The interleukin-6/interleukin-23/T helper 17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: A precision nomothetic psychiatry analysis.

BACKGROUND: Schizophrenia and especially deficit schizophrenia (DSCZ) are characterized by increased activity of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There is no data on whether the interleukin (IL)-6/IL-23/T helper 17 (IL-6/IL-23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. METHODS: This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL-6/IL-23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and the schizophrenia phenome. RESULTS: Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL-6/IL-23/Th17-axis score, as assessed by an LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL-6/IL-23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL-6/IL-23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). CONCLUSION: The pathogenic IL-6/IL-23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia, especially that of DSCZ, due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.

In schizophrenia, non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy.

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and µ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and ß-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

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 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/ß-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/ß-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.

The Endogenous Opioid System in Schizophrenia and Treatment Resistant Schizophrenia: Increased Plasma Endomorphin 2, and κ and µ Opioid Receptors Are Associated with Interleukin-6.

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 ß-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. ß-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 ß-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.

Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines.

Beta-thalassemia major patients are treated with repeated blood transfusions, which may cause iron overload, which in turn may induce immune aberrations, and show an increased risk of depression. The aim of the present study is to examine whether repeated blood transfusions, iron overload, and immune-inflammatory responses are associated with depression in children (6-12 years) with transfusion-dependent thalassemia (TDT). The Children's Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%), and serum levels of CCL11, IL-1ß, IL-10, and TNF-α were measured in TDT with (n = 54) and without (n = 57) a major depression-like episode (MDLE) and in healthy children (n = 55). The results show that MDLE due to TDT is associated with a greater number of blood transfusions and increased iron overload and IL-1ß levels. Partial least squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, iron overload, and increased levels of IL-1ß and TNF-α. The latter two cytokines partly mediate the effects of iron overload on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by iron overload and the path from iron overload to immune activation. Iron overload is also associated with increased IL-10 and lower CCL11 levels, but these alterations are not significantly associated with depression. In conclusion, blood transfusions may be causally related to MDLE in TDT children and their effects are in part mediated by increased iron overload and the consequent immune-inflammatory response. The results suggest that effects of iron overload and its consequences including inflammation and oxidative stress toxicity may cause MDLE. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate iron overload and immune-inflammatory responses and to prevent MDLE in children with TDT.

Plasma Indoleamine-2,3-Dioxygenase (IDO) is Increased in Drug-Naï ve Major Depressed Patients and Treatment with Sertraline and Ketoprofen Normalizes IDO in Association with Pro-Inflammatory and Immune- Regulatory Cytokines.

BACKGROUND: Major Depression Disorder (MDD) is accompanied by an immune response characterized by increased levels of inflammatory and immune-regulatory cytokines and stimulation of indoleamine-2,3-dioxygenase (IDO). There is also evidence that anti-inflammatory drugs may have clinical efficacy in MDD. METHODS: This study examined a) IDO in association with interferon (IFN)-γ, Interleukin (IL)-4 and Transforming Growth Factor (TGF)-ß1 in 140 drug-naïve MDD patients and 40 normal controls; and b) the effects of an eight-week treatment of sertraline with or without ketoprofen (a nonsteroidal antiinflammatory drug) on the same biomarkers in 44 MDD patients. RESULTS: Baseline IDO, IFN-γ, TGF-ß1 and IL-4 were significantly higher in MDD patients as compared with controls. Treatment with sertraline with or without ketoprofen significantly reduced the baseline levels of all biomarkers to levels which were in the normal range (IDO, TGF-ß1, and IL-4) or still somewhat higher than in controls (IFN-γ). Ketoprofen add-on had a significantly greater effect on IDO as compared with placebo. The reductions in IDO, IL-4, and TGF-ß1 during treatment were significantly associated with those in the BDI-II. CONCLUSION: MDD is accompanied by activated immune-inflammatory pathways (including IDO) and the Compensatory Immune-Regulatory System (CIRS). The clinical efficacy of antidepressant treatment may be ascribed at least in part to decrements in IDO and the immune-inflammatory response. These treatments also significantly reduce the more beneficial properties of T helper-2 and T regulatory (Treg) subsets. Future research should develop immune treatments that target the immune-inflammatory response in MDD while enhancing the CIRS.

