Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin

Abstract

Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F_(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine's antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.

Fig. 1. The study drug effect on Montgomery Åsberg Depression Rating Scale (MADRS).

a There is a significant main effect of time (F_(8,245) = 43.5, p < 0.0001), demonstrating significant decrease in MADRS scores from baseline. There is also significant interaction between treatment and time (F_(8,245) = 2.0, p = 0.04), with overall reduction in depression scores following treatment with rapamycin + ketamine (rapamycin; blue line), compared to post placebo + ketamine (placebo; red line). Primary outcome time points included: before infusion, and 1, 2, 4, 24 h, 3 days, 5 days, 1 week, and 2 weeks after infusion. Dashed lines refer to assessments at 1, 2, and 4 h. b Response and remission rates following treatment with rapamycin + ketamine (rapamycin; blue), compared to post placebo + ketamine (placebo; red). Notes: Error bars are standard errors of mean (SEM); d′ = Cohen’s d′ effect size compared to pretreatment MADRS scores.

Fig. 2. A scatter plot of the changes in Montgomery Åsberg Depression Rating Scale (MADRS) at 2 weeks.

a Delta MADRS is the score at 2 weeks minus pre-treatment. b Percent improvement in MADRS scores at 2 weeks. The dotted line separate the responders from non-responders.

Fig. 3. The study drug effect on Clinician Administered Dissociative States Scale (CADSS), and Positive and Negative Symptom Scale (PANSS) positive (PANSS-P) and negative symptoms (PANSS-N).

Error bars are standard errors of mean (SEM); a Comparisons to pretreatment scores are marked with **** for p ≤ 0.0001, *** for p ≤ 0.001, * for p ≤ 0.05, and t for p = 0.10. b–d There were no treatment effects or treatment by time interactions.