A study published in the *Journal of Clinical Psychiatry*, conducted by researchers at Harvard Medical School affiliated with Mass General Brigham, compared for the first time the effects of intravenous (IV) ketamine and intranasal (IN) esketamine in patients with treatment-resistant depression—and the results favor intravenous ketamine in terms of efficacy and speed of response.
The clinical context
About 30% of patients with major depressive disorder do not respond to two or more antidepressants, making treatment-resistant depression one of the greatest challenges in contemporary psychiatry. Intranasal esketamine—a subcomponent of ketamine—was recently approved by the FDA (Food and Drug Administration) as an antidepressant for adults. Intravenous ketamine, initially approved as an anesthetic, continues to be used off-label, despite decades of clinical research demonstrating its antidepressant effects.
How the study was conducted
The study was based on a retrospective analysis of data from 153 adult patients with severe treatment-resistant depression who were treated at McLean Hospital. Of these, 111 received intravenous ketamine and 42 received intranasal esketamine, both administered twice a week over four to five weeks, for a total of eight treatments during the induction phase.
Intravenous ketamine has an advantage
Both treatments resulted in significant reductions in the severity of depressive symptoms. However, intravenous ketamine was more effective overall—with a 49.22% reduction in depression scores after the final dose —while intranasal esketamine showed a 39.55% reduction over the same period.
The speed of response was also greater with intravenous ketamine: patients showed improvement immediately after the first treatment, whereas with intranasal esketamine, significant improvements occurred only after the second treatment. This difference is clinically relevant, particularly in more severe cases and those with a higher risk of suicide, where the time to response can be critical.
The precautions that researchers emphasize
The authors acknowledge that factors such as the clinical context, insurance coverage, accessibility, and the frequency of appointments can influence the choice between the two treatment options. They also warn of the risks associated with the proliferation of centers lacking rigorous protocols and the potential for ketamine abuse. The study’s first author, Robert Meisner, clinical director of the Ketamine Service at McLean Hospital, is blunt: “I strongly believe in the usefulness of ketamine for the right patient in the right setting—but I am also very concerned about the potential for misuse of this substance.”
The researchers conclude that randomized clinical trials are needed to confirm the comparative efficacy of the two approaches and to eliminate confounding variables, such as patients' socioeconomic status or differences in dosing.
Read more about our programs and protocols HERE.
