RESUMO
There is growing interest in clozapine clinical use, monitoring, and research, particularly adverse drug reactions (ADRs) other than agranulocytosis. In this study we focused on clozapine pharmacovigilance. Hence, we contacted clinicians and researchers in Latin America and requested information about local psychiatric services, clozapine availability, clinical use, and ADR monitoring with the VigiBase system. Only two countries have the minimum recommended number of psychiatric beds (15 per 100,000 residents): Uruguay (N = 34.9) and Argentina (N = 17). Bolivia is the only country where clozapine is unavailable. Nine out of twenty countries (45 %) reported ADRs to VigiBase. Argentina, Brazil, Chile, Colombia, and Mexico published national guidelines for schizophrenia treatment. Chile is the sole country with clozapine clinics with drug serum monitoring. Ethnicity-related drug titration in not described in package inserts in any country. We examined in detail the 9 most frequent and important clozapine ADRs in the worldwide database (pneumonia, sudden death, cardiac arrest, agranulocytosis, myocarditis, constipation, arrhythmia, seizure, and syncope). These 9 ADRs led to 294 reports with fatal outcomes in Argentina (N = 3), Brazil (N = 3), Chile (N = 2), and Peru (N = 1). Agranulocytosis was reported from 7 countries: constipation or seizures from 8 countries. Only two countries reported pneumonia and one country reported myocarditis. The number of clozapine reports in VigiBase has no relationship to the country's population. All Latin American countries underreport clozapine associated ADRs. Latin American governments, along with clinicians, researchers, and educators, should optimize clozapine use and monitoring for the benefit of people with severe mental and some neurological disorders.
RESUMO
The quality and quantity of clozapine safety monitoring considerably differs among South American countries and mainly focus on hematological surveillance. Few studies have been conducted on other clozapine-related adverse effects (ADRs) and mainly refer to case reports and literature reviews. We retrieved thirty-nine publications on clozapine related ADRs others than neutropenia. Studies in Brazil and Venezuela accounted for 67 % of all the publications, and 8 out of 12 countries published 2 or less manuscripts. Only Chile offers serum clozapine level measurement in public institutions. Given the recently recognized role of ethnicity, gender, smoking, obesity drug interactions in optimal clozapine administration, modernization of clozapine clinical use and research in psychiatry and neurology most be broadcasted and stimulated in South American countries.
RESUMO
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.
RESUMO
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.
Assuntos
Antipsicóticos , Clozapina , Humanos , Clozapina/uso terapêutico , Antipsicóticos/uso terapêutico , Brasil/epidemiologia , Benzodiazepinas , Fumarato de Quetiapina , PrescriçõesRESUMO
BACKGROUND: To what extent the COVID-19 pandemic and its containment measures influenced mental health in the general population is still unclear. PURPOSE: To assess the trajectory of mental health symptoms during the first year of the pandemic and examine dose-response relations with characteristics of the pandemic and its containment. DATA SOURCES: Relevant articles were identified from the living evidence database of the COVID-19 Open Access Project, which indexes COVID-19-related publications from MEDLINE via PubMed, Embase via Ovid, and PsycInfo. Preprint publications were not considered. STUDY SELECTION: Longitudinal studies that reported data on the general population's mental health using validated scales and that were published before 31 March 2021 were eligible. DATA EXTRACTION: An international crowd of 109 trained reviewers screened references and extracted study characteristics, participant characteristics, and symptom scores at each timepoint. Data were also included for the following country-specific variables: days since the first case of SARS-CoV-2 infection, the stringency of governmental containment measures, and the cumulative numbers of cases and deaths. DATA SYNTHESIS: In a total of 43 studies (331 628 participants), changes in symptoms of psychological distress, sleep disturbances, and mental well-being varied substantially across studies. On average, depression and anxiety symptoms worsened in the first 2 months of the pandemic (standardized mean difference at 60 days, -0.39 [95% credible interval, -0.76 to -0.03]); thereafter, the trajectories were heterogeneous. There was a linear association of worsening depression and anxiety with increasing numbers of reported cases of SARS-CoV-2 infection and increasing stringency in governmental measures. Gender, age, country, deprivation, inequalities, risk of bias, and study design did not modify these associations. LIMITATIONS: The certainty of the evidence was low because of the high risk of bias in included studies and the large amount of heterogeneity. Stringency measures and surges in cases were strongly correlated and changed over time. The observed associations should not be interpreted as causal relationships. CONCLUSION: Although an initial increase in average symptoms of depression and anxiety and an association between higher numbers of reported cases and more stringent measures were found, changes in mental health symptoms varied substantially across studies after the first 2 months of the pandemic. This suggests that different populations responded differently to the psychological stress generated by the pandemic and its containment measures. PRIMARY FUNDING SOURCE: Swiss National Science Foundation. (PROSPERO: CRD42020180049).
