The relationship between serum IL-6, IL-18, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP-1) levels and cognitive functions in treatment-resistant schizophrenia

The Relationship Between Serum IL-6, IL-18, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP-1) Levels and Cognitive Functions in Treatment-Resistant Schizophrenia Objectives:One of the hypotheses focused on in the etiology of schizophrenia is the immune inflammatory system abnormalities and changes in cytokine levels which are small signal molecules involved in these processes. Recently, the hypotheses that treatment-resistant schizophrenia and treatment-responsive schizophrenia may be different diseases rather than being a continuation of each other with different neurobiological processes has come to the fore. The aim of this study was to determine whether there is a difference between serum IL-18, IL-6, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP1) levels among healthy controls, treatment responsive schizophrenia patients, and treatment resistant schizophrenia patients and investigate whether the serum levels of IL-18, IL-6, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP1)are important in predicting the development of treatment resistance, and whether there is a relationship between serum IL-18, IL-6, IL-2, Eotaxin (CCL11), CCL2 (MCP1) levels and the psychopathology of the disease and cognitive symptoms in schizophrenia patients. Material and Method:Patients who applied to Karadeniz Technical University (KTU) Faculty of Medicine, Farabi Hospital Psychiatry Clinic between August 2021 and April 2022, were diagnosed with schizophrenia according to DSM-5, met the inclusion criteria, did not include the exclusion criteria, and accepted to participate in the study. When their medical records were examined retrospectively, included 30 patients who were diagnosed with treatment-resistant schizophrenia according to the criteria created by taking into account the treatment-resistance criteria published in 2017by the Treatment Response and Resistance in Psychosis (TRRIP) Working Group, included 30 patients who did not meet the treatment-resistance criteria and matched with the treatment resistance group as age, gender and education level, did not include the exclusion criteria and 30 healthy volunteers who met the inclusion criteria matched with the patient group as age, gender and education level, did not include the exclusion criteria and agreed to participate in the study. After all participants were informed about the study, sociodemographic and clinical data forms were filled. The Positive and Negative Symptom Scale (PANSS) was applied to the patient groups. Wisconsin Card Sorting Test (WCST), Auditory Verbal Learning Test (AVLT), Stroop Test and Trail Making Test (TMT), which are neuropsychological tests, were applied to all participants to evaluate their cognitive functions. Serum IL-18, IL-6, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP1) levels of all participants were taken simultaneously from matched patients and control groups between 08:00am and 12:00 am on the same day of cognitive tests. Serum IL-18, IL-6, IL-2, Eotaxin-1 (CCL11), CCL2 (MCP1) levels measured using the ELISA kit. Results:Both schizophrenia groups were performed worse compared to the control group in AVLT test sections of instant memory, learning, post-confuse recall, long-term memory, verbal learning curve, recall by recognition, in all Stroop test sections except section 2, in WCST test sections of total number of errors, number of perseverative reactions , perseverative error number conceptual level response and in TMT test section B. In our study, no statistically significant difference was found all cognitive functions test result except for the number of TMT part B errorsbetween the treatment-resistant schizophrenia group and the treatment-responsive schizophrenia group. IL-18, IL-2, IL-6, Eotaxin-1(CCL11) levels were found to be higher in both schizophrenia groups compared to the control. MCP-1(CCL2) level was found to be higher only in the treatment-resistant patient group compared to the control group. All evaluated inflammatory factors were found to be higher in treatment-resistant schizophrenia patients compared toother schizophrenia group, and our results remained the same in the logistic regression model. We found a positive correlation between serum IL-18 level and the failure score to maintain the Wisconsin test setup, serum IL-18 level and executive function dysfunction serum Eotaksin-1 (CCL11) level and verbal memory impairmentin the treatment-responding group anda negative correlation between as the serum IL-18 level and the number of TMT form A errors , serum IL-2 level and AVLT retroactive interference, serum MCP-1 (CCL2) level and Wisconsin test completed category, serum Eotaksin-1(CCL11) level and AVLT recognition list A+B score and the Recognition list B scorein the treatment-resistant group. And no correlation was observed between IL-2, IL-6 and cognitive impairment in either group. Conclusion:Our findings support the hypothesis that treatment-resistant schizophrenia may be a categorically different subtype from treatment-responder. Even if the disease duration, PANSS scores, and degree of cognitive impairment are the same, inflammatory markers such as IL-18, IL-2, IL-6, Eotaxin-1 (CCL11) and MCP1 (CCL2) are higher in the treatment-resistant schizophrenia group compared to the treatment-responsive schizophrenia group. The increase in MCP-1(CCL2) only in the treatment-resistant schizophrenia group compared to the control and the absence of statistically significant difference between the treatment-responding group and the control suggests that MCP-1(CCL2) may be more prominent in the discrimination of treatment-resistant schizophrenia.