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 Introdução A esquizofrenia é um transtorno mental grave. Embora alguns medicamentos antipsicóticos tenham demonstrado eficácia no tratamento de sintomas positivos, não há tratamento amplamente reconhecido para sintomas negativos, o que pode causar sofrimento e prejuízo significativos para pacientes com esquizofrenia. Aqui descrevemos a fundamentação teórica e o design do estudo STARTS (Schizophrenia TreAtment with electRic Transcranial Stimulation), um ensaio clínico destinado a testar a eficácia de um tratamento não farmacológico conhecido como estimulação transcraniana por corrente contínua (ETCC) para tratar os sintomas negativos da esquizofrenia. Métodos O estudo STARTS foi concebido como um ensaio clínico randomizado, controlado por simulação, duplo-cego, avaliando a ETCC para o tratamento dos sintomas negativos da esquizofrenia. Cem pacientes serão incluídos e submetidos a 10 sessões de ETCC sobre o córtex pré-frontal dorsolateral esquerdo (estimulação anódica) e a junção temporoparietal esquerda (estimulação catodal) durante 5 dias consecutivos. Os participantes serão avaliados através de testes clínicos e neuropsicológicos antes e após a intervenção. O desfecho primário é a mudança na pontuação da subescala negativa da Escala da Síndrome Positiva e Negativa (Positive and Negative Syndrome Scale [PANSS]) ao longo do tempo e entre os grupos. Marcadores biológicos, incluindo neurotrofinas e interleucinas do sangue, polimorfismos genéticos e excitabilidade cortical motora, também serão avaliados. Resultados Os resultados clínicos fornecerão informações sobre a ETCC como um tratamento para os sintomas negativos da esquizofrenia, e a investigação dos biomarcadores contribuirá para uma melhor compreensão dos mecanismos de ação da ETCC. Conclusão Nossos resultados podem trazer uma nova técnica terapêutica para o tratamento dos sintomas negativos da esquizofrenia. Registro do ensaio clínico: ClinicalTrials.gov, NCT02535676.

Abstract 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 .

Abstract Background Thirty percent of schizophrenia patients are treatment-resistant. Objective This is a single-blinded sham-controlled trial to assess the efficacy of electroconvulsive therapy (ECT) as augmentation strategy in patients with clozapine-resistant schizophrenia. Methods Twenty three subjects were randomly assigned to 12 sessions of ECT (N = 13) or placebo (Sham ECT) (N = 10). The primary outcome was improvement on psychotic symptoms as measured by the mean reduction of the PANSS positive subscale. The assessments were performed by blind raters. Results At baseline both groups were similar, except for negative and total symptoms of the PANSS, which were higher in the Sham group. At the endpoint both groups had a significant decrease from basal score. In the ECT group the PANSS total score decreased 8.78%, from 81.23 to 74.75 (p = 0.042), while the positive subscale had a mean reduction of 19% (19.31 to 16.17, p = 0.006). In the Sham group, the mean reduction of PANSS total score was 15.27% (96.80 to 87.43; p = 0.036), and the PANSS positive subscale decreased 27.81% (22.90 to 19.14, p = 0.008). The CGI score in ECT group decreased 23.0% (5.23 to 4.17; p = 0.001) and decreased 24.31% in the Sham ECT group (5.80 to 4.86; p = 0.004). Discussion In this pilot study, we found no difference between the groups.

Abstract Background Social dysfunction is an important outcome for schizophrenia and can be measured by the evaluation of social skills. Objectives To compare social skills in patients with schizophrenia classified according the degree of treatment response and severity of psychopathology with normative controls by using the Del Prette Social Skills Inventory (SSI). Methods Cross-sectional study where the 38 questions SSI was applied to 62 outpatients with schizophrenia and compared with data of 99 normal controls from the general population. The SSI was evaluated by five domains. Psychopathology was measured by the Positive and Negative Syndrome Scale (PANSS). Patients were classified as Treatment Resistant (TRS) and Non Treatment Resistant (NTRS) by the International Psychopharmacology Algorithm Project (IPAP) criteria. ANCOVA was used to control for demographic differences between populations. Results Patients showed significantly more impaired than controls except for aggressiveness control. When variables such as age, age of onset, schooling or medication dose entered as covariates, differences between controls and patients, or TRS with NTRS, almost disappeared. The SSI and PANSS showed an inverse relationship between their domains. Discussion The SSI may represent a useful tool for evaluation of social skills in schizophrenia. Antipsychotics may exert a protective effect on social skills.

