The effect of glutamatergic modulators on sleep behavior and architecture in depressive disorders: A systematic review.

Approximately 80% of individuals diagnosed with major depressive disorder (MDD) report symptoms of insomnia. Glutamatergic modulators, such as ketamine, are reported to be effective for the treatment of depressive symptomatology in adults with MDD. Disrupted glutamate homeostasis is linked to poor sleep quality and sleep disorders. Herein, we sought to systematically determine the effect of glutamatergic modulators on sleep mechanisms in preclinical and clinical studies. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to November 27, 2024. Study screening and selection was performed by three reviewers (K.V., B.S., and W.C.). Included studies reported on the effects of glutamatergic modulators on sleep behaviors, architecture, and mechanisms. Preclinical studies reported that glutamatergic modulators, notably ketamine impact mechanistic pathways known to subserve sleep. Including serotonergic, dopaminergic, and GABAergic systems. It was reported that ketamine effects on electroencephalogram (EEG) delta power during non-rapid eye movement (NREM) sleep, and normalizes clock suppressor gene expression. Furthermore, while esketamine enhances delta power during NREM sleep, arketamine does not exhibit a similar effect. Separately, mGlu2/3 activators are suggested to reduce rapid eye movement (REM) sleep. Clinical studies indicate that improved sleep in patients with MDD can mediate ketamine's antidepressant effects. Our findings indicate that glutamatergic modulators, primarily ketamine, are associated with improvement across several sleep behaviors commensurate in MDD, suggesting that mechanisms subserving sleep are potential targets for depression treatment.