & Johnson. Dr Jha has received contract research grants from Acadia Pharmaceuticals and Janssen Research & Development; educational grant to serve as Section Editor of the Psychiatry & Behavioral Health Learning Network; consultant fees from Eleusis Therapeutics US, Janssen Global Services, and Guidepoint Global; and honoraria from North American Center for Continuing Medical Education and Global Medical Education (now a Clinical Care Options company). Dr Fava: All disclosures can also be viewed online at https:// mghcme.org/app/uploads/2022/04/MF-Disclosures-Lifetime-updated-April-2022.pdf. Research support: Abbott Laboratories, Acadia
Funding Information:
income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of ketamine plus scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven; patents for pharmacogenomics of depression treatment with folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolters Kluwer; and World Scientific Publishing. Funding/support: This project was funded by the National Institute of Mental Health (NIMH) under Contract Rapidly Acting Treatments for Treatment-Resistant Depression (RAPID) Number: HHSN271201100006I, to the Massachusetts General Hospital (Maurizio Fava and George Papakostas, co-principal investigators). Role of the sponsor: The NIMH had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Disclaimers: Dr Freeman, Editor in Chief of JCP, was not involved in the editorial review or decision to publish this article. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Supplementary material: Available at Psychiatrist.com.
Publisher Copyright:
© 2023 Physicians Postgraduate Press, Inc.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
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U2 - 10.4088/JCP.22M14991
DO - 10.4088/JCP.22M14991
M3 - Article
C2 - 36383742
AN - SCOPUS:85142401478
SN - 0160-6689
VL - 84
JO - Journal of Clinical Psychiatry
JF - Journal of Clinical Psychiatry
IS - 1
M1 - 22m14491
ER -