Circulating Orexin-A Levels in Patients With Schizophrenia, Bipolar Disorder, and Major Depressive Disorder: A Systematic Review and Meta-Analysis

Orexin-A, a neuropeptide involved in regulating physiological processes, has potential implications in psychiatric disorders. Studies examining orexin-A levels in schizophrenia, bipolar disorder, and major depressive disorder have produced conflicting results, highlighting the need for further research. To address these inconsistencies, this meta-analysis aims to synthesize existing data on orexin-A levels across these disorders, clarifying its role and potential as a diagnostic or prognostic biomarker. This systematic review, registered with PROSPERO, investigated plasma orexin-A levels in schizophrenia, bipolar disorder, and major depressive disorder. Relevant studies were identified through PubMed and PsycINFO using specific keywords. Inclusion criteria targeted adult patients with these disorders and healthy controls, assessing quality and bias using the MINORS tool for non-randomized studies and the AXIS tool for cross-sectional studies. A meta-analysis compared orexin-A levels between groups, using random-effects models and evaluating statistical heterogeneity and publication bias. Of the 64 reviewed articles in full-text screening, 11 met the criteria for analysis, involving 1,778 participants (514 with schizophrenia, 149 with bipolar disorder, and 461 with major depressive disorder). The meta-analysis revealed significantly decreased plasma orexin-A levels in schizophrenia (SMD = -0.38; 95% CI: -0.72 to -0.05; p = 0.03) and increased levels in major depressive disorder (SMD = 0.38; 95% CI: 0.15 to 0.60; p = 0.001) compared to healthy controls. Moderate statistical heterogeneity was noted in the schizophrenia analysis (I^2 = 54%). Methodological quality was generally high; MINORS scores ranged from 12 to 20 (out of 24), and AXIS scores ranged from 17 to 19 (out of 20), indicating a moderate-to-low risk of bias. These findings suggest distinct orexin-A dysregulation in schizophrenia and major depressive disorder. However, findings in bipolar disorder were inconclusive due to high heterogeneity, indicating orexin-A's complex involvement in mood and energy regulation.