Inflammatory markers in outpatients with schizophrenia diagnosis in regular use of clozapine: a cross-sectional study.

It is known that inflammation worsen the course of schizophrenia and induce high clozapine serum levels. However, no study evaluated this change in function of clozapine daily dose in schizophrenia. We assessed the correlation between inflammation and severity symptoms in patients with schizophrenia that take and do not take clozapine. We also assessed the correlation between clozapine daily dose and inflammatory markers to patients who take this drug. Patients were recruited from Schizophrenia Ambulatory and Psychosocial Care Center of Clinical Hospital of Porto Alegre and from an association of relatives of patients with schizophrenia. Exam results, and other important clinical exam were assessed in patients record or patients were asked to show their exam in the case of outpatients. We included 104 patients, 90 clozapine users and 14 non-clozapine users. We calculate the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), and the psychopathology severity by the Brief Psychiatric Rating Scaled anchored (BPRS-a)]. These variables were compared between clozapine users and non-clozapine users. It was used mean/median test according to data distributing, with study factor (SII, MLR, and PLR), the clinical outcome: severity of symptomatology (BPRS score), and clozapine daily dose as adjustment factor. Clozapine users exhibited a significantly higher neutrophil count (mean ± SD: 5.03 ± 2.07) compared to non-clozapine users (mean ± SD: 3.48 ± 1.27; p = 0.031). After controlling for comorbidity, other parameters also showed significant differences. These findings are consistent with previous studies that have demonstrated an inflammatory response following the administration of clozapine.

A controlled open clinical trial of the positive effect of a physical intervention on quality of life in schizophrenia.

Justification: Schizophrenia is a severe mental disorder associated with important physical (obesity and low motor functional capacity) and metabolic (diabetes and cardiovascular diseases) changes that contribute to a more sedentary lifestyle and a low quality of life. Objective: The study aimed to measure the effect of two different protocols of physical exercise [aerobic intervention (AI) versus functional intervention ([FI)] on lifestyle in schizophrenia compared with healthy sedentary subjects. Methodology: A controlled clinical trial involving patients diagnosed with schizophrenia from two different locations [Hospital de Clinicas de Porto Alegre (HCPA) and Centro de Atenção Psicosocial (CAPS) in the city of Camaquã] was carried out. The patients undertook two different exercise protocols (IA: 5-min warm-up of comfortable intensity; 45 min of aerobic exercise of increasing intensity using any of the three modalities-a stationary bicycle, a treadmill, or an elliptical trainer; and 10 min of global stretching of large muscle groups; and FI: a 5 min warm-up with a stationary walk; 15 min of muscle and joint mobility exercises; 25 min of global muscle resistance exercises; and 15 min of breathing body awareness work) twice a week for 12 weeks and were compared with physically inactive healthy controls. Clinical symptoms (BPRS), life quality (SF-36), and physical activity levels (SIMPAQ) were evaluated. The significance level was p ≤ 0.05. Results: The trial involved 38 individuals, of which 24 from each group performed the AI, and 14 from each group underwent the FI. This division of interventions was not randomized but was instead decided upon for convenience. The cases showed significant improvements in quality of life and lifestyle, but these differences were greater in the healthy controls. Both interventions were very beneficial, with the functional intervention tending to be more effective in the cases and the aerobic intervention more effective in the controls. Conclusion: Supervised physical activity improved life quality and reduced sedentary lifestyle in adults with schizophrenia.

Ketamine study: Protocol for naturalistic prospective multicenter study on subcutaneous ketamine infusion in depressed patients with active suicidal ideation.

