For a long time, electroconvulsive therapy (ECT) was the main option once depression had not responded to medication. Ketamine has since entered the picture, but until now there had been no proper head-to-head trial comparing the two.
This study, published in the New England Journal of Medicine, randomly assigned 403 people with treatment-resistant depression to one of two treatments. All had already been referred to an ECT clinic. One group received ECT three times a week; the other received intravenous ketamine twice a week. Both continued for three weeks.
The main finding was that ketamine performed no worse than ECT. Just over half of participants responded, meaning their depression scores fell by at least half. The researchers also measured memory and quality of life, and followed those who improved for a further six months.
What matters here is choice. These were people who had reached the point of referral for ECT, a treatment still surrounded by fear and stigma for many, and this trial suggests there may be another path worth discussing with a treating psychiatrist.
Neither option is something to arrange without specialist support, and both require careful medical oversight. But if you have been told there is nothing left to try, this research suggests that may not be the full picture. It is worth asking.
Background: two very different treatments
When major depression does not respond to an adequate trial of at least one antidepressant medication, it is described as treatment-resistant. Electroconvulsive therapy, which uses brief electrical stimulation of the brain under general anaesthetic to trigger a controlled seizure, has the longest track record for this group. It also carries stigma and a well-documented risk of short-term memory problems.
Subanesthetic ketamine, given intravenously at doses far below those used for anaesthesia, is newer and acts on a different neurochemical system, glutamate signalling, rather than the monoamine systems such as serotonin and noradrenaline that most antidepressants target. Until this trial, no adequately powered study had compared the two directly.
What the study did
This was an open-label randomised noninferiority trial, meaning both patients and clinicians knew which treatment was given. Noninferiority trials do not attempt to prove one treatment better. They test whether a newer, often more convenient or less invasive treatment is not meaningfully worse than the established one, using a margin agreed in advance. Here, 403 adults with nonpsychotic treatment-resistant depression who had already been referred to ECT clinics were randomly assigned to three weeks of either ECT, three sessions weekly, or intravenous ketamine at 0.5 mg/kg over 40 minutes, twice weekly.
The main outcome was response, defined as at least a 50% drop in self-reported depression scores on a standard 16-item symptom scale. The researchers set a noninferiority margin of 10 percentage points, meaning ketamine could be judged noninferior even if its response rate fell up to 10 points below that of ECT. Verbal memory and quality of life were also measured, and responders were followed for six months.
What it found
195 patients received ketamine and 170 received ECT. Response rates were 55.4% with ketamine against 41.2% with ECT, a difference of 14.2 percentage points favouring ketamine, comfortably clearing the noninferiority bar with a 95% confidence interval of 3.9 to 24.2. A confidence interval shows the plausible range for the true difference, and because the whole range stayed above the noninferiority margin, the result was statistically dependable.
ECT was linked to a measurable drop in delayed verbal recall after three weeks, which recovered gradually over follow-up. Ketamine showed almost no change on that measure. Quality-of-life improvements were similar between groups. Side effects differed in kind rather than severity: ECT produced musculoskeletal effects such as muscle soreness, while ketamine produced dissociation, a temporary sense of detachment from one's body or surroundings occurring during and shortly after infusion.
Why it matters, and its limits
This is the first large randomised trial to show that ketamine performs at least as well as ECT for nonpsychotic treatment-resistant depression, with a different and generally milder short-term effect on memory. That is clinically meaningful for anyone weighing the options. Being open-label, expectations could have influenced self-reported outcomes. The trial also examined only an initial three-week phase plus six months of follow-up in responders, so longer-term comparative durability was not its focus. Ketamine is not suitable or accessible for everyone, and neither treatment replaces individualised specialist assessment.
If you are struggling with depression, particularly where past treatments have not helped, speaking with a doctor or mental health professional about the available options is worthwhile.