Researchers Look to Extend Benefits of Ketamine

For all the buzz over the fast-acting antidepressant esketamine—a form of ketamine recently approved by the Food and Drug Administration (FDA)—this medication is not the answer for every person with major depression. For people with severe, hard-to-treat depression, esketamine can offer critical symptom relief in the short term. But for most patients, once-daily medications such as fluoxetine and paroxetine are safer options.

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The limitation of ketamine is that it attaches to numerous cell receptors, which contributes to its potent, unwanted side effects, including dizziness, sedation, and potential for misuse. Researchers are diligently developing ketamine derivatives that they hope will provide a more favorable risk-benefit profile. Modified ketamine derivatives that attach only to therapeutic targets such as GABA receptors, for instance, might provide depression relief without the side effects.

Some investigators such as Samuel Wilkinson, M.D., the assistant director of the Depression Research Program at Yale University, question if the side effects of ketamine are a deterrent for patients. “In my experience, these short-term side effects are not a limiting factor for using ketamine, if you have the right patient,” he said. Wilkinson said he would be hesitant to use ketamine in patients with a history of substance misuse, but for most others the side effects are easily managed so long as a patient is under the supervision of a doctor.

Wilkinson noted that ketamine might be more widely used if the effects of the medication were longer lasting. Though ketamine starts improving depression symptoms within hours, the improvements tend to last only a few days. If that duration could be extended to weeks or even months, then patients would require fewer ketamine treatment sessions.

Extending the duration of symptom improvements from ketamine will require a greater understanding of how ketamine exerts its antidepressant effect. Thanks to recent advancements in microscopy and cell imaging, researchers are learning more about how ketamine works at the cellular level.

For years researchers have suspected that ketamine works by boosting communication between neurons. Recent animal studies by Conor Liston, M.D., Ph.D., an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, and colleagues suggest that this occurs in two stages.

First, ketamine appears to jump-start activity between existing neurons in the prefrontal cortex, which may explain the initial rapid symptom improvements seem in patients taking ketamine. Starting about 12 hours after ketamine injection in animals, cortical neurons begin to make new connections via the formation of spiky tendrils known as dendritic spines. These spines last about a week, which correlates with the average length of symptom improvement seen in patients who have taken ketamine.

Liston and colleagues at Tokyo University confirmed the importance of these spines using a tool known as optogenetics. Using light energy, the researchers were able to manipulate mouse neurons exposed to ketamine and make newly formed spines disappear; eliminating these spines restored depression-like symptoms in the mice. If researchers can find a way to keep the newly formed dendritic spines from disappearing, they might be able to sustain the antidepressant effects of ketamine, Liston said.

Some recent research suggests such a strategy is possible. In a study led by Chadi Abdallah, M.D., a psychiatry professor at Yale and co-authored by Wilkinson, investigators gave patients with depression the immunosuppressant rapamycin prior to a ketamine infusion. Rapamycin targets a protein complex known as mTOR, which regulates spine formation. They found that patients who received rapamycin experienced symptom improvements that lasted twice as long as those previously reported by patients taking ketamine. (These results were a surprise as the study was designed to test whether rapamycin would inhibit ketamine activity.)

Wilkinson explained that while the study did not examine any molecular changes, the findings suggest that solidifying the transient dendritic spines induced by ketamine is a viable strategy.

Rapamycin is an immune system suppressor with its own potent side effects, so it would not be clinically feasible to combine this medication with ketamine. But there might be other drugs that could also extend ketamine’s life. Liston said that combining ketamine with transcranial magnetic stimulation—which, like ketamine, is approved for treatment-resistant depression—might also boost dendrite survival.

Another existing treatment option for patients receiving ketamine is cognitive-behavioral therapy (CBT). Preliminary studies by Wilkinson have found that patients who respond to ketamine have sustained improvements and a reduced risk of depression relapse if they participate in CBT after their ketamine session (24 to 48 hours later to ensure all side effects have worn off). CBT appears to benefit only patients who respond to the ketamine, suggesting there are biological changes that make these patients more responsive to behavioral therapy.

“The work is in the early stages still, but this could be a potentially exciting combination that helps people with severe depression get better in the short and long term,” Wilkinson said. ■