The association between depressive symptom severity and metabolic disturbances in major depressive and bipolar disorders: A systematic review and meta-analysis

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BACKGROUND: Persons with depression are differentially affected by metabolic alterations, notably, insulin resistance and dyslipidemia. Metabolic alterations affect acute pharmacotherapy response and predispose risk for cardiovascular diseases. We aimed to extend knowledge pertaining to the depression-metabolic alteration association by evaluating whether depressive symptom severity moderates the association. METHODS: We conducted a systematic search of PubMed, Ovid and Scopus from inception to May 2025. Two reviewers (S.W. and G.H.L.) independently screened the identified studies. Studies were included if they enrolled adults with depression and reported on at least one metabolic parameter (i.e., fasting glucose, insulin, lipid panels). Standardized mean differences of metabolic parameters were pooled across studies. RESULTS: We identified 28 studies for inclusion. Persons with depression exhibited higher fasting glucose (SMD = 0.30, 95 % CI [0.12, 0.48]) and dyslipidemia [i.e., trends of increased low-density lipoprotein (SMD = 0.21, 95 % CI [-0.03, 0.44]) and lower high-density lipoprotein (SMD = -0.72, 95 % CI [-1.41, -0.03])]. Measures of insulin resistance were positively associated with anhedonia severity, sleep disturbances, and suicidal ideation. LIMITATIONS: Between-study methodological differences, including study design and sociodemographics, affects the synthesis of overall trends. CONCLUSION: Herein, we identify an association between depressive symptom severity and dysglycemia, dyslipidemia and insulin resistance. The results augment the conceptual framework implicating metabolic disturbances in depression pathophysiology and indirectly support testing that therapeutics currently in development in the treatment of depression (e.g., GLP-1 receptor agonists) may exhibit differential efficacy as a function of illness severity.

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