A new  study  published Wednesday in the  New England Journal of Medicine found that intravenous (IV) ketamine performed similarly to electroconvulsive therapy (ECT) — the current "gold standard" for treatment-resistant major depression.

Study details and key findings

For the study, researchers evaluated how effective ketamine was against treatment-resistant major depression.

Last year, a  meta-analysis  of smaller ketamine comparison studies that focused on major depression instead of treatment-resistant depression found that ECT led to better outcomes. However, this new study found that intravenous ketamine was "not inferior" to ECT.

In total, the new study enrolled 403 individuals with major depression without psychosis who did not respond to selective serotonin reuptake inhibitor (SSRI) antidepressants. Overall, 38 patients withdrew from the study before receiving treatment. Ketamine was administered to 195 randomly assigned patients and ECT was administered to 170 randomly assigned patients.

Over a three-week treatment period, ketamine patients received an IV infusion twice a week. Meanwhile, ECT patients were advised to receive three treatments each week. Roughly 93% of both treatment groups completed the full treatment. While ketamine dosing remained constant in almost all patients, 39% of ECT patients changed their regimen during the study period.

Ultimately, 55.4% of the patients who were administered ketamine responded to the treatment, compared to a 41.2% response rate among those who received ECT. Response was defined as a 50% or greater drop from baseline in a patient's score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report.

During a six-month follow-up, 19% of patients who had a treatment response in the ketamine group experienced a relapse at month one, compared with 35.4% in the ECT group. By month six, relapse rates climbed to 34.5% and 56.3%, respectively.

"That ketamine was noninferior was in itself surprising, as ECT is the gold standard for 80 years for treatment of resistant depression," said Amit Anand, lead author of the study and a psychiatrist at Brigham and Women's Hospital. "And actually, ketamine's effectiveness, in the aggregate results, looks a bit better than ECT for major depression not associated with psychotic features."

"However, our starting hypothesis and study design was to find whether ketamine was noninferior to ECT," Anand noted. "So in the paper, we cannot comment on ketamine's superiority compared to ECT for treatment of non-psychotic resistant depression."

Commentary

According to Patrick Oliver, medical director at MindPeace ketamine clinics who was not involved in the study but has researched the drug as treatment for depression, the implications of the findings are "huge." While the study was designed to show "non-inferiority," Oliver said the data suggest ketamine worked better than ECT.

"I would say hands down that this should change the practice of interventional psychiatry," Oliver said, suggesting pushing ketamine from last to first choice for patients who do not show a response to SSRIs. Still, he noted that neither result is great. "We're at a C-minus."

ECT, which is performed under general anesthesia, poses its own set of risks, including the potential for cognitive impairment like long-term memory loss. However, many experts are skeptical of ketamine's future use, citing its addictive potential.

While the exact risks are not well-documented, ketamine is known to be addictive. Without regulation or additional data, some experts are concerned that widespread ketamine use could cause an addiction epidemic similar to the opioid crisis, STAT reports.

"The follow-up period of the current trial was not long, nor did it assess future drug-seeking behavior among those who did or did not have a response to ketamine," Robert Freedman, a psychiatry professor at the University of Colorado Denver School of Medicine, wrote in an editorial published alongside the new study. "We need to remember that only a minority of physicians were responsible for the oxycodone epidemic."

Anand noted that evidence of addictive potential was minimal — especially with the dose used in the trial. "I don't think there's any firm data people are abusing it," he said. "But we have to keep it in mind."

However, 41% of study participants assigned to take ketamine continued using it during the six-month follow-up period. "That to me is a warning," said Boris Heifets, who studies ketamine at Stanford University and was not involved in the new study, noting that it is not a short-term "we fix you and you're done" treatment. "This is a subscription model."

Ultimately, "[i]t's a question of risk assessment for each individual patient," Heifets noted. "Neither of these things is risk-free, neither is transformative." (Goldhill, STAT, 5/24; Gilbert, Washington Post, 5/24; Monaco, MedPage Today, 5/24; Anand et al., New England Journal of Medicine, 5/24)