Abstract Background Thought and language disorders are main features of adults with schizophrenia and bipolar disorders however studies on such abnormalities are scant in young patients with very early onset psychosis (VEOS). The aim of the present study is to assess the relationship between language and thought disorders in patients with very early onset schizophrenia (SCZ), schizoaffective disorders (SCA) and bipolar disorders (BD). Method Forty-one patients (18 SCZ, 16 BD, and 7 SCA) with mean age less than 15 years old were assessed through a series of neurocognitive and psycholinguistic tests, including the Thought, Language and Communication Scale (TLC). Results SCZ group performed worse in all tests as well as the TLC, followed by SCA and BD groups respectively. Thought disorders were related to deficits in executive functioning and semantic processing, and the metaphors’ test was the best predictor of TLC functioning. Discussion TD in SCZ, SCA and BD are one of the most important features in patients with VEOS and that the evaluation of metaphor comprehension can be an important instrument in the early detection of this disorder.

Abstract Background Despite of its global underuse, clozapine is still the golden standard antipsychotic for patients with treatment-resistant schizophrenia (TRS). Objective To evaluate the patterns of clozapine and other antipsychotic drugs prescription in TRS in community mental health centers in São Paulo, Brazil. Methods A multiple-choice questionnaire was applied to fifteen psychiatrists at five centers inquiring about patients’ clinical condition, adherence to oral treatment and current antipsychotic treatment. History of previous and current antipsychotic treatment was collected through medical chart review. Results Out of 442 schizophrenia patients, 103 (23.3%) fulfilled the criteria for TRS. Fifty-eight patients (56.3%) were receiving polypharmacy; 30 (29.1%) were on atypical antipsychotic monotherapy, 14 (13.6%) were on typical antipsychotic monotherapy, 25 (24.3%) were taking depot antipsychotic medication and only 22 (21.4%) were receiving clozapine. Discussion As well as in other parts of the world, many TRS patients (78.6%) receive other drugs instead of clozapine in São Paulo, the best evidence-based medication for patients with TRS. The government should make every effort to provide medical training and the equipment and logistic support to adequately serve those who could benefit from clozapine treatment at the community health centers.

OBJETIVO: Discutir os aspectos atuais do tratamento com os antipsicóticos, levando-se em consideração o perfil de efeitos metabólicos, tais como ganho de peso, diabetes, dislipidemias e síndrome metabólica. Tais fatores aumentam o risco de doença cardiovascular, que é a principal causa de morte nos portadores de esquizofrenia. MÉTODO: Foi realizada uma reunião de consenso com psiquiatras especialistas em esquizofrenia e endocrinologistas, os quais, com base nas evidências provenientes de ampla revisão da literatura, elaboraram um documento com recomendações que auxiliam a prática clínica. RESULTADOS E CONCLUSÕES: A avaliação periódica dos efeitos adversos metabólicos em pacientes que fazem uso de antipsicóticos é fundamental para a prática clínica, especialmente nos caso de antipsicóticos de segunda geração. O equilíbrio entre eficácia e tolerabilidade deve ser cuidadosamente considerado em todas as etapas do tratamento.

OBJECTIVE: To discuss current aspects of use of antipsychotics considering their metabolic side effects profile, which includes weight gain, dyslipidemias, diabetes and metabolic syndrome. Such metabolic effects increase the risk of mortality by cardiovascular disease, which is the leading cause of death among schizophrenic patients. METHOD: A consensus meeting was held, with participation of endocrinologists and psychiatrists specialists in schizophrenia and, based on a literature review, an article was elaborated emphasizing practical and helpful recommendations to clinicians. RESULTS AND CONCLUSIONS: Monitoring metabolic side effects is essential to patients taking antipsychotics, particularly in the case of second generation antipsychotics. Efficacy and tolerability should be carefully balanced in all phases of treatment.

