Rapid acting antidepressants in the mTOR pathway: Current evidence

Despite the growing burden of major depressive disorder (MDD) on the society, therapeutic management that is mostly based on the conventional monoaminergic mechanisms, is significantly delimited especially from low response rate and time lag for treatment response; thus, often prolonging the distress for patients. The mechanistic exploration of drug candidates that could exert antidepressant effects rapidly has highlighted the significance of modulating mammalian target of rapamycin (mTOR) pathway in MDD. Fast acting antidepressants acts at different receptors, subunits and sites, including NMDA, AMPA, m1ACh, mGluR2/3 and GluN2B to enhance mTOR function, leading to increase in synaptic protein synthesis, synaptogenesis and spine-remodeling, which in turn contribute to the rapid antidepressant effects. This review focuses on the preclinical and clinical evidences on the fast acting antidepressants that can modulate mTOR pathway. It can be understood that modulating mTOR pathway for rapid onset of antidepressant effect in MDD is not without challenges as some of the drugs have failed in advanced stages of clinical trials. However, considering the recent approval of esketamine as a breakthrough in decades, fast acting antidepressants in the mTOR pathway may have promising prospects in the drug discovery pipeline.