Jan Aleksander Beszłej

Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation.

The influence of the immune system deregulation on the risk of schizophrenia is increasingly recognized. The aim of this study was to assess the influence of serum interleukin-6 (IL-6) level together with the polymorphism in its gene (IL6 -174G/C) and high sensitivity C-reactive protein (hsCRP) levels on clinical manifestation and cognition in schizophrenia patients. We recruited 151 patients with schizophrenia and 194 healthy control subjects. Psychopathology was evaluated using Operational Criteria for Psychotic Illness checklist, Positive and Negative Syndrome Scale (PANSS) and Scales for Assessment of Positive and Negative Symptoms. Cognitive performance in schizophrenia patients was assessed using following tests: Rey Auditory Verbal Learning Test, Trail Making Test, Verbal Fluency Tests, Stroop and subscales from Wechsler Adults Intelligence Scale-R-Pl (Similarities, Digit Symbol Coding, Digit Span Forward and Backward). Serum IL-6 and hsCRP levels were significantly higher in schizophrenia patients in comparison with healthy controls. Both hsCRP and IL-6 levels were associated with insidious psychosis onset, duration of illness and chronic schizophrenia course with deterioration. After adjustment for age, education level, number of years of completed education, illness duration, total PANSS score, depression severity and chlorpromazine equivalent, there was still a positive association between IL-6 and hsCRP levels and worse cognitive performance. The IL6 -174G/C polymorphism did not influence IL-6 level, but it was associated with the severity of positive symptoms. Our results suggest that elevated IL-6 levels may play the role in cognitive impairment and serve as potential inflammatory biomarker of deterioration in schizophrenia.

The Lifetime Prevalence of Anxiety Disorders Among Patients with Irritable Bowel Syndrome

BACKGROUND The prevalence of irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder, ranges from 10% to 20% in the general population. It is estimated that from 40% to 90% of persons with a diagnosis of IBS suffer from mental disorders, mainly anxiety and depressive disorders. OBJECTIVES The aim of the study was to assess the lifetime prevalence of anxiety disorders in IBS patients and to compare it with the prevalence of these disorders in a control group of patients with gastroesophageal reflux disease (GERD). MATERIAL AND METHODS The study included 106 patients with IBS and 53 patients with GERD. IBS was diagnosed according to the Rome II criteria after a basic evaluation to exclude an organic disease. Anxiety disorders were diagnosed using the Composite International Diagnostic Interview (CIDI) in accordance with ICD-10 diagnostic criteria. RESULTS Anxiety disorders during the patients lifetime were diagnosed in 50 IBS patients (47%). Specific phobias occurred in 23.5% of them, social phobias in 10.4%, generalized anxiety disorder in 10.4%, panic disorder in 3.8% and agoraphobia in 8.5%. In the control group with GERD, anxiety disorders during the subjects lifetime were diagnosed in 30% of the group. The difference in the prevalence of anxiety disorders between patients with IBS and GERD was statistically significant (p<0.05). CONCLUSIONS The lifetime prevalence of anxiety disorders in IBS patients was higher than in the control group with GERD (47% vs. 30%). The prevalence rate of anxiety disorders in the control group with GERD was similar to the prevalence rate in the general population.

Sex differences in TGFB-β signaling with respect to age of onset and cognitive functioning in schizophrenia