Background: Psychiatric disorders are associated with more than 90% of reported suicide attempts worldwide, but few treatments have demonstrated a direct effect in reducing suicide risk. Ketamine, originally an anesthetic, has been shown anti-suicide effects in clinical trials designed to treat depression. However, changes at the biochemical level were assessed only in protocols of ketamine with very limited sample sizes, particularly when the subcutaneous route was considered. In addition, the inflammatory changes associated with ketamine effects and their correlation with response to treatment, dose-effect, and suicide risk warrant further investigation. Therefore, we aimed to assess whether ketamine results in better control of suicidal ideation and/or behavior in patients with depressive episodes and whether ketamine affects psychopathology and inflammatory biomarkers. Materials and methods: We report here the design of a naturalistic prospective multicenter study protocol of ketamine in depressive episodes carried out at Hospital de Clínicas de Porto Alegre (HCPA) and Hospital Moinhos de Vento (HMV). The study was planned to recruit adult patients with Major depressive disorder (MDD) or Bipolar disorder (BD) types 1 or 2, who are currently in a depressive episode and show symptoms of suicidal ideation and/or behavior according to the Columbia-Suicide Severity Rating Scale (C-SSRS) and have been prescribed ketamine by their assistant psychiatrist. Patients receive ketamine subcutaneously (SC) twice a week for 1 month, but the frequency can be changed or the dose decreased according to the assistant physician's decision. After the last ketamine session, patients are followed-up via telephone once a month for up to 6 months. The data will be analyzed using repeated measures statistics to evaluate the reduction in suicide risk as a primary outcome, as per C-SSRS. Discussion: We discuss the need for studies with longer follow-ups designed to measure a direct impact on suicide risk and that additional information about the safety and tolerability of ketamine in particular subset of patients such as those with depression and ideation suicide. In line, the mechanism behind the immunomodulatory effects of ketamine is still poorly understood. Trial registration: https://clinicaltrials.gov/, identifier NCT05249309.

Aerobic and Postural Strength Exercise Benefits in People with Schizophrenia.

BACKGROUND: This study aimed to evaluate the effect of two different types of physical intervention on sedentary behavior and clinical changes in people with schizophrenia. METHOD: This is a clinical trial including people with schizophrenia in regular outpatient care who realized a 3-month exercise protocol and were separated into two groups: aerobic physical intervention (API) and postural physical intervention (PPI). All participants performed an assessment of (a) functional capacity through a 6 min walk test (6MWT), (b) flexibility using Well's bench, (c) disease severity using the Brief Psychiatric Rating Scale (BPRS), (d) quality of life using the SF-36 Questionnaire and (e) physical activity using the Simple Physical Activity Questionnaire (SIMPAQ). RESULTS: Thirty-eight patients with schizophrenia completed the intervention (24 patients in API and 14 patients in PPI). Regarding sedentary behavior, there was an improvement in the API group in the time exercising and in the PPI group concerning time in bed, time walking and exercising. Regarding quality of life, there was an improvement in the API group (functional capacity) and in the PPI group, there was an improvement in physical limitation, pain and emotional limitations. In the API group, there was an improvement in BMI (body mass index), diastolic blood pressure and systolic blood pressure. Functional capacity was improved only in the PPI group. There was no change in flexibility and disease severity. CONCLUSIONS: The study demonstrated a change response in the physical and mental aspects in people with schizophrenia after a change in sedentary behavior.

Clozapine prescription trends in Brazil in the last decade

Objective: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. Methods: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. Results: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. Conclusions: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Clozapine prescription trends in Brazil in the last decade.

OBJECTIVE: Clozapine is a second-generation antipsychotic indicated for treatment-resistant schizophrenia. Studies in several countries have shown a low rate of clozapine use despite the fact that approximately 30% of schizophrenia cases are treatment-resistant. In Brazil, few studies have addressed the frequency and variety of antipsychotic use in individuals diagnosed with schizophrenia (ICD F20). The objective of this study was to measure the rates of clozapine use in this population in the last decade using Brazilian Ministry of Health data. METHODS: Prescriptions made between 2010 and 2020 in all 26 states and the Federal District registered at the Outpatient Information System Database from the Brazilian Health System (SIASUS) were evaluated. RESULTS: A total of 25,143,524 prescriptions were recorded in this period, with clozapine representing 8.86% of all antipsychotics. The most frequently prescribed antipsychotic for patients with schizophrenia was olanzapine (35.8%), followed by quetiapine (27.5%). From 2010 to 2020, the rate of clozapine prescriptions in Brazil increased from 7.2% to 10.9%. CONCLUSIONS: Despite a slight increase in prescriptions in the last decade, clozapine is still underutilized in Brazil.

Allergic reaction induced by subcutaneous administration of ketamine: a case report.

