Pursuing the elusive biosignature for suicide: a decennial update

Suicide is the second leading cause of death for American adolescents and young adults and is transdiagnostic. Suicide risk is impacted by genetic and both distal and proximal environmental factors, particularly stress exposures. This review encompasses the past 10 years of research comparing biological measures between suicide decedents and control decedents and identifies studies focused on stress-related biological pathways, inflammation, neuroplasticity, and the serotonergic system as candidate contributors. Inclusion criteria for studies aimed to maximize confidence that reported biological differences are specific to suicide and independent of confounding psychiatric comorbidity, addressing ambiguity in previous work. The review revealed evidence for alterations in stress-related biological systems and decreased serotonergic tone among suicide decedents. Methodological and conceptual advances over the past decade have driven a shift from hypotheses-driven to data-driven approaches, including genomic, transcriptomic and methylomic analyses. While multi-omic studies have the potential to identify mechanistic molecular targets, to date findings lack interpretability. This review highlights the need for research in larger samples, across multiple brain areas, and in specific cell types to fill a gap in system biology-guided multi-omic studies. Lastly, incorporating poly-environmental stress exposure (exposomic) models in suicide postmortem research may elucidate mechanisms linking environmental stress and biological measures, potentially increasing the reproducibility of postmortem suicide studies.