Milica Borovcanin

Elevated serum level of type-2 cytokine and low IL-17 in first episode psychosis and schizophrenia in relapse

Schizophrenia is chronic and debilitating mental disorder. In broad spectrum of possible causes or contributing factors, immune system and cytokines were investigated in the onset and development of schizophrenia. The aim of our study was to analyze the serum concentrations of type-1 cytokines: TNF-α, IFN-γ, type-2 cytokines: IL-4, IL-10, type-17 cytokine: IL-17 and regulatory cytokines: TGF-β, IL-27, IL-6, in drug-naive patients with First Episode Psychosis - FEP (n = 88) and Schizophrenia in relapse - SC in relapse patients (n = 45), comparing to healthy controls (n = 36). Also, we attempted to determine potential correlation between cytokine levels and/or cytokine ratios with clinical parameters, such as severity of illness, positive, negative and general psychopathology. Our results showed decreased levels of IL-17 (p = 0.018), demonstrating that type-17 response is blunted in psychotic episode. Increased levels of IL-4 (p = 0.033) showed that type-2 response is overweight in psychotic episode. Also, levels of IL-4 in serum of SC in relapse patients were higher than controls (p < 0.0005) and patient with FEP (p = 0.003). This alteration was accompanied with increase in production of TGF-β in psychotic patients (p = 0.009) and also in FEP (p < 0.0005) and SC in relapse (p < 0.0005). Analysis showed that TGF-β can be a valuable marker for psychosis. The presence of enhanced anti-inflammatory/immunosuppressive activity in schizophrenia may be an attempt to counteract or limit ongoing pro-inflammatory processes and downregulating chronic inflammation. Finally we have documented decreased levels of IL-17 and IL-17/TGF-β ratio in these types of psychotic patients, suggesting the new aspects of schizophrenia pathophysiology.

Antipsychotics can modulate the cytokine profile in schizophrenia: Attenuation of the type-2 inflammatory response

OBJECTIVE We recently reported that the type-2 cytokine response is increased in schizophrenia. The aim of this study was to analyse the effects of antipsychotic drugs on the serum levels of type-1 (TNF-α, IFN-γ), type-2 (IL-4, IL-10), type-17 (IL-17) and regulatory cytokines (TGF-β, IL-27 and IL-6). METHODS Cytokine measurements in the patients were performed on day 0 and day 30 of the treatment using standard ELISA assays. Three groups of subjects were studied: patients that were unmedicated with First Episode Psychosis (FEP; n=88), patients that were treated with antipsychotics with Schizophrenia in relapse (SC in relapse; n=45) and healthy controls (n=36). RESULTS TGF-β levels were increased in both patient groups and were further enhanced after treatment in the FEP group (p=0.014) but not in the SC relapse group. Antipsychotic treatment was correlated with lower levels of IL-4, IL-6 and IL-27 (p<0.005) in the FEP group. Finally, the serum levels of IL-17 were not significantly altered between the two measurements but were significantly lower in the FEP group (p<0.001) when compared with healthy controls. After therapy, patients with SC who were in relapse had decreased serum levels of IL-4 (p=0.006) and IL-6 (p=0.007). We also observed a weak negative correlation between the IFN-γ/TGF-β ratio and the total PANSS score and between the IL-17/TGF-β ratio and the negative and general psychopathology subscales. CONCLUSION The increased type-2 cytokine serum levels in schizophrenia appear to be downregulated by antipsychotic treatment.

Increase systemic levels of IL-23 as a possible constitutive marker in schizophrenia

Inflammation appears to play significant role in schizophrenia. IL-23 is key molecule in mediating IL-17 dependent inflammatory response. Therefore, we analyzed the serum concentrations of IL-23 levels in patients with first episode psychosis (78 subjects), in patients with acute exacerbation of schizophrenia who were already treated with antipsychotics (47 subjects) and healthy controls (35 subjects). Diagnoses were established using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10). Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS) and serum levels of IL-23 were measured using sensitive enzyme-linked immunosorbent assay (ELISA). Serum levels of IL-23 were higher in patients with first psychotic episode and in patients with schizophrenia in relapse than in healthy subjects (p=0.000) and no difference was established between these two groups of patients before therapy. Also, after 4 weeks of antipsychotic therapy levels of IL-23 remains elevated in both groups of patients with no differences between two groups. It appears that increased level of IL-23 in psychotic patients independently of antipsychotic therapy can be a constitutive marker in this disorder.

IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis

Schizophrenia and treatment of this disorder are often accompanied with metabolic syndrome and cardiovascular issues. Alterations in the serum level of innate immune mediators, such as interleukin-33 (IL-33) and its receptor IL-33R (ST2) and Galectin-3 (Gal-3) were observed in these conditions. Moreover, these parameters are potential prognostic and therapeutic markers. There is also accumulating evidence that these molecules play a role in neuroinflammation. Therefore, in this study we have investigated the serum level of Gal-3, IL-33 and soluble ST2 (sST2) in different stages of schizophrenia. Gal-3 levels were elevated in remission and lower in schizophrenia exacerbation in comparison with controls. Levels of IL-33 and sST2 are higher in schizophrenia exacerbation in comparison with controls and patients in remission. This initial analysis of new markers of neuroinflammation suggested their involvement in schizophrenia pathophysiology and/or cardiometabolic comorbidity.

In vivo methodology in behavioural pharmacology: Where are we now?

*Institute of Pharmacology, Clinical Pharmacology and Toxicology, Clinic of Neurology and Psychiatry for Children and Youth, Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Department of Psychiatry, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia; Psychiatric Clinic, Clinical Center Kragujevac, Kragujevac, Serbia; Clinic for Psychiatric Disorders “Dr Laza Lazarević”, Belgrade, Serbia

Quality of Life in Primary Insomnia: Three-week Treatment With Zolpidem Vs. Lorazepam

Abstract Insomnia is a condition of inadequate quality or quantity of sleep that has extremely adverse effects on daytime activities. Th e aim of this study was to compare the quality of life in patients with primary insomnia before and after a 3-week treatment with lorazepam (n=20) and zolpidem (n=21) and to compare the potential differences in dysfunctional beliefs and attitudes regarding patients’ sleep between the two groups. Th e diagnosis of primary insomnia was established using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and patients had to complete a specially designed sleep log every day; on scheduled visits, we also administered a Visual Analogue Scale for quality of life and a self-evaluation questionnaire about Dysfunctional Beliefs and Attitudes related to Sleep at the beginning and end of this study. In summary, the examinees in our study had significantly decreased parameters of quality of life, quite lower than expected based on previous findings in this area. However, by the end of the study, quality of life significantly improved with treatment: it improved by approximately 2/3 in the Lorazepam group and more than twice in the Zolpidem group, with a significant difference in favour of Zolpidem (p=0.047). Th is finding is most likely a consequence of its better safety profile and in part its better efficiency in terms of influence on certain domains of sleep itself, as previously discussed. Further specialized studies in this area with larger samples and a more detailed methodology are clearly warranted.

POSITIVE IMPACT OF PRESCRIBED PHYSICAL ACTIVITY ON SYMPTOMS OF SCHIZOPHRENIA: RANDOMIZED CLINICAL TRIAL

BACKGROUND The purpose of this study was to examine functional capacity of cardio-respiratory system in patients with schizophrenia, and to evaluate the effects of 12 weeks prescribed physical activity on aerobic capacity and symptoms of schizophrenia. SUBJECTS AND METHODS Study involved 80 hospitalized patients with any of the subtypes of schizophrenia (42 men, 38 women). They were divided into two groups: exercise and control group, both with 40 patients. Maximal aerobic capacity (VO2 max) as an indicator of cardiovascular fitness has been obtained by cardiopulmonary stress test on a treadmill. Twelve weeks program of prescribed physical activity (45 minutes, four times per week) was made for every patient individually. Patients in exercise group practiced in training zone between 65 and 75% of their maximum heart rate (HR). Target HR was controlled by Polar F4 monitors. Symptoms of schizophrenia were measured by using Positive and Negative Symptoms Scale (PANSS). RESULTS Before the exercise program was introduced, measured VO2 max was significantly lower in patients with schizophrenia, than the expected average value in matched healthy subjects (p<0.001). After twelve weeks, patients in exercise group showed a significant increase of VO2max (p=0.002), and significantly higher level of VO2max compared to the control group (p=0.000). Significant differences were also observed on PANSS general psychopathology subscale (p=0.007) and on PANSS total score (p=0.001). The pharmacotherapy and exercise had influence on PANSS general psychopathology (p=0.002) and PANSS total score (p=0.001). CONCLUSIONS Individuals with schizophrenia have lower levels of aerobic capacity compared to general population. Prescribed physical activity significantly improves aerobic capacity in people with schizophrenia and it is effective in amelioration of some psychiatric symptoms. Prescribed physical activity could be an effective adjunctive treatment for patients with schizophrenia, not only for prevention and treatment of comorbidities, but also having an impact on symptoms of schizophrenia.

