ELEKT-D: Electroconvulsive Therapy (ECT) vs. Ketamine in Patients With Treatment Resistant Depression (TRD)

Patients with treatment resistant depression who meet all inclusion criteria and do not meet any exclusion criteria will be randomized to either electroconvulsive therapy (ECT) three times per week or ketamine infusion two times per week. Patients will answer questionnaires about their symptoms prior to treatments. The acute treatment phase of the study will last three to five weeks. Depending on response to treatment, some patients will be followed for an additional six months.

• electroconvulsive therapy (ECT) (Procedure): ECT is a procedure done under general anesthesia where small electric currents are passed through the brain, intentionally triggering a brief seizure. Patients who have not responded to antidepressant medications may be candidates for ECT. ECT is FDA approved for treatment resistant depression.
• Ketamine (Drug): Ketamine is a medication that is used as a short acting anesthetic in pediatric and adult medicine. Subanesthetic (low) doses will be given to patients via infusion in order to assess whether it helps with depression symptoms in patients who have not responded to antidepressant therapy. Ketamine is not FDA approved for this indication and its effectiveness in treatment resistant depression has not been proven. Prior studies have indicated that subanesthetic doses of ketamine may be helpful for treatment resistant depression.

Primary outcomes

• Number of Participants With Treatment Responses Based on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report Scale (QIDS-SR-16) [Acute Study Phase (Baseline Visit to End of Treatment Visit) - approximately 3-5 weeks]: Response is defined as at least a 50% improvement in the QIDS-SR-16 scale from baseline to the End of Treatment visit. The End of Treatment visit will occur 3-5 weeks after the Baseline visit.

Secondary outcomes

• Number of Participants With Treatment Responses Based on the Montgomery-Åsberg Rating Scale (MADRS) [Acute Study Phase (Baseline Visit to End of Treatment Visit) - approximately 3-5 weeks]: The outcome measure was the percentage of responders at the end-of-treatment visit, defined as a ≥50% decrease in MADRS score from the baseline visit (i.e., first treatment visit) to the end-of-treatment visit (within 3 days of last treatment).

Sex: All, ages: 21 Years to 75 Years

Inclusion Criteria:

1. Written informed consent before any study related procedures are performed
2. Inpatients or outpatients referred by their providers for ECT treatment and eligible for ECT treatment
3. Males/females at least 21 years of age but no older than 75 years of age
4. Meet DSM-5 criteria for Major Depressive Episode as determined by both:

   A. a clinician's diagnostic evaluation and B. confirmed with the MINI International Neuropsychiatric Interview (MINI 7.0.2)
5. A current depressive episode that has lasted a minimum of 4 weeks
6. Meet all of the following criteria on symptom rating scales at screening:

   A. Montgomery Asberg Depression Rating Scale (MADRS) score >20 B. Young Mania Rating Scale (YMRS) of ≤ 5 C. Montreal Cognitive Assessment (MoCA) of ≥18
7. Have had ≥2 adequate trials of antidepressants or augmentation strategies during their lifetime. An adequate trial is defined as 4 weeks of medication at the minimum FDA approved dose. This will be equal to a trial rating of 3 or more.
8. In the opinion of the investigator, the patient is willing and able to comply with scheduled visits, treatment plan, and other trial procedures for the duration of the study

Exclusion Criteria:

1. Meet DSM-5 criteria for bipolar disorder, schizophrenia, schizophreniform disorder, schizoaffective disorder, mental retardation, or pervasive developmental disorder
2. Meets any exclusion criteria for ECT or ketamine treatment as described in the clinical guidelines or according to investigator judgment
3. The patient is pregnant or breast feeding
4. The patient has a severe medical illness or severe neurological disorder
5. The patient has a known ketamine allergy or is taking a medication that may interact with ketamine
6. Diagnosis of major depressive disorder with psychotic features during the current depressive episode
7. Unable to give informed consent
8. Was previously enrolled/randomized into the trial

