Efficacy and safety profiles of FDA-approved dual orexin receptor antagonists in depression: A systematic review of pre-clinical and clinical studies.

BACKGROUND

Sleep disturbances, such as insomnia, are a group of prevalent and debilitating symptoms of Major Depressive Disorder (MDD). Dual Orexin Receptor Antagonists (DORAs) have emerged as potential treatments for insomnia and comorbid psychiatric conditions, such as MDD. We sought to comprehensively examine the efficacy, safety, and pharmacology of DORAs in the context of MDD and insomnia.

METHODS

We performed a systematic review of primary research on daridorexant, lemborexant, and suvorexant retrieved from PubMed and OVID databases up to January 2025. Included studies were limited to randomized controlled trials and other studies investigating DORAs that examined the efficacy and safety of these agents on sleep architecture and depressive symptoms in individuals with MDD, Insomnia Disorder (ID), and healthy controls.

RESULTS

A total of 19 studies were included in this review. DORAs demonstrated significant improvements in sleep onset latency, wake after sleep onset, and total sleep time, which were consistent across individuals with insomnia and comorbid MDD. The impact across DORAs on depressive symptoms was modest. The safety profiles were generally favourable, with most adverse events being mild to moderate.

LIMITATIONS: The studies reviewed were predominantly short-term and there was substantial variability in sample composition. Further research is needed to assess DORAs in larger, long-term clinical trials within the MDD population.

CONCLUSION

DORAs show potential in improving sleep parameters in individuals with MDD. While their effects on depressive symptoms in this review are modest, further research is needed to assess long-term efficacy, safety, and their impact on depressive symptoms, as well as to explore potential combination therapies.