The Comparison Patients Have Been Waiting For

For decades, electroconvulsive therapy (ECT) has been considered the most effective treatment available for severe, treatment-resistant depression. It is also the treatment patients are most reluctant to accept, largely because of its association with memory side effects and general anesthesia. When intravenous ketamine emerged as a rapid-acting alternative, the obvious question was whether it could match ECT head to head.

In 2023, the ELEKT-D trial published in the New England Journal of Medicine provided the largest randomized answer to date. Two subsequent analyses, published in 2024 and 2025, refined that answer considerably. Together they form the most important body of comparative evidence in this field.

How ELEKT-D Was Designed

ELEKT-D (Anand et al., NEJM, June 2023) was an open-label, randomized, non-inferiority trial conducted at five academic medical centers in the United States.

  • Participants: 403 adults randomized; 365 received treatment (195 ketamine, 170 ECT)
  • Population: Adults with non-psychotic treatment-resistant major depression who were referred for ECT and considered clinically appropriate for it
  • Ketamine arm: 0.5 mg/kg intravenous infusions over 40 minutes, twice weekly for three weeks
  • ECT arm: Three times weekly for three weeks, per standard site protocol
  • Primary outcome: Treatment response, defined as a 50% or greater reduction on the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16)
  • Follow-up: Six months after the acute treatment course

Importantly, patients with psychotic depression were excluded. This is a meaningful restriction, because psychotic depression is one of the presentations for which ECT has the strongest evidence.

What the Trial Found

Response rates

Ketamine was not merely non-inferior to ECT in this population — it numerically outperformed it:

  • Ketamine: 55.4% response
  • ECT: 41.2% response
  • Difference: 14.2 percentage points (95% CI, 3.9 to 24.2), well clear of the pre-specified non-inferiority margin of −10 points

Quality-of-life improvements were similar between the two groups.

Memory and cognition

Patients who received ECT showed a decline in memory and recall measures immediately after the treatment course. Patients who received ketamine did not. A 2025 secondary analysis in the Journal of Clinical Psychiatry examined cognition in more detail and reported the same pattern: cognitive performance was worse in the ECT arm immediately after the three-week course, but among patients who responded to treatment, there were no significant differences between groups across the 1-, 3-, and 6-month follow-up assessments.

In practical terms, ECT's cognitive cost in this trial appeared to be real but largely short-lived.

Durability at six months

Relapse after the acute course was common in both arms, which is a point often lost in coverage of this trial. Roughly 35% of ketamine responders and 56% of ECT responders relapsed within six months. Neither treatment is a one-time cure; both typically require a maintenance plan.

The Nuance: Severity Matters

A pre-planned-adjacent secondary analysis by Jha and colleagues (JAMA Network Open, June 2024) examined whether baseline severity changed the picture. Among the 365 treated patients:

  • Moderately severe to severe depression (QIDS-SR-16 of 20 or below): ketamine produced greater symptom reduction (−7.7 vs −5.6 points)
  • Very severe, hospitalized depression (QIDS-SR-16 above 20): ECT worked faster early in the course (−8.4 vs −6.7), though the two treatments converged by the end of the treatment course

The authors cautioned that this analysis was not pre-specified, so it should be read as hypothesis-generating rather than definitive. Still, it aligns with long-standing clinical practice: the most acutely ill, hospitalized patients are still frequently referred to ECT first.

Limitations Worth Understanding

  • Open-label design. Patients and clinicians knew which treatment was given. Expectancy effects cannot be ruled out, and ketamine is a treatment patients often prefer.
  • Referral population. Everyone enrolled was already an ECT candidate, which does not represent the average outpatient seeking ketamine.
  • Psychotic depression excluded. ECT remains a first-line consideration there.
  • Fixed protocols. Real-world ECT and ketamine courses are often individualized in ways the trial could not replicate.
  • Dropout imbalance. More patients discontinued in the ECT arm, which can favor the comparator arm in analysis.

What This Means If You Are Choosing Between Them

ELEKT-D does not establish that ketamine is universally better than ECT. What it reasonably supports is a narrower and still useful conclusion: for adults with non-psychotic treatment-resistant depression who are well enough to be treated as outpatients, a course of IV ketamine is a legitimate first option before ECT, with a lower short-term cognitive burden and comparable quality-of-life benefit.

Questions worth raising with a prescriber include what happens after the acute series, how relapse will be monitored, and whether ECT remains available if ketamine does not work. If you are still deciding whether you are a candidate for either, our guide to candidacy and contraindications covers the screening process, and you can search for clinics by state to compare programs near you.

Sources

  • Anand A, et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. New England Journal of Medicine. 2023;389:1252-1263. PubMed 37224232
  • Jha MK, et al. Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial. JAMA Network Open. 2024;7(6):e2417786. PubMed 38916891
  • 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. Journal of Clinical Psychiatry. 2025. PubMed 40900112