Despite being a major cause of disability worldwide, the pathophysiology of schizophrenia and molecular basis of treatment response heterogeneity continue to be unresolved. Recent evidence suggests that multiple aspects of pathophysiology, including genetic risk factors, converge on key cell signaling pathways and that exploration of peripheral blood cells might represent a practical window into cell signaling alterations in the disease state. We employed multiplexed phospho-specific flow cytometry to examine cell signaling epitope expression in peripheral blood mononuclear cell (PBMC) subtypes in drug-naïve schizophrenia patients (n = 49) relative to controls (n = 61) and relate these changes to serum immune response proteins, schizophrenia polygenic risk scores and clinical effects of treatment, including drug response and side effects, over the longitudinal course of antipsychotic treatment. This revealed both previously characterized (Akt1) and novel cell signaling epitopes (IRF-7 (pS477/pS479), CrkL (pY207), Stat3 (pS727), Stat3 (pY705) and Stat5 (pY694)) across PBMC subtypes which were associated with schizophrenia at disease onset, and correlated with type I interferon-related serum molecules CD40 and CXCL11. Alterations in Akt1 and IRF-7 (pS477/pS479) were additionally associated with polygenic risk of schizophrenia. Finally, changes in Akt1, IRF-7 (pS477/pS479) and Stat3 (pS727) predicted development of metabolic and cardiovascular side effects following antipsychotic treatment, while IRF-7 (pS477/pS479) and Stat3 (pS727) predicted early improvements in general psychopathology scores measured using the Brief Psychiatric Rating Scale (BPRS). These findings suggest that peripheral blood cells can provide an accessible surrogate model for intracellular signaling alterations in schizophrenia and have the potential to stratify subgroups of patients with different clinical outcomes or a greater risk of developing metabolic and cardiovascular side effects following antipsychotic therapy.

尽管是全世界残疾的主要原因，但精神分裂症的病理生理学和治疗反应异质性的分子基础仍未得到解决。最近的证据表明，包括遗传风险因素在内的病理生理学的多个方面都集中在关键的细胞信号通路上，并且对外周血细胞的探索可能代表了疾病状态下细胞信号改变的实用窗口。我们采用多路磷酸化特异性流式细胞术检测未用药精神分裂症患者 (n = 49) 相对于对照组 (n = 61) 外周血单个核细胞 (PBMC) 亚型中的细胞信号转导表位表达，并将这些变化与血清免疫反应联系起来蛋白质、精神分裂症多基因风险评分和治疗的临床效果，包括药物反应和副作用，在抗精神病药物治疗的纵向过程中。这揭示了与 PBMC 亚型相关的先前表征的 (Akt1) 和新的细胞信号转导表位 (IRF-7 (pS477/pS479)、CrkL (pY207)、Stat3 (pS727)、Stat3 (pY705) 和 Stat5 (pY694))精神分裂症发病时，与 I 型干扰素相关血清分子 CD40 和 CXCL11 相关。Akt1 和 IRF-7 (pS477/pS479) 的改变与精神分裂症的多基因风险有关。最后，Akt1、IRF-7 (pS477/pS479) 和 Stat3 (pS727) 的变化预测抗精神病药物治疗后代谢和心血管副作用的发展，而 IRF-7 (pS477/pS479) 和 Stat3 (pS727) 一般预测早期改善使用简要精神病评定量表（BPRS）测量的精神病理学分数。