Review on Treatment Strategies for Insomnia in Major Depressive Disorder: Focus on Sedating Antidepressants and Orexin Receptor Antagonists

Sedating antidepressants, such as mirtazapine, trazodone, and doxepin, vary in dosage, receptor activity, and potential side effects. In contrast, DORAs specifically target orexin-driven wakefulness and show promise for insomnia disorders, mainly focusing on sleep maintenance, though data in the context of active MDD remain sparse. The heterogeneity of insomnia symptoms indicates the need for careful distinction among them, as clinical presentations do not confirm underlying mechanisms or predict treatment responses adequately, thus serving more as a guide than a definitive treatment pathway.

Population estimates indicate that symptom-based insomnia affects approximately one-third of adults, while chronic insomnia disorder, often associated with functional impairment, prevails in about 6-10% of the population. In individuals with MDD, sleep disturbances can arise as an integral part of the depressive syndrome and can also represent an independent therapeutic target. Patients often present with symptoms such as difficulty initiating sleep or waking early, and while these symptoms are clinically informative, they do not pinpoint the fundamental mechanisms at play.

Poor sleep quality in individuals with MDD can exacerbate issues such as concentration difficulties, irritability, and decreased treatment adherence. Additionally, chronic insomnia is linked to higher risks of relapse in mood disorders. As a result, pharmacotherapy is sometimes necessary, especially in cases where psychological interventions like cognitive behavioral therapy for insomnia (CBT-I) are not immediately available.

DORAs present a distinct pharmacological approach as they selectively inhibit orexin-mediated wakefulness rather than acting as generalized sedatives. The evidence supporting their benefits in sleep outcomes primarily emanates from trials in insomnia disorders, and the applicability for patients with active MDD is not firmly established. Presently, the use of DORAs should be cautiously considered, particularly in patients displaying high risks of suicidality or complex medication regimens.

The review underscores the importance of understanding the individual clinical presentation, as patients may present different insomnia patterns that direct treatment choices. For instance, cognitive-emotional hyperarousal, characterized by persistent negative thoughts, may warrant a sedating antidepressant approach, while predominant sleep-maintenance issues may guide the use of DORAs. Overall, this framework aims to optimize treatment strategies and guide clinicians in addressing both mood and sleep symptoms in MDD.