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

This double-blind, randomized, placebo-controlled study (n=20) found that rapamycin (6mg, iv) extended the antidepressant effects (MADRS) of ketamine (35mg/70kg) at two weeks (41% higher response rate, 29% higher remission rate). This is contrasted to (animal/in vitro) studies that found opposing effects.

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.“

Authors: Chadi G. Abdallah, Lynnette A. Averill, Ralitza Gueorguieva, Selin Goktas, Prerana Purohit, Mohini Ranganathan, Mohamed Sherif, Kyung-Heup Ahn, Deepak Cyril D’Souza, Richard Formica, Steven M. Southwick, Ronald S. Duman, Gerard Sanacora & John H. Krystal

Summary

Introduction

Ketamine is an NMDAR antagonist that induces rapid and robust antidepressant effects by increasing brain-derived neurotrophic factor (BDNF) levels, stimulating TrkB receptors, and activating mTORC1. Rapamycin blocks the neuroplasticity and antidepressant-like effects of ketamine.

The current study was designed to test the hypothesis that mTORC1 activation mediates the antidepressant effects of ketamine by evaluating whether the effects are blocked by pretreatment with rapamycin.

In initial test of the mTORC1 hypothesis of ketamine effects in humans, rapamycin was administered as a single 6 mg dose prior to ketamine infusion. The rapamycin dose was chosen to be tolerable to research subjects, and the study was followed for 2 weeks after each ketamine dose.

Rapamycin reduces the phosphorylation of S6 ribosomal protein in brain tissue and has been shown to cross the brain blood barrier. Therefore, rapamycin was used to reduce the antidepressant effects of ketamine.

Materials and Methods

Study design

Three participants received open-label oral rapamycin followed 2 h later by open-label intravenous ketamine in phase I of a clinical trial to assess the safety and feasibility of the co-administration of rapamycin and ketamine. All three participants tolerated the combination well.

In phase II, 23 participants were randomized to first receive either rapamycin or placebo, followed 2 h later by open-label ketamine. The study used an oral single-dose of 6 mg rapamycin in liquid form, diluted in orange juice to maintain the blinding, and ketamine 0.5 mg/kg intravenously infused over 40 min.

The study enrolled subjects between the age of 21 and 65 years, recruited through advertisement and referrals from outpatient clinics, and had the following criteria: diagnosed with current major depressive episode, history of non-response to at least one adequate antidepressant trial, and resting blood pressure >85/55 and heart rate >45/min.

Outcomes assessments included the MINI, MADRS, QIDS-SR, CADSS, PANSS, rapamycin, high-sensitivity C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) prior to randomization, and ketamine levels before and after each infusion.

The study’s primary outcome was MADRS, which was measured immediately prior to rapamycin and placebo administration, and after ketamine infusion.

Descriptive statistics were calculated prior to statistical analysis, and mixed models with fixed effects of treatment, time, the interaction between treatment and time, and order were used to analyze the data. Correlation analyses explored the relationship between rapamycin level and improvement in depression severity.

We targeted to randomize 30 subjects in 3 years, but were able to randomize 23 patients in 2 years. The detectable effect size is 0.68, and a secondary analysis was conducted on the participant who was excluded from the primary analysis.

A total of 20 participants were included in the analysis, 8 men and 12 women, with a mean age of 42.8 years, a BMI of 27.2 kg/m2, and an ESR of 11.5 mm/h.

There was a significant interaction between treatment and time, and a significant main effect of time, demonstrating significant decrease in MADRS scores from baseline. There was no significant main effect of treatment, and the effects of CRP and ESR were non-significant. At 24 h, the response and remission rates following placebo were comparable to those following rapamycin treatment, but at 2 weeks, the response and remission rates following placebo were lower.

The mean QIDS-SR scores at 2 weeks remained significantly lower than baseline following rapamycin treatment, but not following placebo. There were no significant differences in the rate of patients who showed 50% improvement on QIDS-SR at 24 h, but there was a higher rate at 2 weeks following rapamycin + ketamine.

There was a significant main effect of time on HAMA scores, with the highest numerical mean difference achieved at 4 h. There was no significant main effect of treatment or interaction between treatment and time.

Time had a significant effect on CADSS scores, which returned to baseline 2 h post infusion. There was no significant effect of treatment.

There was a significant main effect of time on PANSS-positive scores, with a significant reduction 2 h post infusion. There was no significant main effect of treatment or interaction between treatment and time.

Participants in Phase 1 tolerated the combination treatment with no serious or unexpected adverse events. In Phase 2, 37 adverse events were reported, 21 of which were reported by four participants.

Discussion

This study failed to validate the prediction from preclinical studies that rapamycin pretreatment would reduce the acute antidepressant effects of ketamine. However, rapamycin pretreatment increased the response and remission rates at 2 weeks, suggesting that this treatment approach may prolong the antidepressant effects of ketamine.

Pretreatment with rapamycin appears to prolong the antidepressant effects of ketamine and other rapid-acting antidepressants, without increasing the blood level of ketamine or changing the subjective response to ketamine.

We could not administer rapamycin intracortically to fully parallel the preclinical reports, but we believed it was important to test whether systemic mTORC1 inhibition blocks the antidepressant effects of ketamine in humans. The current study findings rejected this hypothesis, but it remains plausible that higher oral doses or intracortical administration is required.

Ketamine treatment decreased synaptic formation in the PFC and NAc, and this may explain the failure of rapamycin treatment.

The results of the current study suggest that rapamycin inhibits mTORC1, but other alternative possibilities should be considered, such as the validity of the preclinical model of depression that gave rise to the mTORC1 hypothesis.

Rapamycin may prolong the antidepressant effects of ketamine by protecting the newly made synapses, or by enhancing autophagy, which is thought to be critical in the pathology and treatment of depression.

Limitations and Strengths

The study sample was based on feasibility and funding availability, and the effect size of rapamycin on the QIDS-SR was small. Based on the observation in the first phase of the study, we did not ask the participants to guess their treatment in Phase 2. Additionally, we did not examine whether ketamine metabolites were affected by rapamycin, subsequently leading to the prolonged antidepressant effects.

The current study is one of the largest cross-over ketamine studies in depression and is the first to investigate an essential mechanistic pathway that has so far been implicated in the pathology and treatment of depression based primarily on preclinical evidence.

The immune system is involved in both depression pathology and resilience, and the use of combined therapy instead of monotherapy or add-on approaches may overcome many of the shortcomings of anti-inflammatory monotherapy/add-on approaches.

Conclusion

Rapamycin, an immunosuppressant, did not inhibit the antidepressant effects of ketamine at 24 h post treatment, but prolonged the antidepressant effects and increased the response and remission rates at 2 weeks following treatment.

GS, RF, DCD, MR, and OT have received consulting fees, research contracts, or other compensation from companies related to the topic of this article. All other co-authors declare no conflict of interest.

Notes

This paper and its implications were also discussed on r/DrugNerds.