An unexpected frontier: repurposing anesthetics for depression

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

But this was not always true. Researchers only recently discovered the effectiveness of ketamine as an antidepressant, despite its approval for clinical use in anesthesia in 1970.

Connor Brenna explores this new area of research in a review paper in the journal Anesthesiology, published earlier this year. Brenna is a resident in the department of anesthesiology and pain medicine's Clinician Investigator Program, in the Temerty Faculty of Medicine at the University of Toronto.

“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 electroconvulsive therapy for treatment-resistant major depression,” says Brenna, who worked with anesthesiology and pain medicine professor and chair Beverley Orser on the review paper.

“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,” Brenna says.

A secondary analysis of the ELEKT-D trial recently found that people with moderately severe or severe depression experienced more significant symptom improvement with intravenous ketamine than with electroconvulsive therapy.

While ketamine has received the most attention from researchers to date, Brenna notes, several other anesthetics are showing promise as antidepressants. Nitrous oxide, propofol, and isoflurane are all currently under study, as are several 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 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.”

The paper by Brenna and Orser highlights the importance of increased collaboration between psychiatrists and anesthesiologists — whose specialities have traditionally been separate — to promote more growth in this new area of research. It 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,” says Brenna, who is also a clinical research fellow in the Perioperative Brain Health Centre at Sunnybrook Health Sciences Centre. “For example, our department at Temerty Medicine has developed an early-career collaborative grant supporting co-PIs from the anesthesia and psychiatry departments.”

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

Brenna says the slow pace of discovery around the antidepressant properties of ketamine emphasizes the need to speed up future treatments.

“Today, with the benefit of hindsight, we can find reports as early as the 1970s that patients and providers were noticing the antidepressant effects of ketamine, but these 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.”