Gene expression and response prediction to amisulpride in the OPTiMiSE first episode psychoses

Abstract

A fundamental shortcoming in the current treatment of schizophrenia is the lack of valid criteria to predict who will respond to antipsychotic treatment. The identification of blood-based biological markers of the therapeutic response would enable clinicians to identify the subgroup of patients in whom conventional antipsychotic treatment is ineffective and offer alternative treatments. As part of the Optimisation of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) programme, we conducted an RNA-Seq analysis on 188 subjects with first episode psychosis, all of whom were subsequently treated with amisulpride for 4 weeks. We compared gene expression on total RNA from patients' blood before and after treatment and identified 32 genes for which the expression changed after treatment in good responders only. These findings were replicated in an independent sample of 24 patients with first episode psychosis. Six genes showed a significant difference in expression level between good and poor responders before starting treatment, allowing to predict treatment outcome with a predictive value of 93.8% when combined with clinical features. Collectively, these findings identified new mechanisms to explain symptom improvement after amisulpride medication and highlight the potential of combining gene expression profiling with clinical data to predict treatment response in first episode psychoses.

Fig. 1. Differentially expressed genes (DEGs) in patients with first episode psychosis after 4-week treatment with amisulpride.

a Bimodal distribution of total PANSS changes after 4-week amisulpride treatment in first episode psychosis patients (n = 188). Theorical distribution for the whole sample is represented in black. Gaussian probability density functions were obtained by the estimated PANSS changes mixture function and showed two subgroups with poor (red) and good (blue) symptoms improvement. b Volcano plots of DEGs in good (n = 113) and poor (n = 75) responders before and after 4-week amisulpride treatment. Genes over- and under-expressed after Benjamini–Hochberg correction (FDR < 0.1) are shown in red and green, respectively. c Venn diagram representing the overlap between the 32 DEGs identified in good responders of the current study and genes that have been previously reported to be differentially expressed in brain or blood from patients with schizophrenia (SZ) when compared with controls, or after antipsychotic (AP) medication. Either the number of genes or their name is reported in each part of the diagram. Genes for which differential expression has been validated in our replication cohort are shown in bold. *indicates genes that were differentially expressed between good and poor responders before amisulpride treatment. FC Fold change.

Fig. 2. Receiver operator characteristic curves from logistic regression models predicting good or poor response to amisulpride treatment.

The red curve represents the model combining the gene expression level of ALPL, CA4, DGAT2, DHRS13, HOMER3 and WLS. The green curve represents the model combining the age, the sex, the positive PANSS score (PPANSS) and the duration of untreated psychosis (DUP). The blue curve represents the model combining the ALPL, CA4, DGAT2, DHRS13, HOMER3 and WLS gene expression level as well as the age, the sex, the PPANSS and the DUP at inclusion. Area under the curve (AUC) are indicated for each model.