Efficacy and safety of Lemborexant in combination with Escitalopram in treating major depressive disorder with comorbid insomnia: study protocol for a multicenter, randomized, double-blind, placebo-controlled trial

Background Insomnia is a common clinical symptom of major depressive disorder (MDD) and an independent risk factor for the subsequent onset and recurrence of MDD. The short- and long-term efficacy and safety of Lemborexant (LEM), a dual orexin receptor antagonist (DORA), for the treatment of primary insomnia have been well established. However, no randomized controlled trial (RCT) has evaluated its efficacy and safety in patients with MDD and comorbid insomnia. This RCT aims to assess the efficacy and safety of LEM combined with Escitalopram (ESC) for patients with MDD and comorbid insomnia. Methods In this multicenter, double-blind RCT, 286 adult patients with newly diagnosed or recurrent MDD and comorbid insomnia who have not received standard antidepressant therapy during the current depressive episode will be enrolled and randomized in a 1:1 ratio to receive ESC plus LEM or ESC plus placebo (PBO) for 6 weeks. The primary endpoint is the between-group difference in the change from baseline in subjective total sleep time, as measured using a sleep diary, at the end of 6 weeks of treatment. The secondary endpoints include between-group comparisons of changes from baseline in other subjective sleep parameters, objective sleep parameters assessed by polysomnography, the Insomnia Severity Index, and the 17-item Hamilton Depression Rating Scale score, excluding sleep-related items. Adverse events (AEs), treatment-emergent AEs, and serious AEs will be recorded. Discussion This study aims to explore a potentially safer and more effective treatment option than conventional benzodiazepine receptor agonists for patients with MDD and comorbid insomnia. Furthermore, it aims to investigate the potential role of LEM as an adjunctive treatment for MDD, and to provide preliminary evidence as to whether DORAs may confer benefits beyond sleep improvement in this population. Chinese Clinical Trial registry (ChiCTR) registration: ChiCTR2600119476 (Date of registration: February 27, 2026)