Assuntos
COVID-19 , Humanos , Ansiedade/epidemiologia , Ansiedade/psicologia , COVID-19/epidemiologia , Depressão/psicologia , Saúde Mental , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Dimensional approaches can decompose a construct in a set of continuous variables, improving the characterization of complex phenotypes, such as schizophrenia. However, the five-factor model of the Positive and Negative Syndrome Scale (PANSS), the most used instrument in schizophrenia research, yielded poor fits in most confirmatory factor analysis (CFA) studies, raising concerns about its applications. Thus, we aimed to identify dimensional PANSS CFA models with good psychometric properties by comparing the traditional CFA with three methodological approaches: Bayesian CFA, multilevel modeling, and Multiple Indicators Multiple Causes (MIMIC) modeling. METHODS: Clinical data of 700 schizophrenia patients from four centers were analyzed. We first performed a traditional CFA. Next, we tested the three techniques: 1) a Bayesian CFA; 2) a multilevel analysis using the centers as level; and 3) a MIMIC modeling to evaluate the impact of clinical staging on PANSS factors and items. RESULTS: CFA and Bayesian CFA produced poor fit models. However, when adding a multilevel structure to the CFA model, a good fit model emerged. MIMIC modeling yielded significant differences in the factor structure between the clinical stages of schizophrenia. Sex, age, age of onset, and duration of illness did not significantly affect the model fit. CONCLUSION: Our comparison of different CFA methods highlights the need for multilevel structure to achieve a good fit model and the potential utility of staging models (rather than the duration of illness) to deal with clinical heterogeneity in schizophrenia. Large prospective samples with biological data should help to understand the interplay between psychometrics concerns and neurobiology research.
Assuntos
Esquizofrenia , Teorema de Bayes , Análise Fatorial , Humanos , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Psicometria , Reprodutibilidade dos Testes , Esquizofrenia/diagnósticoRESUMO
IMPORTANCE: The occupational goal intervention (OGI) method has been proven effective in improving executive function (EF) in people with schizophrenia, but it has not yet been tested with those with treatment-resistant schizophrenia (TRS). OBJECTIVE: To test the efficacy of the OGI in people with TRS. DESIGN: Single-blind randomized controlled trial. SETTING: The Schizophrenia Program, Institute of Psychiatry, University of São Paulo General Hospital, Brazil. PARTICIPANTS: People with TRS according to Diagnostic and Statistical Manual of Mental Disorders (5th ed.) criteria, ages 18 to 55. Outcomes and Measures: Primary outcome: improvement in EF as measured by the Behavioural Assessment of the Dysexecutive Syndrome (BADS). SECONDARY OUTCOMES: improvement of functionality, as measured by the Direct Assessment of Functional Status-Revised (DAFS-BR), and improvement in autonomy in activities of daily living (ADLs), as measured by the Independent Living Skills Survey (ILSS-BR), administered to caregivers. The outcomes were measured at baseline, posttreatment, and follow-up. INTERVENTION: Participants were divided into two groups: OGI and craft activities (control). Each group participated in 30 sessions during 15 wk, with follow-up at 6 mo postintervention. RESULTS: The OGI group improved significantly compared with the control group, with medium to large effect sizes in posttreatment scores on the BADS and DAFS-BR. The ILSS-BR showed the highest effect sizes at posttreatment and follow-up. CONCLUSIONS AND RELEVANCE: The OGI method is effective for improving EF, occupational performance and ADLs in people with TRS. What This Article Adds: The OGI method is an important therapeutic tool for use in the occupational therapy clinic.
