Efficacy of orexin antagonists for the management of major depressive disorder: A systematic review of randomized clinical trials

Orexin receptor antagonists are a group of medications primarily developed to treat insomnia. Preliminary studies support their efficacy in the treatment of depression. In this systematic review, we aim to evaluate the efficacy of orexin receptor antagonists for the treatment of major depressive disorder (MDD). Electronic databases were searched from inception to February 2024 to find relevant studies. Original studies in English that evaluated efficacy of orexin receptor antagonists were included. A total of five randomized clinical trials involving 498 participants were included. Seltorexant (20 mg) significantly decreased depression scores when compared to placebo, as measured by the Hamilton Depression Rating Scale (HDRS). In patients with inadequate responses to antidepressants, seltorexant (20 mg) also showed improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total scores compared to placebo. However, filorexant did not exhibit a significant difference in MADRS total scores compared to placebo. A separate study on seltorexant (40 mg) for MDD patients resulted in a non-significant decrease in depressive symptoms compared to placebo, as measured by the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Taken together, these findings highlight the potential of orexin receptor antagonists, particularly seltorexant, as a novel avenue for managing depressive symptoms in MDD. Further research is warranted to better understand their role in depression treatment and their safety profile.