Ketamine can be used for depression and suicidal ideation due to its effectiveness and low complication rates; moreover, allergic reactions are rare. Immediately after subcutaneous (SC) ketamine administration, a 22-year-old man rapidly developed hives on the trunk and face without oxygen desaturation. Symptoms disappeared after treatment with prednisolone. This case presents an allergic reaction to ketamine compatible with mast cell activation and release of preformed mediators, without being able to prove whether the event was mediated by immunoglobulin E. This is the only case reported to date of an allergic reaction to SC ketamine for psychiatric treatment.

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients

Objective: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. Methods: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. Results: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). Conclusions: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

Risk of neutropenia among clozapine users and non-users: results from 5,847 patients.

OBJECTIVE: Clozapine is underprescribed due to neutropenia risk. Blood tests every 3 months in those on continuous treatment for > 1 year who have never had an absolute neutrophil count (ANC) < 2,000/µL has been proposed as a monitoring strategy; however, there are no South American data to support this recommendation. This study sought to investigate whether clozapine use and other variables could explain the occurrence of ANC < 1,000/µL in patients with severe mental disorders. METHODS: A total of 5,847 subjects were included, 1,038 on clozapine. We performed a Cox regression considering the outcome as ANC < 1,000/µL at any time point. Predictors were sex, age, ethnicity, clozapine use, ANC > 2,000/µL during the first year of blood monitoring, and presence of a severe medical condition. RESULTS: In the Cox regression model, ethnicity (white) (hazard ratio [HR] 0.53; 95%CI 0.29-0.99, p < 0.05) and ANC > 2,000/µL (HR 0.04; 95%CI 0.01-0.10, p < 0.001) were protective factors, while presence of a severe medical condition (HR 69.35; 95%CI 37.45-128.44, p < 0.001) was a risk factor for ANC < 1,000/µL. Other variables were not significant, including clozapine use (HR 1.33; 95%CI 0.74-2.39, p > 0.05). CONCLUSIONS: These findings suggest that clozapine does not increase the risk of neutropenia in subjects with ANC > 2,000/µL during the first year of use and in the absence of a severe medical condition. These results could help guide clinical and public-health decisions regarding clozapine blood monitoring guidelines.

Differential Physical and Mental Benefits of Physiotherapy Program Among Patients With Schizophrenia and Healthy Controls Suggesting Different Physical Characteristics and Needs.

In contrast to several other severe illnesses marked by inflammation and autoimmunity that now have potent and efficient treatments and even cures, schizophrenia (SCZ) is a disease still associated with poor outcome, incapacity, and social burden. Even after decades of research on the brain and behavior, this illness is still associated with profound effects on both mental health and physical health, with recent studies showing that treatment is more efficient when associating drugs with psychological and physical treatments. Most of the studies measured the effects of physical intervention compared with usual care and demonstrated a positive effect as an add-on treatment. What remains unclear is the different effects of the same intervention in normal subjects in a sample of patients with the illness. The study aimed to evaluate the effects of physical intervention over motor functional capacity and mental health in patients with SCZ compared with healthy controls (HC). The outcomes were (a) functional capacity [by 6-min walk test (6MWT)], (b) body flexibility index (Wells' bench), (c) disease severity [by Brief Psychiatric Rating Scale (BPRS)], (d) quality of life [by 36-Item Short Form (SF-36) questionnaire], and (e) physical activity [Simple Physical Activity Questionnaire (SIMPAQ)]. The intervention was associated with significant decrease of body mass index (BMI), blood pressure, disease severity, and improvement in daily life activities. Unexpectedly, it was observed that schizophrenics, compared with matched HC, were at a lower level of performance in the beginning, remained below HC over the studied time despite similar physical intervention, and had different changes. The intervention had lower effects over physical capacity and better effects over quality of life and disease severity. The results confirm previous studies comparing patients receiving physical intervention but suggest that they may receive different types of intervention, suited for their different baseline fitness, motivation, and capacity to engage in physical effort over sustained time. Additionally, they point to extended time of intervention of multidisciplinary treatment (physical and psychological-cognitive techniques) to improve outcomes in SCZ.

Proinflammatory and anti-inflammatory biomarkers in schizophrenia and influence of simvastatin on the interleukin-6.

