Mapping the Heterogeneity of Major Depressive Disorder: A Systematic Review of Multi-Omics Integration Studies

Abstract

Major depressive disorder (MDD) has a widespread heterogeneity as per the psychiatric nosology, and traditional symptom-based diagnosis frameworks do not offer many clues regarding tailored therapy techniques. The recent development of multi-omics and data-driven solutions has now provided evidence for pathophysiologically different subtypes of MDD, moving the field toward precision psychiatry. The systematic review aggregates multimodal studies that combing neuroimaging, genomics, transcriptomics, epigenomics, metabolomics, and proteomics to define MDD subtypes. There are two to four candidate clusters that have been formed across these heterogeneous modalities, and each has a neurobiological and clinical profile. Cognitive subtypes are characterized by executive failure and loss of prefrontal and temporal gray matter. Neuroimaging-derived subtypes show specific patterns of functional connectivity that may predict response to selective serotonin reuptake inhibitors (SSRIs) or repetitive transcranial magnetic stimulation (rTMS) in preliminary studies. There are immune-metabolic subtypes characterized by increased inflammatory cytokines and dysregulation of metabolic pathways. Molecular subtypes appear to be differentiated by cellular mechanisms such as mitophagy and pyroptosis. Taken together, these results indicate that multi-omics integration, in addition to explaining the molecular architecture of MDD, also characterizes patient subgroups with pathophysiological mechanisms, dimensions of symptoms, and disease treatment. The growing body of literature demonstrates that there is a shift in psychiatry toward a more mechanistic approach and that biomarker-based diagnostics and personalized treatment regimens are urgently needed to improve clinical outcomes in depressive diseases.