Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.
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PMID:Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. 2439 93

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.
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PMID:Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. 2734 65

Lumateperone tosylate (ITI-007 tosylate, ITI-722) is a first-in-class investigational drug which acts syn-ergistically through multiple systems (serotonergic, dopaminergic and glutamatergic), thus representing a unique approach for the therapeutic management of a range of neuropsychiatric disorders. It possesses a potent antagonistic activity at 5-hydroxytryptamine (serotonin) 2A (5-HT2A) receptors and also binds to dopamine (D1, D2) receptors with partial agonism at presynaptic D2 receptors and postsynaptic antagonism. Further, preclinical data demonstrated that lumateperone uniquely acts as an indirect modulator of glutamatergic phosphoprotein with D1-dependent augmentation of both NMDA and AMPA activity via the mammalian target of rapamycin (mTOR) pathway, mechanisms thought to predict potent and rapid antidepressant effects. Previous results of schizophrenia efficacy studies found robust improvements in depressive as well as psychotic symptoms for those patients who were comorbidly depressed. In various clinical trials to date, the safety profile of lumateperone was found to be similar to that of placebo. These promising results and strong performance in phase II studies point to the potential of lumateperone to display potent and rapid antidepressant effects in patients suffering from a range of mood disorders. Currently, this novel drug is in phase III of its clinical development for schizophrenia, agitation associated with dementia and bipolar depression.
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PMID:Lumateperone: a new treatment approach for neuropsychiatric disorders. 3059 90