What Do Plasma Proteomes Capture in Psychopathology? Liability, State, and Social Adversity

AbstractPsychiatric plasma proteomics has long been constrained by the wrong benchmark. For many years, the field has asked whether circulating proteins can validate symptom-defined diagnostic categories as distinct biological entities. That question is no longer adequate. As large-scale plasma protein profiling, prospective cohort studies, repeated-measures clinical designs, social-exposure analyses, and pQTL-based causal prioritization continue to advance, a different picture is emerging. Plasma proteomic signal relevant to psychopathology is real, but it is not unitary. It is layered. We argue that psychiatric plasma proteomics should be reinterpreted through three distinct but partially overlapping signal classes. The first class reflects liability: circulating variation that precedes illness expression or marks susceptibility. The second class reflects current state: signal associated with symptom burden, episode phase, treatment response, or short-term clinical change. The third class reflects social adversity: proteomic signatures of chronic psychosocial burden and its multisystem embodiment. Much of the apparent instability in psychiatric biomarker research can be better understood as a category error: these different forms of signal have repeatedly been analyzed as though they were interchangeable and then judged against a single standard of diagnostic specificity. This reinterpretation changes both the meaning of the existing literature and the field’s more realistic future. The strongest current evidence supports liability-linked signal. Adversity-linked plasma signal is also emerging across studies of social isolation, loneliness, social support, and broader social disadvantage, although current support still rests on a limited number of large cohort lines. By contrast, state-sensitive plasma signal remains clinically compelling, but it is supported by only a small and heterogeneous body of strict repeated-measures studies. Plasma proteomics therefore matters less as a route to diagnosis-perfect blood tests than as an empirical instrument for biological stratification across and within disorders. The next phase of the field requires repeated within-person sampling, adversity-rich phenotyping, module-level rather than single-protein inference, and a tighter correspondence between research design and claim strength. The core task is no longer to ask whether plasma proteins can diagnose psychiatric disorders, but to determine which layers of psychopathology they encode. Version noteThis record contains the author’s preprint manuscript made publicly available prior to journal submission. It has not undergone peer review.