High Mobility Group Protein 1 and Dickkopf-Related Protein 1 in Schizophrenia and Treatment-Resistant Schizophrenia: Associations With Interleukin-6, Symptom Domains, and Neurocognitive Impairments

Background: Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated With aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGBI), an inflammatory mediator, and Dickkopf-related protein (DKKI), a Wnt/beta-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits. Aim: The present study aims to examine HMGBI and DDKI in nonresponders to treatments (NRTT) with antipsychotics (n = 60), partial RTT (PRTT, n = 55), and healthy controls (n = 43) in relation to established markers of SCZ, including interleukin (IL)-6, IL-10, and CCLII (eotaxin), and to delineate whether these proteins are associated with the SCZ symptom subdomains and neurocognitive impairments. Results: HMGB1, DKK1, IL-6, and CCL11 were significantly higher in SCZ patients than in controls. DKKI and IL-6 were significantly higher in NRTT than in PRTT and controls, while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that SCZ was best predicted by increased DDKI and HMGB1, while NRTT (vs PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism, and negative (PHEMN) symptoms and formal thought disorders was explained by HMGB1, IL-6, and CCL11, while most neurocognitive functions were predicted by HMGB1, DDKI, and CCL11. Conclusions: The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wntifl-catenin signaling pathway may cause impairments in executive functions and working, episodic, and semantic memory and explain, in part, PHEMN symptoms and a nonresponse to treatment with antipsychotic drugs.

Automated summary

The study found significantly higher levels of HMGB1, DKK1, IL-6, and CCL11 in SCZ patients. NRTT patients had significantly higher levels of IL-6 and DDKI compared to PRTT and controls, with IL-10 being higher in NRTT than in controls. HMGB1, IL-6, and CCL11 explained a large part of the variance in PHEMN symptoms and formal thought disorders, while most neurocognitive functions were predicted by HMGB1, DDKI, and CCL11.