There are studies showing that gene polymorphisms within the transforming growth factor-β (TGF-β) signaling constitute schizophrenia risk variants. However, the association between TGFB1 gene polymorphisms (+869T/C and +915G/C), TGF-β level with schizophrenia course, and its symptomatology together with cognitive functioning has not been investigated so far. We included 151 patients with schizophrenia and 279 healthy controls. Cognitive functioning was assessed using Rey Auditory Verbal Learning Test, Trail Making Test (TMT)-A and TMT-B, Verbal Fluency task, Stroop test, as well as selected subtests from the Wechsler Adults Intelligence Scale – Revised, Polish adaptation (WAIS-R-Pl): Digit Symbol Coding, Digit Span Forward and Backward, and Similarities. Additionally, serum TGF-β levels were measured in 88 schizophrenia patients and 88 healthy controls. Serum TGF-β level was significantly higher among patients with schizophrenia in comparison with healthy controls; however, the studied polymorphisms were not associated with TGF-β level in schizophrenia patients. Subjects carrying the +869T allele performed significantly worse in comparison with +869CC homozygotes on Stroop task, Verbal Fluency task and Digit Symbol Coding task. There was a significant difference in age of psychosis onset in female schizophrenia patients with respect to the TGFB1 +869T/C polymorphism. Additionally, adjustment for possible confounders revealed that there was a significant difference in cognitive performance on Digit Symbol Coding task with respect to the TGFB1 +869T/C polymorphism among female schizophrenia patients. Our results suggest that TGF-β signaling might be a valid link contributing to observed differences in age of onset and the level of cognitive decline between male and female schizophrenia patients.

Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study

We aimed to profile a broad panel of inflammatory markers in patients with schizophrenia and healthy controls. Additionally, we performed a meta-analysis of chemokine alterations that have not been subjected to quantitative synthesis so far. We recruited 78 patients with schizophrenia and 78 healthy controls, and measured inflammatory markers using the Luminex technology. After adjustment for multiple testing, we found elevated levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, interferon-γ, eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor with two B subunits (PDGF-BB), macrophage inflammatory protein (MIP)-1α, MIP-1β, vascular endothelial growth factor A (VEGF-A) and RANTES in multiple-episode schizophrenia (MES) patients. These differences, except for the difference in eotaxin-1 levels, appeared to be significant after co-varying for the dosage of antipsychotics. There were no significant differences in the levels of immune markers between first-episode schizophrenia (FES) patients and controls. Our meta-analysis revealed elevated levels of MCP-1 in first-episode psychosis (FEP) patients and MES individuals. Other chemokine alterations (elevated levels of IL-8, eotaxin-1 and MIP-1β) were present only in MES patients. Our results indicate that dysregulation of immune response in schizophrenia develops with illness progression or appears as a long-term medication effect. Chemokine alterations are another example of aberrant immune response in schizophrenia patients. Elevated levels of MCP-1 might represent trait markers since these alterations were found in FEP and MES patients. Other chemokine alterations might be the markers of disease progression or might represent medication effects.

Polymorphisms in immune-inflammatory response genes and the risk of deficit schizophrenia

Polymorphisms in immune-inflammatory response genes are believed to impact schizophrenia susceptibility. However, it remains unknown whether immunogenetic factors play a role in the etiology of deficit schizophrenia (D-SCZ). Therefore, we genotyped four polymorphisms in genes encoding two immune system regulatory proteins (CTLA-4 rs231775 and CD28 rs3116496), interleukin-6 (IL6 rs1800795) and transforming growth factor-β (TGFB1 rs1800470) in 513 schizophrenia patients and 374 controls. The CD28 rs3116496-CC genotype and C-allele were significantly more frequent in the whole group of patients and D-SCZ patients compared to controls. Our results indicate that the CD28 rs3116496 polymorphism might impact the risk of schizophrenia, especially D-SCZ.

Effects of antipsychotics on insight in schizophrenia: results from independent samples of first-episode and acutely relapsed patients.

