Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

Abstract

BACKGROUND: Ketamine exerts rapid and robust antidepressant effects 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. METHODS:Twenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by 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). Antidepressant response was defined as a MADRS improvement of 50% or more. RESULTS:Over the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine. CONCLUSION:Unexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of ketamine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treatment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…Unexpectedly, rapamycin prolonged the sustained antidepressant actions of ketamine in these patients. There was a significantly higher response rate in the rapamycin plus ketamine group (41%) than that in the placebo plus ketamine group (13%) . These data do not support the previous preclinical report from the same university; however, the treatment route of these two studies was different (i.e., oral administration for human study vs i.c.v.…”

Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

“…96 A recent RCT of 20 patients demonstrated the surprising finding that pre-treatment with rapamycin, an mTORC1 inhibitor, actually tripled the response rate at 2 weeks after treatment. 118 The authors suggested that rapamycin may have augmented ketamine’s effects by targeting neuroinflammation via its immunosuppressant actions or by promoting homeostasis of synaptic density. However, it has also been noted that it is unknown whether low-dose rapamycin would reach appropriate levels to inhibit mTOR in the brain and that it may exert its augmenting effects through dampening inflammation in the periphery.…”

Have no fear

“…Ketamine is an antagonist of the N ‐methyl‐ d ‐aspartate (NMDA) receptor, which plays a key role in transmitting positively charged ions including magnesium, zinc, calcium, sodium and potassium through cell membranes. Antagonizing NMDA interferes with transmission of pain signals along the spinal cord, which has made ketamine a popular drug for anaesthesia, pain relief, sedation and memory loss [preprint: ]. It also acts as an antidepressant at lower doses, probably through a different mechanism.…”

“…It used an ascending single‐dose design with 0.25, 0.5 and finally 1 mg/kg administered subcutaneously at weekly intervals. Within one hour of dosing, the patients reported reduced anxiety persisting for up to seven days [preprint: ]. “We have generated data showing ketamine improving anxiety symptoms in social and generalized anxiety disorders, and patients who had panic disorder and agoraphobia also reported improvements”, commented Paul Glue from the Dunedin School of Medicine in New Zealand and lead author on the study.…”

“…One such drug is rapamycin, an immunosuppressant that regulates cellular metabolism, growth and proliferation by signalling through two protein complexes, mTORC1 and mTORC2. It has no effect on mood directly, but it triples the antidepressant response rate of ketamine two weeks after treatment [preprint: ]. The study was set up to test the hypothesis that ketamine itself exerts rapid and robust antidepressant effects through the activation of the mechanistic target of the mTORC1 protein.…”