Abstract
Major depressive disorder is one of the most widespread mental illnesses, affecting more than 264 million people worldwide (World Health Organization, 2019) and causing enormous personal and socioeconomic burden. Conventional monoaminergic antidepressants have significant limitations, including delayed onset of therapeutic response and low efficacy: approximately one-third of depressed patients fail to respond to multiple antidepressant treatments and are considered treatment-resistant depression. Recent studies reveal that ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine as an antidepressant is limited due to its serious drawbacks including psychotomimetic/dissociative effects and abuse potential. Thus, there is a continuing unmet need for the development of safer rapid-acting antidepressants. I have demonstrated that resolvins, bioactive metabolites derived from docosahexaenoic acid and eicosapentaenoic acid, produce antidepressant effects through mechanisms (activation of mTORC1 signaling) similar to those underlying the rapid antidepressant effects of ketamine. Taken together, resolvins could be promising targets for the development of novel rapid-acting antidepressants with fewer side effects than ketamine, since resolvins are endogenous lipid mediators that play an important role in homeostasis.
