Three-week effect of amisulpride, aripiprazole, and olanzapine on gene expression in peripheral blood in individuals with schizophrenia spectrum disorders

Abstract Objective Antipsychotic drugs are to varying degrees associated with hematological side-effects and peripheral metabolic and immunological changes. Here, we aimed to characterize the initial transcriptional changes in peripheral leukocytes from individuals with schizophrenia spectrum disorder (SSD) after starting antipsychotic treatment with amisulpride, aripiprazole, or olanzapine. Methods We analyzed RNA sequencing data obtained from peripheral whole blood samples from 100 individuals with SSD (41 antipsychotic-naïve [AP-naïve], 10 AP-free, and 49 AP-switching at inclusion) collected at baseline and after 1 and 3 weeks of antipsychotic drug use. Data from 36 healthy controls (HC) collected at baseline and after 3 weeks without any intervention were included. We analyzed age- and sex-adjusted differentially expressed genes between SSD and HC before and after treatment and stratified by previous antipsychotic use. A linear mixed model was applied to study longitudinal gene expression changes associated with the antipsychotic drug that was used. Results After 3 weeks of antipsychotic use, the AP-switching group had the most significant transcriptional changes, characterized by increased expression of genes typically transcribed by immature erythroid cells and immature neutrophil cells. This gene profile showed no correlation with symptoms score. Interestingly, the immature neutrophil-associated gene signature was more pronounced in participants receiving olanzapine, and partly also amisulpride, but not aripiprazole. In contrast, only minor transcriptional changes were observed in the AP-naïve participants. Conclusions These findings suggest that prior antipsychotic exposure may have a priming effect on leukocyte gene expression, which results in a transcriptional response indicative of stress erythropoiesis and neutropoiesis when switching to a new antipsychotic drug. This response appears to be independent of psychosis symptom severity.