Assuntos
Disfunção Cognitiva , Esquizofrenia , Atividades Cotidianas , Adolescente , Adulto , Objetivos , Humanos , Pessoa de Meia-Idade , Método Simples-Cego , Adulto JovemRESUMO
This is a case description of a patient with clozapine and ECT resistance schizophrenia with several suicide attempts. We discussed evidence-based clinical decisions to deal with such conditions.
Assuntos
Antipsicóticos , Clozapina , Eletroconvulsoterapia , Esquizofrenia , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Terapia Combinada , Humanos , Esquizofrenia/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Brain magnetic resonance imaging studies have not investigated the cortical surface comprehensively in schizophrenia subjects by assessing thickness, surface area and gyrification separately during the first-episode of psychosis (FEP) or chronic schizophrenia (ChSch). METHODS: We investigated cortical surface abnormalities in 137 FEP patients and 240 ChSch subjects compared to 297 Healthy Controls (HC) contributed by five cohorts. Maps showing results of vertexwise between-group comparisons of cortical thickness, area, and gyrification were produced using T1-weighted datasets processed using FreeSurfer 5.3, followed by validated quality control protocols. RESULTS: FEP subjects showed large clusters of increased area and gyrification relative to HC in prefrontal and insuli cortices (Cohen's d: 0.049 to 0.28). These between-group differences occurred partially beyond the effect of sample. ChSch subjects displayed reduced cortical thickness relative to HC in smaller fronto-temporal foci (d: -0.73 to -0.35), but not beyond the effect of sample. Differences between FEP and HC subjects were associated with male gender, younger age, and earlier illness onset, while differences between ChSch and HC were associated with treatment-resistance and first-generation antipsychotic (FGA) intake independently of sample effect. CONCLUSIONS: Separate assessments of FEP and ChSch revealed abnormalities that differed in regional distribution, phenotypes affected and effect size. In FEP, associations of greater cortical area and gyrification abnormalities with earlier age of onset suggest an origin on anomalous neurodevelopment, while thickness reductions in ChSch are at least partially explained by treatment-resistance and FGA intake. Associations of between-group differences with clinical variables retained statistical significance beyond the effect of sample.
Assuntos
Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Antipsicóticos/uso terapêutico , Córtex Cerebral/diagnóstico por imagem , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológicoRESUMO
Cognitive deficits and negative symptoms in schizophrenia are associated with poor functional outcomes and limited in terms of treatment. The Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) trial has shown efficacy of transcranial direct current stimulation (tDCS) for improving negative symptoms. In this secondary analysis, we investigate its effects on cognitive performance. In STARTS, a double-blinded, sham-controlled, randomized clinical trial, patients were treated with twice-daily, 20-min, 2-mA fronto-temporal tDCS over 5 days or sham-tDCS. In 90 patients, we evaluated the cognitive performance up to 12 weeks post-treatment. We found that active-tDCS showed no beneficial effects over sham-tDCS in any of the tests. Based on a 5-factor cognitive model, improvements of executive functions and delayed memory were observed in favor of sham-tDCS. Overall, the applied active-tDCS protocol, primarily designed to improve negative symptoms, did not promote cognitive improvement. We discuss possible protocol modification potentially required to increase tDCS effects on cognition. ClinicalTrials.gov identifier: NCT02535676.