The present study sought to assess biomarkers of inflammation in stable patients with schizophrenia (SZ) on clozapine therapy. We recruited 60 outpatients with SZ and 60 healthy controls, matched for sex and age. Compared with controls, patients had significantly increased concentrations of interleukin-6 and tumor necrosis factor-α. Interestingly, patients on simvastatin had lower interleukin-6 levels compared with patients not on simvastatin and controls. This study corroborated previous evidence for increased inflammatory biomarkers in SZ and detected a potential anti-inflammatory action of simvastatin in patients with a clinical diagnosis of SZ on clozapine therapy.

Perda significativa de peso em pacientes com esquizofrenia na dieta hipocalórica de longo prazo: estudo piloto / Significant weight loss in patients with schizophrenia in long-term hypocaloric diet: a pilot study

Objetivo: A esquizofrenia está associada ao aumento da obesidade e morbidade por doença cardiovascular. O objetivo do presente estudo foi avaliar alterações no peso e índice de massa corporal (IMC) de pacientes com esquizofrenia após tratamento nutricional de longo prazo. Método: Estudo piloto retrospectivo envolvendo 42 indivíduos com esquizofrenia em tratamento nutricional entre 2004 e 2010. Os prontuários médicos foram revisados após aprovação institucional e coleta de dados para peso, índice de massa corporal (IMC), idade, gênero e dieta. O peso e o IMC foram avaliados no início do tratamento nutricional, após seis meses, após 12 meses e no momento da coleta de dados. Resultados: Houve perda significativa de peso e diminuição significativa do IMC quando comparados a cada grupo com o valor basal (p<0,001). Conclusões: Demonstramos que as intervenções nutricionais podem promover uma significativa perda de peso na esquizofrenia. Estes resultados suportam a importância da intervenção nutricional na esquizofrenia e trazem evidências de que a perda de peso permanece ao longo do tempo.(AU)

Objective: Schizophrenia is associated with increased obesity and morbidity from cardiovascular disease. The aim of the present study was to evaluate changes in weight and body mass index (BMI) of patients with schizophrenia following a long-term nutritional treatment. Methods: Retrospective pilot study involving 42 individuals with schizophrenia on nutritional treatment from 2004 to 2010. Medical charts were reviewed after institutional approval and data collection was conducted for weight, body mass index (BMI), age, gender and diet prescription. Weight and BMI were evaluated at baseline of nutrition treatment, after six months, after 12 months and at the time of data collection. Results: There was a significant weight loss and significant decreased in BMI when compared each group to baseline (p<0.001). Conclusions: We demonstrate that nutritional interventions can promote a significant weight loss in schizophrenia. These results support the importance of nutritional intervention in schizophrenia and bring evidences that weight loss remains along the time.(AU)

Postural changes in different stages of schizophrenia is associated with inflammation and pain: a cross-sectional observational study.

OBJECTIVES: To assess the relationship between posture and inflammatory response markers (C-reactive protein [CRP] and von Willebrand factor [vWF]) in schizophrenics. METHODS: Forty patients with stable schizophrenia were divided into early-stage (<10 years since first episode, n = 15) and late-stage (≥10 years since first episode, n = 25) groups. Both groups were compared to controls (n = 26). All participants underwent postural assessment by biophotogrammetry. Cases alone underwent blood collection. The significance level was set at 5%, and analyses were carried out in SPSS 18.0. RESULTS: In the early-stage group, 15 postural angles were significantly different from their reference ranges, whereas in the late-stage group, only seven angles were significantly different. In comparison with the control group, only six angles were significantly different. There was no difference in inflammation markers between the early- and late-stage groups. However, CRP levels were higher in cases with greater disease severity, and vWF was associated with forward head posture. Pain correlated with five postural angles, and late-stage patients reported more pain than early-stage cases. CONCLUSIONS: CRP was associated with disease severity, while vWF and pain were associated with forward head posture, hyperlordosis and scoliosis, suggesting an association between vascular inflammation and pain, with an influence on posture.

