Peripheral Transcription of NRG-ErbB Pathway Genes Are Upregulated in Treatment-Resistant Schizophrenia

Investigation of peripheral gene expression patterns of transcripts within the signaling pathway, other than neuregulin-1 ( ), among patients with schizophrenia and more specifically treatment-resistant schizophrenia (TRS) is limited. The present study built on our previous work demonstrating elevated levels of EGFα, EGFβ, and type I containing transcripts in TRS by investigating 11 signaling pathway mRNA transcripts ( ) in whole blood of TRS patients ( = 71) and healthy controls ( = 57). We also examined the effect of clozapine exposure on transcript levels using cultured peripheral blood mononuclear cells (PBMCs) from 15 healthy individuals. Five transcripts ( ) were significantly elevated in TRS patients compared to healthy controls but only expression of ( = 0.018), a protein kinase linked to protein synthesis, cell growth, and cell proliferation, survived correction for multiple testing using the Benjamini-Hochberg method. Investigation of clinical factors revealed that , and expression were negatively correlated with duration of illness. However, no transcript was associated with chlorpromazine equivalent dose or clozapine plasma levels, the latter supported by our PBMC clozapine exposure experiment. Taken together with previously published results, our findings suggest an overall upregulation of transcripts within the signaling pathway among individuals with schizophrenia some of which attenuate over duration of illness. Follow-up studies are needed to determine if the observed peripheral upregulation of transcripts within the signaling pathway are specific to TRS or are a general blood-based marker of schizophrenia.