Review of: Anand A et al, N Engl J Med 2023;388(25):2315–2325

Study type: Randomized open-label controlled trial

Intravenous ketamine is a promising intervention for treatment-resistant depression, but how does it compare to the gold standard of ECT? When the two were compared head-to-head in study, ECT had higher remission rates (63% vs 46%), but this was not a strictly treatment-resistant sample (Ekstrand J et al, Int J Neuropsychopharmacol 2022;25(5):339–349). The current study compared the two in treatment-resistant depression.

The authors identified 403 patients with non-psychotic, treatment-resistant major depression who had been referred to an ECT clinic. These patients were then randomly assigned to receive either three weeks of ketamine or ECT. Ketamine was delivered twice per week (0.5 mg per kg body weight) and ECT three times a week (beginning as right unilateral, with the option to switch to bilateral if no response). The primary outcome was response, defined as a reduction of ≥50% from baseline on the self-reported Quick Inventory of Depressive Symptomatology. After the initial three-week treatment phase, responders were treated at the discretion of their providers and followed for six months. 

Most were outpatients (89%) with moderate to severe depression that had lasted a median of two years. Most had comorbid psychiatric disorders and were taking antidepressants with or without augmentation agents, 14%–15% had melancholic features, and 39% had attempted suicide. Patients’ mean age was 46, the majority were White (88%), and 51% were women. 

After three weeks of treatment, response rates were higher for ketamine (55% vs 41%; p<0.001). At six months follow-up, relapse rates were lower in the ketamine group (34% vs 56%). Cognitive and musculoskeletal adverse effects were greater with ECT, while dissociation was higher on ketamine. Improvements in quality of life were similar for both groups. 

Several factors may have worked against ECT. Most subjects entered the trial with a preference for ketamine, causing more to drop out when they discovered they were randomized to ECT (31 drop-outs vs four with ketamine). Typical ECT responders were excluded or underrepresented in this study: psychotic depression, catatonic depression, severe or inpatient depression, and older adults. ECT may have been underdosed with six to nine sessions instead of the standard 12 treatments (93% of the study participants received at least six ECT sessions, and 70% received all nine). Although most of the ECT response is observable by six sessions, the abbreviation may have raised the rate of relapse down the road.

Carlat Take

In this large trial, outpatients with treatment-resistant, non-psychotic depression were more likely to get well and stay well with ketamine than ECT. However, ECT remains the treatment of choice for psychotic and catatonic depression and may be more effective for inpatients and older adults.