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.
