White Blood Cell Proportions Are Associated With Response to Psychosocial Therapy in Young People at Ultra-High Risk...

White blood cell (WBC) counts, DNA methylation, and gene expression are reported to be associated with psychosis. However, it is not known whether these associations precede the onset of psychosis or whether they are relevant for the stratification of psychosis risk in clinically high-risk individuals. The STEP (Staged Treatment in Early Psychosis) clinical trial evaluated the effectiveness of a sequential intervention strategy for preventing psychosis in a cohort of young people at ultra-high risk (UHR) of psychosis. Participants were assessed for remission of UHR status after up to 6 months of treatment with psychosocial therapy.

Cell-type proportions estimated from whole-blood DNA methylation samples (N = 91) were used to test for associations between WBC proportions at trial baseline and remission of UHR status (31 remitters, 60 nonremitters), including at which step of the trial remission occurred. DNA methylome-wide association and differential expression analyses were conducted to test for associations with remission of UHR status.

Baseline lymphocyte cell proportions (odds ratio [OR], 0.23; 95% CI, 0.07-0.62; p = 9.2 × 10^-3) and neutrophil-lymphocyte ratio (OR, 2.9; 95% CI, 1.37-7.46; p = .012) were significantly associated with remission status. There were suggestive associations between specific cell types and the timing of remission during the trial; however, these did not survive correction for multiple testing. No methylation probes or differentially expressed genes were associated with remission status when cell-type proportions were included as covariates.

Our results indicate the potential importance of WBCs for further stratification of psychosis risk in UHR individuals and reinforce the importance of routine collection of WBC data for future clinical trials.