Assuntos
Disfunção Cognitiva , Esquizofrenia , Estimulação Transcraniana por Corrente Contínua , Cognição , Método Duplo-Cego , Humanos , Esquizofrenia/complicações , Esquizofrenia/terapiaRESUMO
BACKGROUND: Paliperidone palmitate is a long-acting, second-generation antipsychotic (SGA) indicated for the treatment of acute exacerbations and maintenance treatment of adults with schizophrenia. This study addressed the response to paliperidone palmitate in Latin American patients with acute symptoms and recently diagnosed schizophrenia. OBJECTIVE: Explore the efficacy and tolerability of paliperidone palmitate administered once a month for 4 months in patients with acute phase and recent diagnosis (within 1-6 years) of schizophrenia in 3 Latin American countries. METHODS: This was a non-randomized, open-label, multicenter study with paliperidone palmitate injected intramuscularly in the deltoid muscle at an initial loading dose of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 (± 4 days). The recommended maintenance dose was 75 mg eq. (117 mg) from day 36 to day 92. Efficacy was evaluated with PANSS and CGI-S. The last observation carried forward (LOCF) was used for efficacy analysis for imputation of missing data; no adjustments were made for multiplicity. Adverse events were evaluated during treatment. RESULTS: The patient retention rate was 84.0% (144 patients received study drug; 121 finished the study). The percentage of patients with a reduction of at least 30% in PANSS total score compared to baseline gradually increased during the study, and at the end, 78.4% of patients showed response. The PANSS total score and CGI-S scores decreased significantly from baseline to LOCF endpoint (P <0.0001 for both); significant reduction in PANSS total score was observed at day 8 and persisted to the end of the study. Most common adverse events were muscle rigidity (11.8%), akathisia (11.1%), injection-site pain (7.6%), weight gain (7.6%), and insomnia (7.6%). CONCLUSION: Paliperidone palmitate was efficacious in Latin American patients studied with an acute exacerbation and recent diagnosis of schizophrenia, and no new safety signals were identified.
RESUMO
BACKGROUND: Study-level meta-analyses have demonstrated the efficacy of cognitive-behavioural therapy for psychosis (CBTp). Limitations of conventional meta-analysis may be addressed using individual-participant-data (IPD). We aimed to determine a) whether results from IPD were consistent with study-level meta-analyses and b) whether demographic and clinical characteristics moderate treatment outcome. METHODS: We systematically searched PubMed, Embase, PsychInfo and CENTRAL. Authors of RCTs comparing CBTp with other psychological interventions were contacted to obtain original databases. Hierarchical mixed effects models were used to examine efficacy for psychotic symptoms. Patient characteristics were investigated as moderators of symptoms at post-treatment. Sensitivity analyses were conducted for risk of bias, treatment format and study characteristics. RESULTS: We included 14 of 23 eligible RCTs in IPD meta-analyses including 898 patients. Ten RCTs minimised risk of bias. There was no significant difference in efficacy between RCTs providing IPD and those not (p >0.05). CBTp was superior vs. other interventions for total psychotic symptoms and PANSS general symptoms. No demographic or clinical characteristics were robustly demonstrated as moderators of positive, negative, general or total psychotic symptoms at post-treatment. Sensitivity analyses demonstrated that number of sessions moderated the impact of treatment assignment (CBTp or other therapies) on total psychotic symptoms (p = 0.02). CONCLUSIONS: IPD suggest that patient characteristics, including severity of psychotic symptoms, do not significantly influence treatment outcome in psychological interventions for psychosis while investing in sufficient dosage of CBTp is important. IPD provide roughly equivalent efficacy estimates to study-level data although significant benefit was not replicated for positive symptoms. We encourage authors to ensure IPD is accessible for future research.
RESUMO
We conducted a randomized controlled trial to assess the effectiveness of social skills training (SST) in improving negative symptoms in patients with treatment-resistant schizophrenia with predominantly negative symptoms. Patients were randomized to receive SST (n = 29) or to a control group (n = 33), in a 20-week program with weekly group sessions. Patients were assessed at baseline, post-treatment (20 weeks) and 6-month follow-up with the Positive and Negative Syndrome Scale. There was no significant improvement in the negative symptoms in either group, at any timepoint. Caution is warranted to interpret the results due to small sample size.
