Orexinergic Dysregulation in Major Depressive Disorder: Insights from a Prospective Cohort Study Evaluating MADRS, PSQI, and MoCA Scores

Background: Major depressive disorder (MDD) is a complex psychiatric condition characterized by affective, cognitive, and somatic symptoms. Disturbances in sleep and cognition are common yet underexplored features of MDD. Orexin, a hypothalamic neuropeptide, plays key roles in arousal, sleep–wake regulation, and cognition. This was a prospective, observational study with longitudinal follow-up investigating the correlation between serum orexin- A levels and depression symptom severity, sleep quality, and cognitive status, as assessed with standard psychometric tools. Methods: A total of 113 patients with MDD and 60 age- and sex-matched healthy controls were assessed in this study. Patients were followed up after 6–12 weeks of antidepressant therapy. Symptom severity, sleep quality, and cognitive status were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS), the Pittsburgh Sleep Quality Index (PSQI), and the Montreal Cognitive Assessment (MoCA), respectively. Serum orexin- A was quantified using an enzyme-linked immunosorbent assay (ELISA). The correlation between changes in serum orexin- A levels and clinical scale scores was assessed. Results: The median (Q1–Q3) serum orexin levels in patients and healthy controls were 192.6 (183.2–209.3) pg/mL and 207.4 (203.8–218.7) pg/mL, respectively, with a statistically significant difference ( p < .001). Serum orexin- A levels in the patient group at baseline and follow-up were not statistically significant. Changes in various score components of the questionnaires were statistically significant. However, serum orexin- A levels were correlated only with the apparent sadness component of MADRS. No correlation was observed between orexin- A levels and PSQI or MoCA questionnaire components. Conclusions: Serum orexin- A showed potential as a biomarker for MDD, exhibiting correlation with a MADRS score component. However, no correlation was observed with sleep quality and cognitive status, necessitating validation in larger cohorts.