Lowered zinc and copper levels in drug-naïve patients with major depression: Effects of antidepressants, ketoprofen and immune activation.

Objectives: The aim of the present work is to examine the effects of treatment with sertraline with and without ketoprofen on serum levels of zinc and copper in association with immune-inflammatory biomarkers in drug-naïve major depressed patients.Methods: We measured serum zinc and copper, interleukin (IL)-1ß, IL-4, IL-6, IL-18, interferon-γ, and transforming growth factor-ß1 in 40 controls and 133 depressed patients. The clinical efficacy of the treatment was measured using the Beck Depression Inventory-II (BDI-II) at baseline and 8 weeks later.Results: We found significantly reduced serum zinc and copper in association with upregulation of all cytokines, indicating activation of the immune-inflammatory responses system (IRS) and the compensatory immune regulatory system (CIRS). Treatment with sertraline significantly increased zinc and decreased copper. During treatment, there was a significant inverse association between serum zinc and immune activation. The improvement in the BDI-II during treatment was significantly associated with increments in serum zinc coupled with attenuation of the IRS/CIRS.Conclusions: Lower zinc is a hallmark of depression, while increments in serum zinc and attenuation of the immune-inflammatory response during treatment appear to play a role in the clinical efficacy of sertraline.

In major depression, increased kappa and mu opioid receptor levels are associated with immune activation.

OBJECTIVE: This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the ß-endorphin - mu opioid receptor (MOR) and immune-inflammatory system. METHODS: The present study examines dynorphin, KOR, ß-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males. RESULTS: Serum dynorphin, KOR, ß-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and ß-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, ß-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence. CONCLUSION: Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and ß-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

Total and ionized calcium and magnesium are significantly lowered in drug-naïve depressed patients: effects of antidepressants and associations with immune activation.

Major depressive disorder (MDD) is associated with alterations in calcium (Ca) and magnesium (Mg), as well as circulating pro- and anti-inflammatory cytokines. Anti-inflammatory drugs are commonly used as adjuvant treatments for MDD. However, no studies examined the effects of a combinatorial treatment with sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg levels in MDD. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of sertraline and ketoprofen on Ca and Mg (both total and ionized). In the same patients, we also examined the associations between both cations and IL-1ß, IL-4, IL-6, IL-18, IFN-γ, TGF-ß1, zinc, and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was assessed using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for 2 months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit-weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, lowered levels of both cations play a role in the pathophysiology of major depression. Antidepressant-induced increases in Ca are associated with clinical efficacy and attenuation of the immune response. The suppressant effect of antidepressants on Mg levels is probably a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg. Graphical abstract.

Development of a Novel Neuro-immune and Opioid-Associated Fingerprint with a Cross-Validated Ability to Identify and Authenticate Unknown Patients with Major Depression: Far Beyond Differentiation, Discrimination, and Classification.

Major depressive disorder (MDD) is characterized by signaling aberrations in interleukin (IL)-6, IL-10, beta-endorphins as well as µ (MOR) and κ (KOR) opioid receptors. Here we examined whether these biomarkers may aid in the classification of unknown subjects into the target class MDD. The aforementioned biomarkers were assayed in 60 first-episode, drug-naïve depressed patients and 30 controls. We used joint principal component analysis (PCA) performed on all subjects to check whether subjects cluster by classes; support vector machine (SVM) with 10-fold validation; and linear discriminant analysis (LDA) and SIMCA performed on calibration and validation sets and we computed the figures of merit and learnt from the data. PCA shows that both groups were well separated using the first three PCs, while correlation loadings show that all five biomarkers have discriminatory value. SVM and LDA yielded an accuracy of 100% in validation samples. Using SIMCA, there was a highly significant discrimination of both groups (model-to-model distance = 110.2); all biomarkers showed a significant discrimination and modeling power, while 100% of the patients were authenticated as MDD cases with a specificity of 93.3%. We have delineated that MDD is a distinct class with respect to neuro-immune and opioid biomarkers and that future unknown subjects can be authenticated as having MDD using this SIMCA fingerprint. Precision psychiatry should employ SIMCA to (a) authenticate patients as belonging to the claimed target class and identify other subjects as outsiders, members of another class, or aliens; and (b) acquire knowledge through learning from the data by constructing a biomarker fingerprint of the target class.