OBJETIVO: O propósito deste artigo é o de revisar vários aspectos da esquizofrenia refratária levando em conta questões relacionadas à definição, aspectos clínicos, correlatos psicobiológicos, tratamentos farmacológicos e não farmacológicos, assim como preditores de resposta terapêutica. MÉTODO: Pesquisa no Medline, assim como artigos dos autores. RESULTADOS E CONCLUSÕES: Pelo menos um terço dos pacientes com esquizofrenia são refratários a tratamento com antipsicóticos e as evidências apontam a clozapina em monoterapia como a principal opção nesses casos. A politerapia com antipsicóticos não tem apoio em evidências. Ensaios clínicos recentes mostraram que a potencialização da clozapina com outros antipsicóticos não é superior ao placebo.

OBJECTIVE: The aim of the present paper is to review the various aspects of refractory schizophrenia regarding issues such as definitions, clinical aspects, psychobiological correlates, pharmacological and non-pharmacological treatment options and predictors of treatment response. METHOD: Medline search as well as articles of the authors. RESULTS AND CONCLUSIONS: Refractory schizophrenia affects at least one third of patients with schizophrenia and the best evidence shows that is monotherapy with clozapine remains the mainstay for the treatment of such condition. Antipsychotic polipharmacy is not supported by current evidence and recent clinical trials have shown that clozapine augmentation with antipsychotics has no benefit over placebo.

Resumo A população idosa vem aumentando em todo o mundo, levando a um impacto nos transtornos psiquiátricos, principalmente os quadros de demência. Contudo, revisões e meta-análises prévias têm mostrado alta variabilidade nas taxas mundiais de prevalência de demência. Objetivo: O objetivo deste estudo foi realizar uma ampla revisão de trabalhos recentes de prevalência de demência. Métodos: O levantamento foi feito em três bases de dados, Medline, Lilacs e EMBASE, no período de 1994 a 2000. Os principais critérios de inclusão foram: uso de critérios diagnósticos padronizados e investigação de amostra comunitária. Resultados: A seleção final incluiu 42 artigos, de todos os continentes. A taxa média de prevalência de demência, na idade maior ou igual a 65 anos, entre continentes, variou de 2.2% na África, até 8.9% na Europa, e entre países, de 1.3% na Índia, até 14.9% na Espanha. Contudo, a maioria dos estudos reportou taxas entre 4.2% e 7.2% (³65 anos). A idade exerceu influência direta sobre as taxas de prevalência, com taxas médias de 1.2% na faixa etária 65-69 anos, e 39.9% na faixa etária 90-94 anos, mostrando, no entanto, um efeito menos pronunciado nos idosos muito idosos. A população de procedência urbana teve taxas significativamente maiores, e não houve diferença significativa entre os sexos. Conclusão: A influência da idade sobre as taxas de prevalência de demência diminuiu entre os idosos mais "idosos", e a tendência de resultados similares em todo o mundo provavelmente foi influenciada pela homogeneidade nos critérios diagnósticos.

