In a new study, investigators compared the effects of repeated intravenous (IV) ketamine and intranasal (IN) esketamine in patients with treatment-resistant depression and found both reduced depression severity, with IV ketamine showing relatively earlier and greater improvements.

Led by researchers at Harvard-affiliated Mass General Brigham, the study was published in the Journal of Clinical Psychiatry. The research was based on retrospective analysis of data from 153 adult patients being treated at McLean Hospital for severe treatment-resistant depression.

Nearly 30 percent of patients with major depressive disorder fail to respond to two or more antidepressants, necessitating multiple strategies to manage their symptoms. Recently, intranasal esketamine — a subcomponent of ketamine — has emerged as a promising treatment for this challenging condition and is an FDA-approved antidepressant for adults. By contrast, IV ketamine, initially approved by the FDA as an anesthetic, remains an off-label treatment option despite decades of clinical research that demonstrates its antidepressant effects.

Researchers evaluated efficacy and rapidity of therapeutic responses in 111 patients who received IV ketamine and 42 patients who received IN esketamine, administered twice weekly over four to five weeks for a total of eight treatments during the induction treatment phase. 

“We examined data naturally accumulated from patients over the course of clinical work, in one of the largest naturalistic comparison of the two drugs to date,” said corresponding author Shuang Li of the Psychiatric Neurotherapeutics Program at McLean Hospital and an instructor in psychiatry at Harvard Medical School.

Both groups showed significant overall decreases in depression severity after the final treatment compared to pretreatment baseline. IV ketamine showed greater overall efficacy, with a 49.22 percent reduction in depression scores by the final dose while IN esketamine resulted in a 39.55 percent reduction in the same period.

In addition, IV ketamine was associated with faster responses, with patients exhibiting improved symptoms immediately after the first treatment, whereas IN esketamine led to significant improvements after the second treatment.

“While I believe strongly in the utility of ketamine for the right patient in an appropriate setting, I am also very concerned about the potential for misuse and abuse of this medication,” said study first author Robert Meisner, medical director of the Ketamine Service in the Psychiatric Neurotherapeutics Program at McLean Hospital and a clinical fellow in psychiatry at HMS. “We always strive to seek evidence-based, data-driven, safety-first, care when we consider these two treatment options.”

The authors emphasize that differences in clinical contexts, as well as logistical factors like insurance coverage and the accessibility and frequency of appointments, may factor into the decision of which treatment a patient may pursue. They add that risks of ketamine misuse and the proliferation of boutique providers with varying protocols and degrees of regulation necessitate rigorous studies like these. Future randomized clinical trials are needed to confirm comparative efficacy and to eliminate confounding factors such as socioeconomic status, differences in dose and effects due to other psychiatric treatments.