Resolvins as novel targets for rapid-acting antidepressants

Abstract

Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and relatively low efficacy. Recent studies reveal that the NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant depressed patients. Despite the unique antidepressant efficacy, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks, such as abuse potential and psychotomimetic/dissociative effects. The molecular and neuronal mechanisms underlying the antidepressant actions of ketamine have been intensively studied to pave the way for the development of novel, rapid and more efficacious antidepressants with fewer side effects than ketamine. Preclinical studies demonstrate that ketamine produces antidepressant effects through rapid release and/or expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and stimulation of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex and hippocampus. We have recently found that resolvins (RvD1, RvD2, RvE1, RvE2 and RvE3), bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects, and that the antidepressant effects of RvD1, RvD2 and RvE1 require mTORC1 activation. These findings suggest that resolvins could be promising targets for the development of novel rapid antidepressants with fewer side effects than ketamine because they are endogenous lipid mediators that play an important role in homeostasis.