Abstract Ageing has occurred in all regions of the world, with impact on neuropsychiatric disorders, particularly dementia. However, previous meta-analysis and reviews have shown high variability in world dementia prevalence rates. Objective: The aim of this study was to perform a wide-ranging review of the dementia prevalence studies published in recent years. Methods: The search was made on Medline, Lilacs and Embase databases for research conducted between 1994 and 2000. The main inclusion criteria were: use of standard diagnostic criteria and investigation of community samples. Results: The final selection included 42 papers, from all continents. The mean prevalence rate of dementia in subjects aged 65 years and older, for continents, ranged from 2.2% in Africa to 8.9% in Europe, and among countries, from 1.3% in India to 14.9% in Spain. However, there was a trend of clustering of the world prevalence rates with the majority of studies reporting rates between 4.2% and 7.2% (³65 years). Age directly influenced the rates, with a mean prevalence rate of 1.2% (95% CI: 0.8-1.5) for the 65-69 years group and 39.9% (95% CI: 34.4-45.3) for the 90-94 year group, but showing less pronounced influence in the very elderly age group. The urban samples had higher rates, where no significant gender difference was evidenced. Conclusion: The age influence over dementia rates apparently leveled off in the very elderly group while a trend toward similar dementia prevalence rates around the world was probably influenced by greater homogeneity in diagnostic criteria.

OBJETIVO: Cerca de 30% dos pacientes de esquizofrenia resistentes ao tratamento não respondem completamente à clozapina. Esses pacientes são denominados não respondedores à clozapina ou portadores de esquizofrenia super-refratários. O objetivo deste estudo foi caracterizar pacientes com esquizofrenia super-refratária de acordo com as variáveis demográficas e psicopatológicas, em comparação com pacientes com esquizofrenia refratária e indivíduos não refratários. MÉTODO: Cento e dois pacientes ambulatoriais que preenchiam os critérios do DSM-IV para esquizofrenia foram acompanhados durante seis meses. Os indivíduos foram classificados em três grupos: não refratários (n = 25), refratários (n = 43) e super-refratários (n = 34). A psicopatologia foi avaliada pela Escalas de Síndrome Positiva e Negativa, pelo questionário para a Síndrome Deficitária, pela Escala de Depressão de Calgary e pela Escala de Qualidade de Vida. Os pacientes foram avaliados em intervalos de dois meses. RESULTADOS: Encontrou-se que índices mais elevados de gravidade no início da doença, bem como maior gravidade dos sintomas positivos foram preditivos de super refratariedade. CONCLUSÕES: Os pacientes com esquizofrenia super-refratária apresentam fatores preditivos psicopatológicos que necessitam maior investigação em estudos de imagens cerebrais, características genéticas e outras comparações clínicas.

OBJECTIVE: Approximately 30% of treatment-resistant schizophrenic patients do not fully respond to Clozapine and such patients are termed Clozapine non-responders or super-refractory schizophrenics. The aim of this study was to characterize patients with super-refractory schizophrenia according to demographic and psychopathological variables, as compared with patients with refractory schizophrenia or non-refractory subjects. METHOD: One hundred two outpatients meeting DSM-IV criteria for schizophrenia were followed-up for 6 months. Subjects were classified into 3 groups: non-refractory (n = 25), refractory (n = 43) and super-refractory (n = 34). Psychopathology was assessed by the Positive and Negative Syndrome Scale, the Schedule for Deficit Syndrome, the Calgary Depression Scale and the Quality of Life Scale. Patients were rated at 2-month intervals. RESULTS: Higher levels of severity at the disease onset as well as higher severity of positive symptoms were found to be predictive of super-refractoriness. CONCLUSIONS: The super-refractory schizophrenia patients have psychopathological predictive factors that need studies comparing brain images, genetical features and other clinical comparisons.

OBJETIVO: O propósito desse estudo foi observar as taxas de re-hospitalização de pacientes com esquizofrenia que receberam alta do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo em uso de haloperidol, risperidona ou clozapina. MÉTODO: Este foi um estudo naturalístico conduzido de forma a observar as taxas de re-hospitalizações dos pacientes que receberam alta em uso de haloperidol (n = 43), risperidona (n = 22) ou clozapina (n = 31). O tempo de re-hospitalização foi analisado de acordo com a fórmula produto-limite (Kaplan-Meier) por três anos. Fatores de risco associados à internação foram examinados. RESULTADOS: Aos 36 meses, permaneceram em seguimento extra-hospitalar 74% dos pacientes em uso de haloperidol, 59% em uso de risperidona e 84% em uso de clozapina. O grupo tratado com haloperidol apresentou predomínio do gênero feminino, idade de início mais tardia e menor tempo de doença que os demais grupos, enquanto o oposto ocorreu em relação ao grupo com clozapina. CONCLUSÕES: Pacientes em uso de clozapina apresentaram taxas de re-hospitalização menores que aqueles em uso de haloperidol e risperidona. No entanto, variáveis tais como distribuição de gênero e idade de início da doença podem representar limitações importantes que devem ser levadas em consideração na interpretação dos resultados.

