Abstract
Background: activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) plays a key role in schizophrenia (SCZ) and treatment resistant SCZ. There are only a few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ. Methods: we examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls. Results: serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions. Conclusion: the EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.
Highlights
The first comprehensive neuro-immune theory of schizophrenia (SCZ) was published by Smith and Maes in 1995 and suggested that activated monocytes and T-lymphocytes are key phenomena in the pathophysiology of SCZ [1]
Eleven patients had a partial response to treatment and were categorized as partial responders to treatment (PRTT), whereas sixty patients did not show any improvement on the Clinical Global Impression (CGI)-I and, were categorized as non responders to treatment (NRTT)
The first major finding of this study is that serum levels of KOR, MOR, endomorphin 2, IL-6 and IL-10 are significantly increased in SCZ as compared with controls
Summary
The first comprehensive neuro-immune theory of schizophrenia (SCZ) was published by Smith and Maes in 1995 and suggested that activated monocytes and T-lymphocytes are key phenomena in the pathophysiology of SCZ [1]. It is widely accepted that SCZ is accompanied by activation of the immune-inflammatory response system (IRS) with activated M1 macrophages as indicated by increased levels of interleukin (IL)-6, IL-1β and tumour necrosis factor-alpha (TNFα) levels, T-helper (Th)-1 cells and Th-17 cells [2,3,4,5,6,7,8]. SCZ is accompanied by activation of the compensatory immune-regulatory system (CIRS) with increased activity of Th-2 immunocytes as indicated by increased levels of IL-4 and IL-13, and T-regulatory (Treg) cells with increased production of IL-10, and elevated levels of immune-regulatory compounds including acute phase proteins (e.g., haptoglobin) and soluble interleukin receptors such as sIL-2R, sIL-1RA, sTNFR1 and sTNFR2 [7,8]. In humans and animal models, EOs negatively regulate immune responses [20,21] including downregulation of cytokine and chemokine levels and associated receptors [22] and immune cell proliferation and activities [23]
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