MTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression

Abstract

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.