Participant flow

Outcome results

• Number of Participants With Treatment Responses Based on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report Scale (QIDS-SR-16) (Primary), Count of participants, Participants: Electroconvulsive Therapy (ECT) 70; Ketamine Infusion 108 (p <.001)
• Number of Participants With Treatment Responses Based on the Montgomery-Åsberg Rating Scale (MADRS) (Secondary), Count of participants, Participants: Electroconvulsive Therapy (ECT) 70; Ketamine Infusion 99

Adverse events

Time frame: Adverse events are reported for the period from baseline to the end-of-treatment visit (up to 5 weeks from baseline)

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Our trial has several limitations. ECT was started with right unilateral placement and was then switched to bilateral placement in the event of inadequate response. The open-label design of our trial could have influenced response. Maintenance treatment was not studied. Other limitations of our trial include a lack of placebo, the flexibility of treatment methods, and a follow-up period during which the patients received treatment as presc

• Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007;68 Suppl 8:17-25. PMID 17640154
• Kellner CH, Greenberg RM, Murrough JW, Bryson EO, Briggs MC, Pasculli RM. ECT in treatment-resistant depression. Am J Psychiatry. 2012 Dec;169(12):1238-44. doi: 10.1176/appi.ajp.2012.12050648. PMID 23212054
• Lisanby SH. Electroconvulsive therapy for depression. N Engl J Med. 2007 Nov 8;357(19):1939-45. doi: 10.1056/NEJMct075234. No abstract available. PMID 17989386
• Newport DJ, Carpenter LL, McDonald WM, Potash JB, Tohen M, Nemeroff CB; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. Am J Psychiatry. 2015 Oct;172(10):950-66. doi: 10.1176/appi.ajp.2015.15040465. PMID 26423481
• Sanacora G, Heimer H, Hartman D, Mathew SJ, Frye M, Nemeroff C, Robinson Beale R. Balancing the Promise and Risks of Ketamine Treatment for Mood Disorders. Neuropsychopharmacology. 2017 May;42(6):1179-1181. doi: 10.1038/npp.2016.193. Epub 2016 Sep 19. No abstract available. PMID 27640324
• Results publication: Kumpf KT, Wilkinson ST, Hu B, Chen R, Krishnan K, Chakrabarti S, Rhee TG, Grezmak T, Mathew SJ, Sanacora G, Murrough JW, Goes FS, Collins KA, Barnett BS, Anand A. Comparing the Cognitive Effects of Repeated Intravenous Ketamine and Electroconvulsive Therapy in Patients With Treatment-Resistant Depression: A Secondary Analysis of the ELEKT-D Trial. J Clin Psychiatry. 2025 Sep 3;86(4):25m15781. doi: 10.4088/JCP.25m15781. PMID 40900112
• Results publication: Anand A, Mathew SJ, Sanacora G, Murrough JW, Goes FS, Altinay M, Aloysi AS, Asghar-Ali AA, Barnett BS, Chang LC, Collins KA, Costi S, Iqbal S, Jha MK, Krishnan K, Malone DA, Nikayin S, Nissen SE, Ostroff RB, Reti IM, Wilkinson ST, Wolski K, Hu B. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med. 2023 Jun 22;388(25):2315-2325. doi: 10.1056/NEJMoa2302399. Epub 2023 May 24. PMID 37224232
• Results publication: Mathew SJ, Wilkinson ST, Altinay M, Asghar-Ali A, Chang LC, Collins KA, Dale RM, Hu B, Krishnan K, Kellner CH, Malone DA, Murrough JW, Ostroff RB, Sanacora G, Shao M, Anand A. ELEctroconvulsive therapy (ECT) vs. Ketamine in patients with Treatment-resistant Depression: The ELEKT-D study protocol. Contemp Clin Trials. 2019 Feb;77:19-26. doi: 10.1016/j.cct.2018.12.009. Epub 2018 Dec 17. PMID 30572160

• Study Protocol (PDF, 2022-02-16)
• Statistical Analysis Plan (PDF, 2022-07-01)

• Amit Anand, MD, Principal investigator, The Cleveland Clinic