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.

In Schizophrenia, Depression and Anxiety Symptoms Are Driven by Immune-Inflammatory Pathways.

“…All patients were diagnosed with schizophrenia according to DSM-IV-TR criteria. A non-response to treatment (NRTT) was defined as resistance to two trials with antipsychotic treatments at adequate doses each for at least 8 weeks, with no improvement in symptoms as assessed with the Clinical Global Impression (CGI) Improvement (CGI-I) scale (Guy, 1976;Al-Dujaili et al, 2020). Patients who showed a partial response were classified as partial responders to treatment (PRTT) (Al-Dujaili et al, 2020).…”

“…In animal models, social stress may induce IL-6 thereby facilitating anxiety (Niraula et al, 2019). Recently, we reviewed that HMGB1 may cause breakdown of the BBB, propagate IRS activation, and neuroinflammatory and neurodegenerative processes, and damage hippocampal neurons, thereby inducing neurotoxicity and memory impairments (Al-Dujaili et al, 2020). In humans, CCL11 acts as an "endogenous cognitive deteriorating chemokine (ECDC)" or an "accelerated brain ageing chemokine (ABAC)" (Sirivichayakul et al, 2019) by decreasing hippocampal neurogenesis and impairing hippocampal learning and memory (Villeda et al, 2011).…”

“…Increased DKK1 may impact neuronal processes, including stress-induced hippocampal damage, disassembly of synapses in mature neurons, synaptic loss, neurogenesis in the hippocampus, BAX-related cell death, neurotoxicity, and breakdown of the BBB ultimately leading to cognitive deficits (Liebner et al, 2008;Artus et al, 2014;Liu et al, 2014;Orellana et al, 2014;Wang et al, 2019). Moreover, DKK1 (or Dickkopf WNT signaling pathway inhibitor 1) is a negative regulator of the canonical Wnt signaling transduction pathway and abnormal Wnt gene expression and plasma proteins are detected in schizophrenia (Hoseth et al, 2018;Al-Dujaili et al, 2020) and in bipolar disorder (Hoseth et al, 2018).…”

“…Moreover, in schizophrenia new biomarkers were discovered which are associated with the IRS/CIRS response and may cause blood-brain-barrier (BBB) damage and neurodegenerative processes, namely increased levels of a) the master inflammatory protein high mobility group box 1 (HMGB1), and b) the pro-inflammatory glycoprotein Dickkopf-related protein 1 (DKK1) (Al-Dujaili et al, 2020;Menet et al, 2020). The latter is an endogenous inhibitor of the canonical Wnt pathway which may trigger a disassembly of excitatory synapses and affect neuro-repair mechanisms (Al-Dujaili et al, 2020;Menet et al, 2020). We reported that PHEM, negative symptoms and neurocognitive impairments are significantly associated with a combination of HMGB1, DKK1, IL-6, and CCL11 (Al-Dujaili et al, 2020).…”

In (deficit) schizophrenia, a general cognitive decline (G-CoDe) partly mediates the effects of neuro-immune and neuro-oxidative toxicity on the symptomatome and quality of life

“…The neurocognitive dysfunctions in (deficit) schizophrenia can adequately be assessed using cognitive tests, such as the Consortium to Establish a Registry for Alzheimer's disease ( CERAD) including the Mini mental State Examination (MMSE), 9,10 the Brief Assessment of Cognition in Schizophrenia (BACS), 11 and the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB). 5,9,12 Nevertheless, it remains unknown whether the impairments in attention, semantic and episodic memory, working memory, executive functions, planning, and emotional recognition are distinct features of schizophrenia or whether they are intertwined manifestations of a general factor (or a single latent trait) reflecting a "general cognitive decline" (G-CoDe).…”