We aimed to investigate whether antipsychotics differentially impact insight and whether these effects appear because of improvement in psychopathological manifestation in 132 first-episode schizophrenia patients and 201 acutely relapsed schizophrenic patients, who were followed up for 12 weeks. Olanzapine and risperidone were administered to first-episode schizophrenia patients, whereas acutely relapsed schizophrenic patients were treated with olanzapine, perazine and ziprasidone. The Positive And Negative Syndrome Scale (PANSS) was used to assess psychopathology. Insight was assessed using the G12 item of PANSS. Unadjusted mixed-model regression analysis indicated a significant improvement in the PANSS G12 item score in both groups. There were no significant differences between distinct treatment subgroups of patients in terms of improvement in the PANSS G12 item score. After adjustment for the trajectories of changes in symptom dimensions, a decrease in the PANSS G12 item score was because of an improvement in positive, negative and excitement symptoms. A decrease in the PANSS G12 item score was also related to an increase in the severity of depressive symptomatology. Our results indicate that antipsychotics exert similar effects on insight in acute psychosis. These effects are likely because of an improvement in psychopathological manifestation. The improvement in insight might be related to the development of depressive symptoms.

CTLA4 and CD28 Gene Polymorphisms with Respect to Affective Symptom Domain in Schizophrenia

Background: Accumulating evidence indicates that immune alterations in schizophrenia are due to genetic underpinnings. Here, we aimed at investigating whether polymorphisms in CTLA4 and CD28 genes, encoding molecules that regulate T-cell activity, influence schizophrenia symptomatology. Method: We recruited 120 schizophrenia patients and 380 healthy age- and sex-matched controls. We divided the patients into two groups: one with no co-occurrence between psychotic and affective symptoms and the second one with psychotic symptoms dominating in the clinical manifestation, although also with occasional affective disturbances in the course of illness. Results: Among the patients with co-occurring affective symptoms, there were significantly more CTLA4 c.49A>G[A] alleles (p = 0.018, odds ratio (OR) 2.03, 95% confidence interval (CI) 1.2-3.66) and more CTLA4 g.319C>T[T] alleles (p = 0.07, OR 1.93, 95% CI 0.94-4.13) in comparison to the second group. Additionally, we have shown that CD28 c.17 + 3T>C[C+] were more significantly overrepresented among patients with co-occurring psychotic and affective symptoms (p = 0.0003, OR 3.36, 95% CI 1.69-6.68) than in patients without co-occurence between these symptoms (p = 0.012, OR 1.88, 95% CI 1.15-3.10). Conclusion:CTLA4 and CD28 gene polymorphisms may not only act in immune deregulation observed in schizophrenia, but may also influence the course of the illness by modifying the susceptibility to the co-occurrence of psychotic and affective symptoms.

Mo2040 Association of Polymorphisms in 5-HT2A and 5-HT2C Receptors Genes With Depressive and Anxiety Disorders in Patients With Irritable Bowel Syndrome

BACKGROUND: Subgroups of patients with irritable bowel syndrome (IBS) may have low grade mucosal immune activity. Fecal calprotectin (f-calprotectin) levels are considered a marker for mucosal neutrophil inflammation and may be used as a biomarker for disease activity in inflammatory diseases. IBS patients are reported to have normal levels of calprotectin, but the levels may vary within the patient group, and it is not known whether this variation within or slightly above the normal range may reflect pathology or symptoms of the patients. AIM: To determine if levels of f-calprotectin may reflect the clinical and pathophysiological phenotype of IBS patients. METHODS: Analyses of f-calprotectin in stool samples of 98 IBS patients and 35 healthy controls were performed with Buhlmann ELISA (lower detection limit 10 ug/g). All IBS subjects completed the Bristol stool form (BSF) scale and the IBS symptom severity scale (IBS-SSS) questionnaire to assess gastrointestinal symptom severity. Patients also underwent a rectal barostat test with ballon distentions and colonic transit time measurement with ingestion of radiopaque rings. RESULTS: IBS patients had comparable levels of f-calprotectin to controls (17.5 (10-47.0) vs. 11(10-44.0) (median (2575%) percentiles) ug/g; p=0.21)). Among IBS patients, 13 subjects (13.2%) had f-calprotectin levels above the 90th percentile in the controls (98.8ug/g). There was no difference in IBS subgroup according to Rome III (IBS-C, IBS-D, IBS-M, IBS-U) in patients with high as compared to normal f-calprotectin. Also the disease duration was comparable in the two groups (9.5 (2-15) vs. 10 (5-15.3) years; p=0.46). There was no difference between IBS patients with high vs. normal levels of f-calprotectin regarding intensity or frequency of pain, bloating severity, bowel habit dissatisfaction, or daily life as estimated by IBS-SSS (Table 1). Also, total IBS-SSS score was comparable in the two groups (Table 1). The average stool form according to BSF (3.7 (2.9-4.4) vs. 4.1 (3.3-4.9); p=0.2) and stool frequency (1.5 (0.75-1.9) vs. 1.6 (1.2-2.3); p=0.29) were also similar in patients with high respective normal calprotectin levels. The pain threshold in rectal barostat test was comparable in IBS patients with high respective normal levels of f-calprotectin (24 (24-28) vs. 24 (20-32) mmHg; p=0.65). Moreover, oroanal transit time (OATT) was comparable in the two groups (1.5 (0.5-1.9) vs. 1.2(0.7-1.9) days; p=0.95) CONCLUSION: Fecal calprotectin within the normal range is not associated with the severity of IBS symptoms or key pathophysiological factors. Our data do not support that mucosal neutrophil inflammation is of major importance for symptom generation in IBS. Table 1. Symptom severity assessed by -IBS-SSS in IBS patients with high respective normal levels of fecal calprotectin.