Assuntos
Terapia Cognitivo-Comportamental/métodos , Esquizofrenia/diagnóstico , Esquizofrenia/terapia , Psicologia do Esquizofrênico , Habilidades Sociais , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Resultado do TratamentoRESUMO
Importance: Negative symptoms represent a substantial burden in schizophrenia. Although preliminary studies have suggested that transcranial direct current stimulation (tDCS) is effective for some clusters of symptoms, the clinical benefits for negative symptoms are unclear. Objective: To determine the efficacy and safety of tDCS vs sham as an add-on treatment for patients with schizophrenia and predominant negative symptoms. Design, Setting, and Participants: The double-blind Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) randomized clinical trial was conducted from September 2014 to March 2018 in 2 outpatient clinics in the state of São Paulo, Brazil. Patients with schizophrenia with stable negative and positive symptoms and a minimum score of 20 points in the negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS) were included. Interventions: Ten sessions of tDCS performed twice a day for 5 days or a sham procedure. The anode and the cathode were positioned over the left prefrontal cortex and the left temporoparietal junction, respectively. Main Outcomes and Measures: Change in the PANSS negative symptoms subscale score at week 6 was the primary outcome. Patients were followed-up for an additional 6 weeks. Results: Of the 100 included patients, 20 (20.0%) were female, and the mean (SD) age was 35.3 (9.3) years. A total of 95 patients (95.0%) finished the trial. In the intention-to-treat analysis, patients receiving active tDCS showed a significantly greater improvement in PANSS score compared with those receiving the sham procedure (difference, 2.65; 95% CI, 1.51-3.79; number needed to treat, 3.18; 95% CI, 2.12-6.99; P < .001). Response rates for negative symptoms (20% improvement or greater) were also higher in the active group (20 of 50 [40%]) vs the sham group (2 of 50 [4%]) (P < .001). These effects persisted at follow-up. Transcranial direct current stimulation was well tolerated, and adverse effects did not differ between groups, except for burning sensation over the scalp in the active group (43.8%) vs the sham group (14.3%) (P = .003). Conclusions and Relevance: Transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia. Trial Registration: ClinicalTrials.gov identifier: NCT02535676.
Assuntos
Esquizofrenia/terapia , Estimulação Transcraniana por Corrente Contínua , Adulto , Antipsicóticos/uso terapêutico , Terapia Combinada , Método Duplo-Cego , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Psicologia do Esquizofrênico , Estimulação Transcraniana por Corrente Contínua/efeitos adversos , Estimulação Transcraniana por Corrente Contínua/métodos , Resultado do TratamentoRESUMO
INTRODUCTION: Schizophrenia is a severe mental disorder. While some antipsychotic medications have demonstrated efficacy in treating positive symptoms, there is no widely recognized treatment for negative symptoms, which can cause significant distress and impairment for patients with schizophrenia. Here we describe the rationale and design of the STARTS study (Schizophrenia TreAtment with electRic Transcranial Stimulation), a clinical trial aimed to test the efficacy of a non-pharmacological treatment known as transcranial direct current stimulation (tDCS) for treating the negative symptoms of schizophrenia. METHODS: The STARTS study is designed as a randomized, sham-controlled, double-blinded trial evaluating tDCS for the treatment of the negative symptoms of schizophrenia. One-hundred patients will be enrolled and submitted to 10 tDCS sessions over the left dorsolateral prefrontal cortex (anodal stimulation) and left temporoparietal junction (cathodal stimulation) over 5 consecutive days. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in the Positive and Negative Syndrome Scale (PANSS) negative subscale score over time and across groups. Biological markers, including blood neurotrophins and interleukins, genetic polymorphisms, and motor cortical excitability, will also be assessed. RESULTS: The clinical results will provide insights about tDCS as a treatment for the negative symptoms of schizophrenia, and the biomarker investigation will contribute towards an improved understanding of the tDCS mechanisms of action. CONCLUSION: Our results could introduce a novel therapeutic technique for the negative symptoms of schizophrenia. Clinical trial registration: ClinicalTrials.gov, NCT02535676 .