Orexin Receptor Antagonists as Adjunct Drugs for the Treatment of Depression: A Mini Meta-Analysis

There is growing interest in the efficacy of orexin receptor antagonists (ORA), one of the new psychopharmacological agents used in the treatment of insomnia, in other psychiatric disorders such as depression.

This meta-analysis was conducted in accordance with PRISMA requirements. Literature searches were conducted using PubMed, Scopus and EBSCO (Medline) databases. Search words were (depression OR mood disorder OR affective disorder) AND (orexin OR orx OR hypocretin OR orx1 OR orx2 OR orexin receptor antagonist OR almorexant OR suvorexant OR lemborexant OR daridorexant OR seltorexant OR vornorexant OR filorexant). No date restrictions were used. The random effects model was used for analyses with I² values above 50% and fixed effects model was used for analyses with I² values below 50%.

In the acute phase, ORAs had no significant effect on core, sleep-adjusted and total symptoms of depression respectively; Standardized Mean Difference (SMD) for random effect -0.422, 95% CI [-0.90; 0.06], p=0.089, I²=62.4%; SMD for random effect -0.375, 95% CI [-1.24; 0.49], p=0.400; I²=66.6% and SMD for random effect -0.477, 95% CI [-0.97; 0.01], p=0.059; I²=83.1%). However, they had a significant effect on core and total symptoms of depression in the early period respectively; SMD for fixed effect=-0.228, 95% CI [-0.44; -0.01], p=0.036, I²=9.1%; and SMD for fixed effect=-0.186, 95% CI [-0.37; -0.001], p=0.048, I²=0.0%, respectively).

The results of this meta-analysis suggest that ORAs may provide direct antidepressant efficacy when added to existing antidepressant treatment and may also have indirect antidepressant effects through improvement in sleep symptoms. Considering the physiological effects of orexin on behaviors, ORAs may be promising new treatment modalities in the treatment of many psychiatric disorders other than insomnia. However, these results are preliminary and further studies with different ORAs at different doses and with different samples are needed.