MODULATION OF THE ANTIDEPRESSANT RESPONSE OF KETAMINE BY AN IMMUNOSUPPRESSANT RAPAMYCIN: A PROSPECTIVE RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY IN THE PATIENTS WITH REFRACTORY DEPRESSION

Abstract Background Our ketamine studies on the refractory depression (TRD) in the past 10 years have observed a short effect of a single dose of ketamine infusion lasting less than14 days. The antidepressant effect of ketamine was believed to activate the mechanistic target of rapamycin complex 1 (mTORC1), and produce synaptogenesis. Theoretically, inhibition of mTORC1 by an immunosuppressant rapamycin, prior to ketamine infusion, its antidepressant effect by ketamine would be diminished. However, in a comparison study using rapamycin plus ketamine vs. placebo plus ketamine, Abdallah found the antidepressant effect of the former was 47% whereas the later was 13 %, indicating that rapamycin might have other mechanisms beyond activation of mTORC1. To assess the role of rapamycin in ketamine treatment of TRD patients and to test if rapamycin might enhance and prolong the antidepressant effect of ketamine, we will conduct a parallel, randomized, double blind and placebo controlled study. Method The clinical trial has two study phases: in phase 1 study, 48 subjects with TRD will be enrolled. Two group of patients with each 24 subjects, randomly sampled, will receive either oral rapamycin 6 mg or placebo 2 hours before ketamine (0.5mg/kg) infusion once every two weeks for three times. Ratings for depression, anxiety and suicidality will be assessed at baseline, 2nd week, 4th week and 6th week. Response is defined by 50% reduction of the baseline mood symptoms at each timepoint and 2 out of 3 - timepoint response is defined as clinical responder. The outcome is to compare the number of responder between these two parallel trial groups. The responder obtained from phase 1 trial will be enrolled for the phase 2 open-label study. These subjects will continue to receive oral rapamycin 6 mg, 2 hours prior to a single dose of ketamine 0.5mg/kg infusion at the timepoint of the end of 6th week. Result Our initial results revealed 24 subjects (50%) received oral rapamycin 6mg + ketamine (0.5mg/kg) infusion while another 24 subjects received oral placebo + ketamine (0.5mg/kg) infusion. Response rate was found equally in the rapamycin ketamine group and placebo ketamine group. The effect of rapamycin ketamine group was not superior to that of the placebo ketamine group. Conclusion The initial finding was not compatible with the previous result from Abdallah’ s study, and did not show that rapamycin might prolong the duration of efficacy of ketamine.. Further detailed analysis might answer the differences.