Ketamine noninferior to ECT for symptom management in treatment-resistant major depression

1. In this randomized controlled trial, ketamine was noninferior to electroconvulsive therapy (ECT) for reducing symptoms of treatment-resistant major depression (TRMD).

2. ECT was associated with temporarily decreased memory recall and musculoskeletal adverse effects, while ketamine was associated with dissociation.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Major depressive disorder is a leading cause of disability worldwide. Although pharmacologic antidepressants are standard of care, approximately one-third of patients have suboptimal responses. TRMD is defined as depression with an unsatisfactory response to at least two trials of antidepressants. ECT is a well-established modality for treating TRMD but remains underutilized due to limited access and concerns about its adverse effects. Ketamine, at subanesthetic doses, has emerged as a potential treatment for TRMD. Though, the relative efficacy and safety of ketamine compared to ECT has not been elucidated. This study was a noninferiority trial where patients with TRMD without psychosis were randomized to receive ECT or ketamine over three weeks. Ketamine infusion was shown to be noninferior to ECT in patient-reported treatment response and quality of life. ECT was associated with decreased memory recall at three weeks, which recovered upon follow-up, and myalgias. Conversely, Ketamine was associated with dissociation. The trial was limited by its open-label design and the lack of a placebo or maintenance treatment. Overall, in this trial ketamine demonstrated noninferiority to ECT for the initial treatment of nonpsychotic TRMD.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: The current study was an open-label, randomized, noninferiority trial to evaluate ketamine compared to ECT for the treatment of TRMD without psychosis. Those between 21 and 75 years of age with TRMD without psychosis and a score greater than 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS) were included. Exclusion criteria included bipolar disorder, psychotic disorders, developmental disorders, and contraindications to ECT or ketamine. Overall, 403 patients were randomized 1:1 to receive ECT three times per week or intravenous ketamine infusion at 0.5mg/kg twice per week. The primary outcome was a response to treatment, defined as a decrease of ≥50% from baseline in the score on the Quick Inventory of Depressive Symptomatology – Self-Report [QIDS-SR-16]). By three weeks, 55.4% of patients treated with ketamine and 41.2% of those receiving ECT reported a response (difference, 14.2 percentage points; 95% Confidence Interval, 3.9 to 24.2; p<0.001). Both MADRS-defined treatment response and quality of life measures demonstrated the noninferiority of ketamine compared to ECT. The ECT group reported a mean decrease in memory tests after three weeks. However, upon follow-up at one and six months, this score had normalized and was comparable between the two groups. Muscle pain and weakness were reported more frequently following ECT (5.3%) than ketamine infusion (0.5%) while ketamine was associated with higher scores of dissociative symptoms. In summary, this study provided evidence of the noninferiority of ketamine compared to ECT for treating adult patients with TRMD without psychosis.

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