Depression Heterogeneity and the Potential of a Transdiagnostic and Dimensional Approach to Identify Biologically Relevant Phenotypes

Major depressive disorder (MDD) is the most prevalent mood disorder worldwide and the third leading cause for years lived with disability. Major challenges encountered in the treatment of MDD include high non-responder and relapse rates and delayed therapeutic onset. MDD is a heterogeneous condition, and the identification of more homogenous groups of patients may facilitate the selection of optimal therapeutic strategies. Different approaches have been considered for the subtyping of depression, including etiological factors, clinical symptoms, biological markers, and treatment response. However, the optimal strategy for the identification of more homogenous groups of patients remains elusive. In this chapter, the subdivision of depression into melancholic and atypical subtypes, the significance of considering hypomanic or manic symptoms in the diagnosis and treatment of depression, and the importance of combining biological and clinical findings based on the approach implemented by the Research Domain Criteria (RDoC) project are discussed. Phenotypic associations between atypical depressive symptoms and obesity-related traits have also been identified that may arise from shared pathophysiologic mechanisms. Thus, the development of treatments effectively targeting immunometabolic dysregulations may benefit patients with atypical depression. The presence of hypomanic or manic symptoms in patients with depression may be relevant for the selection of a therapeutic strategy. Notably, the longitudinal course of mood-related symptoms should be considered, and a dimensional approach should be applied to capture the complexity of mood disorders. The application of the RDoC framework to mood-related symptoms allows the use of a transdiagnostic dimensional approach, which incorporates pathophysiological and clinical data and considers the influence of neurodevelopmental and environmental factors. Future studies on MDD subtypes and more broadly defined mood-related symptoms should focus on the identification of biologically relevant disease phenotypes and take into account the role of neurodevelopmental and environmental factors for the identification of new therapeutic targets.

Keywords: Atypical depression, Biomarkers, Data-driven phenotypes, Depression subtypes, Hypomanic symptoms, Major depressive disorder, RDoC.