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Randomized Controlled Trial
. 2024 Jun 3;7(6):e2417786.
doi: 10.1001/jamanetworkopen.2024.17786.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial

Manish Kumar Jha  1   2 , Samuel T Wilkinson  3 , Kamini Krishnan  4 , Katherine A Collins  5 , Gerard Sanacora  3 , James Murrough  6 , Fernando Goes  7 , Murat Altinay  8 , Amy Aloysi  6 , Ali Asghar-Ali  9   10   11 , Brian Barnett  8 , Lee Chang  12 , Sara Costi  6   13 , Donald Malone  8 , Sina Nikayin  3 , Steven E Nissen  14 , Robert Ostroff  3 , Irving Reti  7 , Kathy Wolski  14 , Dong Wang  15 , Bo Hu  15 , Sanjay J Mathew  9   10   11 , Amit Anand  16
Affiliations
Randomized Controlled Trial

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial

Manish Kumar Jha et al. JAMA Netw Open. .

Abstract

Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.

Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.

Design, setting, and participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians.

Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks.

Main outcomes and measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses.

Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment.

Conclusions and relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Jha reported receiving grants from Janssen Research & Development, Neurocrine Biosciences, Navitor/Supernus, and Acadia Pharmaceuticals and personal fees from the Psychiatry & Behavioral Health Learning Network, Elsevier, Eleusis Therapeutics, Janssen Global Services, Janssen Scientific Affairs, Boehringer Ingelheim, Guidepoint Global, Worldwide Clinical Trials, Vicore Pharma, IQVIA, North American Center for Continuing Medical Education, Medscape/WebMD, Clinical Care Options, Global Medical Education, and H.C. Wainwright & Co., LLC, outside the submitted work. Dr Wilkinson reported receiving grants from Janssen and Oui Therapeutics and personal fees from Janssen and Sage Therapeutics outside the submitted work. Dr Collins reported receiving grants from the Patient-Centered Outcomes Research Institute during the conduct of the study and receiving personal fees from Relmada Therapeutics, Inc, Cronos Clinical Consulting Services, Inc, MedAvante-ProPhase, A. Stein- Regulatory Affairs Consulting, Ltd, and the University of Texas Southwestern outside the submitted work. Dr Sanacora reported receiving personal fees from AbbVie, Atai, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Clexio, Denovo Biopharma, ECR1, EMA Wellness, Embark, Daiichi Sankyo, Freedom Biosciences, Gilgamesh, Janssen, Merck, Neurocrine, Novartis, Perception Neuroscience, Relmada Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Tetricus, Transcend Therapeutics, the Usona Institute, and XW Laboratories; equity from Biohaven Pharmaceuticals, Freedom Biosciences, Relmada Therapeutics, and Tetricus; and grants from Janssen, Merck, and the Usona Institute outside the submitted work and reported having a patent licensed to Biohaven and to Freedom Biosciences as a coinventor on a US patent and reported that Yale University (employer) has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship but reported receiving no direct payments through this relationship because Yale University has put multiple measures in place to mitigate this institutional conflict of interest. Dr Murrough reported receiving personal fees from LivaNova, Biohaven, Clexio Biosciences, Merck, and Xenon Pharmaceuticals outside the submitted work and reported that the Icahn School of Medicine at Mount Sinai (employer) is named on a patent and has entered into a licensing agreement and will receive payments related to the use of ketamine or esketamine for the treatment of depression and is named on a patent related to the use of ketamine for the treatment of posttraumatic stress disorder; Dr Murrough is not named on these patents and will not receive any payments. Dr Barnett reported receiving personal fees from Compass Pathways, Cerebral, Dynamed, and Janssen Pharmaceuticals and receiving grants from MindMed and Compass Pathways outside the submitted work. Dr Costi reported receiving personal fees from Guidepoint and TCG Crossover outside the submitted work and having US patents and several pending US patent applications related to ketamine and esketamine for treatment-resistant depression, suicidal ideation, and other disorders from the Icahn School of Medicine at Mount Sinai, which has entered into a licensing agreement with Janssen Pharmaceuticals, Inc, and has received and will receive payments from Janssen under the license agreement related to these patents during the conduct of the study. Dr Malone reported receiving grants from the Cleveland Clinic Patient-Centered Outcomes Research Institute (PCORI) during the conduct of the study. Dr Hu reported receiving grants from PCORI during the conduct of the study. Dr Mathew reported receiving grants from PCORI during the conduct of the study and receiving personal fees from Abbott, Almatica, Biohaven, BioXCel, Boehringer-Ingelheim, Brii Biosciences, Clexio Biosciences, Compass Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Freedom Biosciences, Liva Nova, Levo Therapeutics, Merck, Motif Neurotech, Neumora, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion, Xenon Pharmaceuticals, Worldwide Clinical Trials, and XW Pharma and receiving grants from Engrail Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Treatment Outcomes of Ketamine vs Electroconvulsive Therapy (ECT) Stratified by Less or More Severe Baseline Depression Severity
The least-squares mean from mixed-effects model analyses was plotted for both treatment groups (ECT and ketamine) based on the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16) baseline depression severity thresholds of moderate severe or severe (score of ≤20) or very severe (score of >20), in which scores range from 0 to 27, with more than 20 indicating very severe depression. EOT indicates end-of-treatment visit.
Figure 2.
Figure 2.. Differential Improvement in Clinician-Rated Depression Severity With Electroconvulsive Therapy (ECT) Based on the North American Adult Reading Test-35 (NAART-35), a Premorbid Intelligence Measure
Clinician-rated depression severity was measured with the Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item scale, in which scores range from 0 to 60, with more than 36 indicating very severe depression. The binary outcome for NAART-35 was assigned using a standard score of less than 85 (low average or below), indicating scores that were 1.5 SDs or more below published normative data by the developers of NAART-35, in which scores range from 57 to 113 in the ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) trial, with higher scores indicating higher premorbid intelligence. EOT indicates end-of-treatment visit.
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