Cytokine alterations and cognitive impairment in major depressive disorder: From putative mechanisms to novel treatment targets

Overwhelming evidence indicates the involvement of immune-inflammatory processes in the pathophysiology of major depressive disorder (MDD). Peripheral cytokine alterations serve as one of most consistently reported indices of subthreshold inflammatory state observed in MDD. Although cytokines cannot pass directly through the blood-brain barrier, a number of transport mechanisms have been reported. In addition, peripheral cytokines may impact central nervous system via downstream effectors of their biological activity. Animal model studies have provided evidence that cytokines might impact cognitive performance through direct and indirect effects on long-term potentiation, neurogenesis and synaptic plasticity. Therefore, it has been hypothesized that cytokine alterations might contribute to cognitive impairment that is widely observed in MDD and persists beyond episodes of acute relapse in the majority of patients. Although several studies have provided that peripheral cytokine alterations might be related to cognitive deficits in patients with MDD, the quality of evidence still leaves much to be desired due to methodological heterogeneity and limitations. In this article, we provide an overview of studies investigating the association between peripheral cytokine alterations and cognitive performance in MDD, discuss underlying mechanisms and neural substrates. Finally, we propose possible treatment targets related to cytokine alterations taking into account existing evidence for antidepressant efficacy of anti-inflammatory pharmacological treatment modalities.

Decreased use of active coping styles contributes to elevated allostatic load index in first-episode psychosis

Accumulating evidence indicates that stress plays an important role in the development of psychotic disorders. Recent studies have revealed that patients with first-episode psychosis (FEP) present systemic biological dysregulations related to stress-exposure in terms of elevated allostatic load (AL) index. However, the mechanisms underlying this observation remain unknown. Therefore, in this study we aimed to investigate the AL index with respect to stress coping strategies in 36 FEP patients and 31 matched controls. We found significantly higher AL index in FEP patients compared to controls after co-varying for potential confounding factors. Patients with FEP were less likely to use active and task-focused coping. Lower odds of using these coping styles, planning as well as positive reinterpretation and growth were related to higher AL index in FEP patients, but not in controls. Depressive symptoms were associated with lower likelihood of using task-focused coping as well as positive reinterpretation and growth. Additionally, depressive symptoms were related to higher AL index. Finally, depressive symptoms mediated the effects of task-focused coping as well as positive reinterpretation and growth on the AL index. Our results confirm systemic biological dysregulation indexed as AL in FEP patients. Lower odds of using active coping styles might contribute to higher AL index via the mediating effect of depressive symptoms in patients with FEP. Longitudinal studies are required to establish causal inferences between coping styles, depressive symptoms and the AL index in early psychosis.