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Melancholia is a severe form of depression that is typified by greater genetic and biological influence, distinct symptomatology, and preferential response to physical treatment. This paper sought to broadly overview potential biomarkers of melancholia to benefit differential diagnosis, clinical responses and treatment outcomes. Given nuances in distinguishing melancholia as its own condition from other depressive disorder, we emphasised studies directly comparing melancholic to non-melancholic depression. A comprehensive literature search was conducted. Key studies were identified and summarised qualitatively. 105 studies in total were identified. These studies covered a wide variety of biomarkers, and largely fell into three domains: endocrinological (especially cortisol levels, particularly in response to the dexamethasone suppression test), neurological, and immunological (particularly inflammatory markers). Less extensive evidence also exists for metabolic, genetic, and cardiovascular markers. Definitive conclusions were predominantly limited due to substantial heterogeneity in how included studies defined melancholia. Furthermore, this heterogeneity could be responsible for the between- and within-group variability observed in the candidate biomarkers that were examined. Therefore, clarifying these definitional parameters may help identify underlying patterns in biomarker expression to improve diagnostic and therapeutic precision for the depressive disorders.

Differentiating melancholic and non-melancholic depression via biological markers: A review