The mTORC1 signaling network underlying the pathogenesis and treatment of depression: new insights into rapid-acting antidepressant therapies

Depression is a devastating mental disorder and major depressive disorder(MDD) that afflicts 16% of the global population at some point in their lives.Currently available classical antide.pressants(SSRIs,SNRIs,TCAs and MOIs),require a minimum of 2–4 weeks of continuous treat.ment to elicit therapeutic relief in depressed patients and are associated with high rates of non-respon.siveness,and limited duration of efficacy.Therefore,faster-acting antidepressant therapies are need.ed,particularly for patients at risk for suicide for current therapies for depression.Although the molecu.lar mechanisms underlying the pathogenesis of depression are still largely unclear,previous studies have suggested that modulators of mammalian target of rapamycin complex 1(mTORC1) signaling may have beneficial neuroprotective and antidepressant effects.Here,we review recent advances in understanding mTORC1 signaling in depression and potential therapeutic strategies resulting from modulation of the mTORC1 signaling network.We also highlight recent studies considered to support mTORC1 signaling modulation as a rapid-acting antidepressant therapy(e.g.ketamine,scopolamine,GLYX-13,(2R,6 R)-HNK,Ro-256891 etc.) and discuss future research directions.Studies on prospec.tive next-generation rapid-acting antidepressant therapies should focus on developing more selective glutamate receptors(e.g.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors(AMPARs)agonists or activators) that activate the mTORC1 signaling pathway free of ketamine's adverse effects.