Pharmacological modulation of hyperarousal in insomnia associated with major depressive disorder: a narrative review of sedating antidepressants and orexin receptor antagonists.

Insomnia symptoms in major depressive disorder (MDD) are clinically heterogeneous, ranging from presleep rumination and prolonged sleep latency to repeated nocturnal awakenings and early-morning awakening. Their clinical significance and treatment implications may also differ between active MDD and residual insomnia symptoms during partial remission. This narrative review examines how these presentations may inform the use of sedating antidepressants and dual orexin receptor antagonists (DORAs). Sedating antidepressants, including mirtazapine, trazodone, doxepin, and other tricyclic antidepressants, differ in dose-dependent antidepressant activity, receptor profile, and adverse-effect burden. DORAs directly target orexin-mediated wake drive and have the strongest evidence for insomnia disorder, particularly sleep-maintenance outcomes, although evidence in active MDD remains limited. Because clinical presentations neither establish an underlying mechanism nor reliably predict treatment response, the proposed framework should be used as a hypothesis-generating aid rather than a validated treatment algorithm. Pharmacological selection should also consider suicide risk, substance-use history, comorbid sleep disorders, concomitant central nervous system depressants, and next-day functioning.