Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Ketamine is a novel antidepressant medication with mounting evidence suggesting it produces fast-acting symptom reductions in depression, even among individuals who have struggled to obtain clinical benefit from other traditional antidepressant medications. Some controversy exists in the field regarding exactly how ketamine works in the brain to produce these antidepressant effects. Better understanding the mechanisms underlying ketamine’s antidepressant effects is very important as this can inform novel drug development for depression as well as other psychiatric disorders.

The immunosuppressant drug sirolimus (also called rapamycin) is known to have an impact on depressive symptoms based on some preclinical or animal studies. Sirolimus works in the brain along part of the same pathway it is suspected ketamine may work. The purpose of this study is to investigate what effect a single dose of sirolimus has on the antidepressant effects of ketamine. It is possible this will have a no demonstrated effect on ketamine response or perhaps will have a synergistic effect or a blocking effect. The results will provide additional evidence as to whether this is in fact, the pathway ketamine is working on, as well as giving some insight into what happens when part of this pathway is blocked.

This is a double-blind, randomized, cross-over clinical trial. All study participants will receive two doses of ketamine separated by a two-week period, they will be randomized to one of two groups – ketamine+sirolimus (with placebo at infusion 2) or ketamine+placebo (with sirolimus at infusion 2). Each infusion visit requires a 24-hour follow-up in which our research team members will carefully assess for any changes in symptoms, side-effects, or adverse events. The visit occurs 24-hours after the ketamine dose as this appears to be the peak-time of ketamine’s antidepressant effects. Further, data from neuroimaging studies suggest 24-hours is also the peak of brain changes (e.g., alterations in functional connectivity and neuroplasticity) secondary to ketamine administration.