OBJECTIVE:The purpose of this study was to evaluate the rehospitalization rates of patients discharged from the Institute of Psychiatry of the Hospital das Clínicas of the Universidade de São Paulo Medical School while being treated with haloperidol, risperidone or clozapine. METHOD: This is a naturalistic study designed to monitor rehospitalization rates for patients discharged on haloperidol (n = 43), risperidone (n = 22) or clozapine (n = 31). Time to readmission over the course of three years was measured by the product-limit (Kaplan-Meier) method. Risk factors associated with rehospitalizations were examined. RESULTS: At 36 months, remained in the community 74% of the haloperidol-treated patients, 59% of the risperidone-treated patients and 84% of the clozapine-treated patients. The haloperidol group showed a higher proportion of women, a late age of onset and shorter length of illness than the other groups, whereas the opposite was observed in the clozapine group. CONCLUSIONS: This study suggests that the rehospitalization rates of patients taking clozapine are lower than the rate for patients treated with haloperidol and risperidone. However confounding variables such as gender distribution and age of onset represent limitations that should be taken into account for the interpretation of the results.

A introdução de diretrizes internacionais de Boas Práticas Clínicas, em 1996, imediatamente seguida pela publicação da Resolução do Conselho Nacional de Saúde 196/96, abriu uma grande oportunidade para a participação de centros de pesquisa brasileiros em estudos internacionais. Tais estudos devem ser estritamente monitorados, a fim de assegurar a adesão às legislações, assim como garantir a segurança dos pacientes envolvidos. A fim de evitar possíveis conflitos de interesse durante e após o estudo, todos os aspectos relacionados devem ser claramente definidos previamente entre o pesquisador, o patrocinador e a instituição. Aspectos operacionais, tais como tempo para aprovação regulatória do estudo, métodos de recrutamento e retenção de pacientes e a logística em geral, também são importantes. Em 2005, a Rede Nacional de Pesquisa Clínica foi criada no Brasil, somando a experiência de vários centros de pesquisa ligados a hospitais de ensino. Seu objetivo é reforçar a atividade de pesquisa clínica no país, com práticas atualizadas e adequado treinamento técnico-científico. O desenvolvimento de protocolos de pesquisa que foquem as prioridades de saúde do país é outro objetivo fundamental da Rede. Aspectos gerais da pesquisa clínica e algumas particularidades em Psiquiatria são discutidos no artigo. O objetivo final de todo o trabalho nesta área de pesquisa é, sem dúvida, a busca de melhores condições de saúde e qualidade de vida da população.

The introduction of international guidelines on Good Clinical Practices (GCP) in 1996, immediately followed by the publication of Resolution CNS 196/96 in Brazil, created a great opportunity for Brazilian research centers to participate in international trials. Such studies must be strictly monitored in order to assure compliance with the regulations, as well as with the standards of patient safety. Clear agreement among the investigator, the sponsor and the institution carrying out the study must be previously defined in order to avoid any conflicts of interest during or after the study. Operational aspects, such as the time needed to gain regulatory approval of the study design, strategies for patient recruitment/retention and appropriate logistics, are also important. In 2005, the Brazilian National Clinical Research Network was established, bringing together a number of research centers in teaching hospitals. The objective was to subsidize public clinical research with state-of-the-art practices and appropriate technical/scientific training programs. The development of research protocols that prioritize public health care needs in Brazil is other fundamental goal of this network. This article addresses general aspects of clinical research, as well as some specific issues in psychiatry. Improving the health and quality of life of the global population is certainly the major objective of all of the work done in this area.