Exploring the role of mTOR signaling pathway in ketamine's therapeutic effects on suicide risk in depression: Insights into circadian dysregulation mechanisms

Abstract

Depression is a common psychiatric condition with a substantial number of patients, who fail to achieve response or remission despite index antidepressant treatment. Insomnia and circadian misalignment are established and modifiable suicide risk factors. In recent years suicide rates have significantly increased. Commonly used methods (lithium, clozapine, or dialectical behavioral therapy and cognitive-behavioral therapy) reduce the long-term suicide risk but are inefficient in emergencies. Ketamine is a non-competitive N-methyl-D-aspartate receptor novel agent with rapid-acting antidepressant and anti-suicidal properties. Yet, anti-suicidal effects are only partially mood-dependent, implying other pathways are involved in the reduction of suicidal ideation. Ketamine induces an increase in mammalian target of ramapycin and brain-derived neurotrophic factor expression, influencing circadian dysregulation and stimulating synaptogenesis and restoring the synaptic integrity. In addition, ketamine seems to improve sleep and alter circadian clock gene expression (i.e., Bmal1, CLOCK, PER1, PER2, PER3, Cry 1, Cry 2). Objective estimates in nocturnal electroencephalography show an increase in slow wave sleep, total sleep time and rapid eye movement sleep. It may be hypothesized that ketamine’s anti-suicidal properties stem from the improvement in both sleep and circadian dysregulation. Further studies should investigate the relationship between ketamine, sleep, circadian rhythms and suicidality. The aim of the paper is to put forward a hypothesis about circadian dysregulation in depression and suicidality via ketamine use in mood disorders.