Chronic Fatigue Syndrome and Fibromyalgia-Like Symptoms Are an Integral Component of the Phenome of Schizophrenia: Neuro-Immune and Opioid System Correlates

Background: Physiosomatic symptoms are an important part of schizophrenia phenomenology. The aim of this study is to examine the biomarker, neurocognitive and symptomatic correlates of physiosomatic symptoms in schizophrenia. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured the Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) scale, schizophrenia symptom dimensions, and the Brief Assessment of Cognition in Schizophrenia. We measured neuro-immune markers including plasma CCL11 (eotaxin), interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box 1 protein (HMGB1) and endogenous opioid system (EOS) markers including κ-opioid receptor (KOR), µ-opioid receptor (MOR), endomorphin-2 (EM2) and β-endorphin. Results: Patients with an increased FF score display increased ratings of psychosis, hostility, excitement, formal though disorders, psychomotor retardation and negative symptoms as compared with patients with lower FF scores. A large part of the variance in the FF score (55.1%) is explained by the regression on digit sequencing task, token motor task, list learning, IL-10, age (all inversely) and IL-6 (positively). Neural network analysis shows that the top-6 predictors of the FF score are (in descending order): IL-6, HMGB1, education, MOR, KOR and IL-10. We found that 45.1% of the variance in a latent vector extracted from cognitive test scores, schizophrenia symptoms and the FF score was explained by HMGB-1, MOR, EM2, DKK1, and CCL11. Conclusions: FF symptoms are an integral part of the phenome of schizophrenia. Neurotoxic immune and neurodegenerative pathways and to a lesser extent the EOS appear to drive FF symptoms in schizophrenia.