Question听 Are inflammatory biomarkers associated with subsequent risk of psychiatric disorders?

Findings听 In this cohort study evaluating data of 585鈥�279 individuals from the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort and validated with the data of 485鈥�620 individuals from the UK Biobank, inflammatory biomarkers including leukocytes, haptoglobin, C-reactive protein, and immunoglobulin G were associated with the risk of psychiatric disorders using cohort and nested case-control study analysis. Moreover, mendelian randomization analyses suggested a possible causal link between leukocytes and depression.

Meaning听 This study suggests a role of inflammation in the development of psychiatric disorders and may aid in identifying individuals at high risk.

Importance听 Individuals with psychiatric disorders have been reported to have elevated levels of inflammatory biomarkers, and prospective evidence is limited regarding the association between inflammatory biomarkers and subsequent psychiatric disorders risk.

Objective听 To assess the associations between inflammation biomarkers and subsequent psychiatric disorders risk.

Design, Setting, and Participants听 This was a prospective cohort study including individuals from the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort, with no prior psychiatric diagnoses and having a measurement of at least 1 inflammatory biomarker. Data from the UK Biobank were used for validation. Longitudinal trajectories of studied biomarkers were visualized before diagnosis of psychiatric disorders in the AMORIS cohort via a nested case-control study. In addition, genetic correlation and mendelian randomization (MR) analyses were conducted to determine the genetic overlap and causality of the studied associations using publicly available GWAS summary statistics.

Exposures听 Inflammatory biomarkers, eg, leukocytes, haptoglobin, immunoglobulin G (IgG), C-reactive protein (CRP), platelets, or albumin.

Main Outcomes and Measures听 Any psychiatric disorder or specific psychiatric disorder (ie, depression, anxiety, and stress-related disorders) was identified through the International Statistical Classification of Diseases, Eighth, Ninth, and Tenth Revision codes.

Results听 Among the 585鈥�279 individuals (mean [SD] age, 45.5 [14.9] years; 306鈥�784 male [52.4%]) in the AMORIS cohort, individuals with a higher than median level of leukocytes (hazard ratio [HR], 1.11; 95% CI, 1.09-1.14), haptoglobin (HR, 1.13; 95% CI, 1.12-1.14), or CRP (HR, 1.02; 95% CI, 1.00-1.04) had an elevated associated risk of any psychiatric disorders. In contrast, we found an inverse association for IgG level (HR, 0.92; 95% CI, 0.89-0.94). The estimates were comparable for depression, anxiety, and stress-related disorders, specifically, and these results were largely validated in the UK Biobank (n = 485鈥�620). Analyses of trajectories revealed that individuals with psychiatric disorders had higher levels of leukocytes and haptoglobin and a lower level of IgG than their controls up to 30 years before the diagnosis. The MR analysis suggested a possible causal relationship between leukocytes and depression.

Conclusions and Relevance听 In this cohort study, inflammatory biomarkers including leukocytes, haptoglobin, CRP, and IgG were associated with a subsequent risk of psychiatric disorders, and thus might be used for high-risk population identification. The possible causal link between leukocytes and depression supports the crucial role of inflammation in the development of psychiatric disorders.