IL-10 is associated with increased mu-opioid receptor levels in major depressive disorder.

OBJECTIVE: Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) and aberrations in endogenous opioids play a role in the pathophysiology of major depressive disorder (MDD). There are no studies which examined the associations between both systems in MDD. The aim of the present study was to examine the relation between ß-Endorphin (ß-EP), Endomorphin-2, and their mu-opioid receptor (MOR) as well as interleukin (IL)-6 and IL-10, an anti-inflammatory cytokine, in MDD patients. METHOD: The study included 60 depressed drug-free male patients and 30 matched controls. Serum ß-EP, Endomorphin-2, MOR, IL-6 and IL-10 levels were measured using ELISA techniques. RESULTS: The results revealed a significant increase in serum ß-EP, MOR, IL-6 and IL-10 in MDD patients versus healthy controls. MOR levels were strongly associated with IL-10 levels. There were no significant correlations between endogenous opioids and IL-6 and IL-10. CONCLUSION: The results show that MOR levels may function as a possible component of the CIRS whilst there is no evidence that ß-EP and EM-2 may modify the IRS. The significant correlation between MOR levels and IL-10 may be explained through central activation of the HPA-axis and increased B-cell numbers expressing MOR as a response to cytokine over-secretion in MDD.

Serum Interleukin Levels and Insulin Resistance in Major Depressive Disorder.

BACKGROUND & OBJECTIVE: Major depressive disorder (MDD) has been associated with inflammatory processes, including increased cytokine levels, even in individuals who are otherwise physically healthy, while some MDD patients may show insulin resistance (IR). METHOD: However, correlations between cytokines and IR parameters have not been studied extensively in MDD. In the present study, we measured IL-1ß, IL-4, IFN-γ, TGF-ß1, insulin and glucose in 63 MDD patients and 27 healthy controls. The associations between cytokine levels and IR were examined. RESULTS: The results revealed a significant increase (p<0.05) in serum levels of IL-1ß, IL-4, IFN-γ, TGF-ß1, insulin, insulin/glucose ratio, and insulin resistance (HOMA2IR) in MDD patients as compared with controls. There was a significant correlation between HOMA2IR with both IFN-γ (ρ=0.289, p<0.05) and TGF-ß1 (ρ=0.364, p<0.05). CONCLUSION: The present study further confirms that MDD is accompanied by activation of the immune system with significant elevations in the levels of four cytokines. These results indicate stimulation of the immune system and increased IR and modulation of IR by increased cytokine levels in MDD. These findings show that immune activation and associated IR are a new drug target in depression.

IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation.

Major depressive disorder (MDD) and schizophrenia are associated with inflammatory processes. Studies have shown that these disorders exhibit increase in the level of one or more proinflammatory markers. However, these studies did not exclude patients with obvious inflammation (i.e., CRP>6mg/L). Therefore, a comprehensive study should include those inflammatory disorders. In the present study, the inflammatory natures of MDD and schizophrenia were investigated. To achieve this goal, serum levels of interleukin-6 (IL-6), interleukin-18 (IL-18), tumor necrosis factor alpha (TNFα), and soluble interleukin 2 receptor (sIL-2R) in depressed and schizophrenic patients were obtained and compared with those of the control group. Results showed a significant increase (p<0.05) in serum levels of IL-6, IL-18, TNFα, and sIL-2R in MDD and schizophrenic patients compared with the control group. Also patients with schizophrenia group showed higher levels of the inflammatory markers than MDD and control groups. The current study concluded that the immunological response in the MDD and schizophrenic patients groups was significantly stimulated. These disorders may be considered an inflammatory disorder because of elevated levels of proinflammatory cytokines in spite of lacking an overt inflammation. Furthermore results of this study suggested the possibility of the use of anti-inflammatory drugs as adjuvant therapy in schizophrenic and depressive disorders.