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

Abstract

Background: Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits.

Aim: The present study aims to examine HMGB1 and DDK1 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 CCL11 (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. DKK1 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 DDK1 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, DDK1, and CCL11.

Conclusions: The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wnt/β-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.

Keywords: cytokines; inflammation; neuro-immune; neurocognition; schizophrenia; treatment resistance.

Fig. 1.

Flow diagram of both patients and treatments with number of nonresponders to treatment (NRTT), partial responders to treatment (PRTT), and loss to follow-up. We recruited 142 schizophrenia (SCZ) patients treated with antipsychotic drugs during 2 trials with antipsychotic drugs. During the first trial, patients were treated for 8 weeks and after this trial divided into those without a clinical response (n = 84) and a partial response (n = 51) according to Clinical Global Impression Improvement (CGI-I) scores (loss to follow-up: n = 7). The partial responders continued to take the same medication for another 2 months, while we lost again 7 patients in the follow-up yielding a final PRTT study group of n = 55. The nonresponders to a first antipsychotic agent were switched to another antipsychotic treatment for another 8 weeks, and during this follow-up period, we lost 13 patients. Two months later, 11 patients showed a partial response to treatment. Finally, 55 PRTT or 60 NRTT according to CGI-I scores and Conley and Kelly criteria participated in this study. CPZE, chlorpromazine equivalents mg/day.

Fig. 2.

Bar plot displaying the scores on the SANS (Scale for the Assessment of Negative Symptoms) psychosis, hostility, excitement, mannerism, FTD (formal thought disorders), and PMR (psychomotor retardation) was significantly different between the 3 study groups and increased from healthy controls (HC) to partial responders to treatment (PRTT) to nonresponders to treatment (NRTT).

Fig. 3.

Partial regression plot of the mannerism scores on high mobility group box (HMGB)1 plasma concentrations.

Fig. 4.

Partial regression plot of the Symbol Coding test scores on high mobility group box (HMGB)1 plasma concentrations.

Fig. 5.

The proposed mechanisms of action of the different pathways leading to the phenome features of schizophrenia, including neurocognitive deficits and psychosis, hostility, excitation, mannerism, and negative symptoms (PHEMN) and a nonresponse to treatment (NRTT). We suggest that an infectious process or increased LPS from Gram-negative bacteria may activate peripheral immune-inflammatory pathways, including interleukin-6 (IL-6), high mobility box protein 1 (HMGB1), Dickkopf 1 (DKK1), and CCL11 (eotaxin). Increased IL-6 levels associate with increased HMGB1 and DKK1. The latter may cause a downregulation of Wnt signaling, and all factors together may cause the breakdown of the blood-brain barrier (BBB) and, consequently, neuroinflammation. NRTT patients also show marginally increased levels of IL-10, a negative immune-regulatory cytokine, which has protective functions and is part of the protectome. Nevertheless, impairments are detected in other parts of the protectome (eg, lowered natural protective immunoglobulin M) leading to lowered (neuro)protection,^, which together with increased neurotoxicity may cause the phenome of schizophrenia.