Interleukin-6 in Schizophrenia—Is There a Therapeutic Relevance?

Renewing interest in immune aspects of schizophrenia and new findings about the brain-fat axis encourage us to discuss the possible role of interleukin-6 (IL-6) in schizophrenia. Previously, it was suggested that a primary alteration of the innate immune system may be relevant in schizophrenia. Functional dichotomy of IL-6 suggests that this chemical messenger may be responsible for regulating the balance between pro- and anti-inflammatory responses, with tissue-specific properties at the periphery and in the central nervous system. Specific phase of this chronic and deteriorating disorder must be considered, which can involve IL-6 in acute or possible chronic inflammation and/or autoimmunity. We give an overview of IL-6 role in the onset and progression of this disorder, also considering cognitive impairment and metabolic changes in patients with schizophrenia. Data suggest that decreased serum level of IL-6 following antipsychotic therapy could be predisposing factor for the development of obesity and obesity-related metabolic disorders in schizophrenia. As we reviewed, the IL-6 plays significant role in disease genesis and progression, so the use of specific inhibitors may not only be beneficial for exacerbation and alleviation of positive symptoms, but may attenuate cognitive impairment in patients with schizophrenia.

Cannabis as a Possible Treatment for Spasticity in Multiple Sclerosis / Kanabis Kao Moguci Tretman U Lecenju Spasticnosti Kod Multiple Skleroze

Abstract The therapeutic potential of cannabis has been known for centuries. Cannabinoids express their effects through two types of receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). Present studies indicate that cannabis-based drugs can make a positive impact in the treatment of different diseases. For many years, multiple sclerosis patients have self-medicated with illegal street cannabis to alleviate spasticity, a common and debilitating symptom that impairs quality of life. Nabiximols is the cannabis-based medicine approved in many countries as an add-on therapy for symptom improvement in patients with spasticity who have not responded adequately to other medications. Adverse events such as dizziness, diarrhoea, fatigue, nausea, headache and somnolence occur quite frequently with nabiximols, but they are generally of mild-to-moderate intensity and their incidence can be markedly reduced by gradual uptitration. The prerequisite for the therapeutic use of cannabis in Serbia arerequires legal clarification for the use of the drug in a clinical environment

Possible Role of TGF – B Pathways in Schizophrenia / Moguća Uloga TTGF - B Signalnih Puteva U Shizofreniji

Abstract The phenomenological uniqueness of each patient with schizophrenia is determined by complex symptomatology, particularly the overlapping of symptoms and their prominence in certain phases of this mental disorder. Establishing biological markers is an important step in the further objectivisation and quantification of schizophrenia. Identifying the cytokine profiles that precede a psychotic episode could direct the strategies for relapse prevention and be useful in predicting disease progression and treatment response. In the context of infl ammation, TGF-β exerts potent anti-inflammatory and immunosuppressive functions by inhibiting pro-inflammatory cytokine synthesis, but it can also have pro-inflammatory functions through its stimulatory effects on inflammatory Th17 cells. It has been shown that the T helper cell type-1 and type-17 responses are reduced and type-2 response is increased in patients with schizophrenia. Both data from the literature and our results also indicate the presence of an anti-inflammatory response through production of the TGF-β regulatory cytokine. A meta-analysis of plasma cytokine alterations suggested that TGF-β is the state marker for acute exacerbation of schizophrenia, and we showed that TGF-β can also be a valuable marker for psychosis. Hyperactivity of TGF-β signalling pathways in schizophrenia may be both a neuroprotective mechanism and a possible therapeutic target.