Trends in elderly psychiatric admissions to the Brazilian public health care system

Objective: To evaluate trends in psychiatric bed occupancy by elderly inpatients in the Brazilian public health care system between 2000 and 2010 and to determine the leading psychiatric diagnosis for hospital admissions. Methods: Data from all 895,476 elderly psychiatric admissions recorded in the Brazilian Public Health Care Database (DATASUS) between January 2000 and February 2010 were analyzed. Polynomial regression models with estimated curve models were used to determine the trends. The number of inpatient days was calculated for the overall psychiatric admissions and according to specific diagnoses. Results: A moderate decreasing trend (p < 0.001) in the number of inpatient days was observed in all geriatric psychiatric admissions (R2 = 0.768) and in admissions for organic mental disorders (R2 = 0.823), disorders due to psychoactive substance use (R2 = 0.767), schizophrenia (R2 = 0.680), and other diagnoses (R2 = 0.770), but not for mood disorders (R2 = 0.472). Most admissions (60 to 65%) were due to schizophrenia. Conclusion: There was a decreasing trend in inpatient days for elderly psychiatric patients between 2000 and 2010. The highest bed occupancy was due to schizophrenia, schizotypal, and delusional disorders.

Resveratrol Supplementation Did Not Improve Cognition in Patients with Schizophrenia: Results from a Randomized Clinical Trial.

BACKGROUND: Schizophrenia (SZ) is associated with psychotic experiences and cognitive deficits. Therefore, cognitive function is one of the most critical determinants of quality of life in this pathology. Resveratrol has been related to neuroprotective action, but there are no studies evaluating resveratrol in SZ. The objective of this study was to determine the efficacy of resveratrol supplementation on cognition in individuals with SZ. METHODS: This is a 1-month randomized, double-blind, and controlled trial (NCT 02062190), in which 19 men with diagnosis of SZ, aged 18-65 years, were assigned to a resveratrol supplementation group (200 mg) or placebo group (200 mg), with a 1-month follow-up. Applying a series of cognitive tests assessed neuropsychology performance (Hopkins Verbal Learning Test, Stroop Color and Word Test, and Weschler Adult Intelligence Scale) and Brief Psychiatric Rating Scale assessed psychopathology severity. RESULTS: There were no significant improvement in neuropsychology performance (episodic memory, working memory, attention and concentration capacity, inhibitory control, interference measures, selective attention, and mental flexibility) and psychopathology severity after 1 month of resveratrol supplementation (P > 0.05). CONCLUSION: In conclusion, we have shown that 1 month of a resveratrol supplementation (200 mg/day) did not improve episodic memory, working memory, attention and concentration capacity, inhibitory control, interference measures, selective attention, and mental flexibility as compared with placebo in patients with SZ.

Physical Functional Capacity and C-Reactive Protein in Schizophrenia.

INTRODUCTION: Schizophrenia is a severe, debilitating mental disorder that affects both the physical health and the functional capacity of patients, causing great impairment throughout the life course. Although physical and cognitive impairments may represent different expressions of a single systemic inflammatory process, little is known about the relationship between motor function and schizophrenia. OBJECTIVE: To evaluate physical functional capacity in patients with schizophrenia and ascertain whether it correlates with markers of inflammation, disease severity, and pharmacotherapy. METHODS: Cross-sectional study using a convenience sampling strategy. Forty patients with stable schizophrenia, undergoing treatment, were recruited from the Outpatient Program of Hospital de Clínicas de Porto Alegre, University Hospital linked to Public Health System. Physical functional capacity was assessed by the 6-min walk test (6MWT), and inflammatory markers were measured by C-reactive protein (CRP) and Von Willebrand factor. RESULTS: Mean functional capacity and clinical variables differed among patients and Brazilian population regarding heart rate (p = 0.004), diastolic (p = 0.001) and systolic (p < 0.001) blood pressure, respiratory rate (p < 0.001), CRP (p = 0.015), Borg Scale of Perceived Exertion scores (BSPE) (p < 0.001), and 6MWT both in men (p < 0.001) and women (p = 0.024). Additionally, 6MWT and dyspnea in BSPE were positively associated with CRP (r = -0.369, p = 0.019) and (r = -0.376, p = 0.017) and (r = 0.354, p = 0.025 and r = 0.535, p < 0.001, respectively). CONCLUSION: The present study detected significant association between measures of functional impairment and markers of inflammation, especially elevated CRP in a group of stable outpatients with DSM-IV and ICD10 diagnosis of schizophrenia. Possible explanations for the associations could be linked to continued use of antipsychotics, although underlying neuroinflammatory mechanisms directly related to illness (schizophrenia) could not be ruled out. The findings of this study expand evidences of neuroinflammation to systemic inflammation in schizophrenia linking it to alterations of physical functional capacity and point to the need of additional studies exploring general inflammation and novel therapeutic interventions.