New Insights on How Ketamine Can Lessen Symptoms of Depression But Also Cause Dissociative Side Effects

BOSTON – Ketamine is useful for treating depression, but unfortunately, it can cause dissociative symptoms—such as having an out-of-body experience or feeling emotionally numb.

A team led by investigators at Massachusetts General Hospital (MGH) recently uncovered how ketamine influences different circuits in the brain to produce its antidepressant and dissociative effects.

The research, which is published in Nature Communications, could lead to novel treatments for depression with fewer side effects.

The study involved 10 patients with epilepsy who had received electrode implants in the brain to detect abnormal electrical activity that causes seizures. The patients were given ketamine before they underwent general anesthesia for electrode removal surgery.

Before the electrode implants were removed, they collected data on patients’ brain activity before and after exposure to ketamine.

The electrode recordings revealed that ketamine engages different neural circuits in distinct frequency-dependent patterns of brain activity to produce its antidepressant and dissociative effects.

Ketamine produced “gamma oscillations” (25 to 55 Hz) in brain areas related to depression—specifically, the prefrontal cortex and hippocampus. It produced a 3 Hz oscillation in the posteromedial cortex, a region involved in dissociative symptoms.

“In this study, we show, for the first time to our knowledge in humans, a detailed description of the principal oscillatory changes in a variety of cortical and subcortical structures after administration of a subanesthetic dose of ketamine,” says lead author Fangyun Tian, PhD, an Instructor in the Department of Anesthesia, Critical Care and Pain Medicine at MGH and an Instructor in Anaesthesia at Harvard Medical School.

Additional co-authors include Laura D. Lewis, David W. Zhou, Gustavo A. Balanza, Angelique C. Paulk, Rina Zelmann, Noam Peled, Daniel Soper, Laura A. Santa Cruz Mercado, Robert A. Peterfreund, Linda S. Aglio,
Emad N. Eskandar, G. Rees Cosgrove, Ziv M. Williams, R. Mark Richardson, Emery N. Brown, Oluwaseun Akeju, and Sydney S. Cash.

This work was supported by the National Institutes of Health and the Tiny Blue Dot Foundation.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.