An Unexpected Frontier: Repurposing Anesthetics for Depression

Today, a quick online search for ketamine will yield just as many results regarding its potential for treating depression as its traditional use as an anesthetic drug in the operating room.

However, this was not always the case. Researchers discovered the effectiveness of ketamine as an antidepressant only recently, despite its approval for clinical use in the United States in 1970.

Anesthesia resident Dr. Connor Brenna explores research investigating the use of anesthetic drugs in the treatment of depressive disorders in his paper titled “Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care”, published this June in Anesthesiology. Chair of the Department of Anesthesiology & Pain Medicine at the University of Toronto, Dr. Beverley Orser, was the senior author of the report.

“What first piqued my interest in this topic was stumbling across several of the recent success stories of ketamine as an antidepressant, including the 2023 ELEKT-D trial, which showed that ketamine is non-inferior to ECT for treatment-resistant major depression. That body of work has challenged me to think more about anesthetics as psychotropics and about how narrow the boundary between anesthesiology and psychiatry is,” he says.

Brenna notes that while ketamine has received the most attention to date, several other anesthetics are showing promise. Nitrous oxide, propofol, and isoflurane are actively being studied, and ongoing work is beginning to signal the potential antidepressant effect of numerous general anesthetic drugs.

“Toronto is a hotbed for this type of research,” Brenna adds. “For example, Dr. Akash Goel at St. Michael’s Hospital just received an exciting award from the CAS for the MIND Trial (methohexital for depression), Dr. Karim Ladha at Toronto Western Hospital is leading the SMILE Trial (nitrous oxide for treatment-resistant depression), and Dr. Ben Goldstein at CAMH recently published a randomized trial of nitrous oxide for refractory bipolar depression.”

Brenna highlights the importance of increased collaboration between psychiatrists and anesthesiologists, whose specialities have traditionally been separate, in order to promote more growth in this area. He also emphasizes the importance of what he calls “bilingual” trainees — who have a sound foundation in both specialties.

“UofT is a good example of proactively encouraging these types of collaborations. For example, the Department of Anesthesiology & Pain Medicine has developed an early-career collaborative grant supporting co-PIs from the anesthesia and psychiatry departments.”

“Beyond the ECT list, our communities seldom interface in the hospital, and engineering other settings like shared resident curricula and research rounds where we can swap ideas are other opportunities to develop these partnerships.”

Dr. Brenna hopes his paper will inspire further research to unlock the potential of other anesthetics for treating depression. He highlights the slow pace of discovery around the antidepressant properties of ketamine and emphasizes the need to narrow the gap for future treatments.

“Today, with the benefit of hindsight, we can find reports as early as the 1970s that patients and providers were beginning to notice the antidepressant effects of ketamine, but they were not formally explored until the turn of the century,” he says.

“That type of lag time makes me think of opportunity cost and the many millions of patients who would have developed new depressive disorders—many not responsive to conventional therapies—in the intervening decades.”