Treatments for Tourette syndrome in children and young adults: a systematic review / Tratamento da síndrome de Tourette em crianças e jovens adultos: uma revisão sistemática

INTRODUCTION: Tourette's Syndrome (TS) is a neurodevelopmental disorder characterized by motor and / or vocal tics for more than 12 months. TS affects about 0.8% of pediatric patients and is associated with great functional impairment and psychological distress. The present study aims to list and compare the effectiveness of therapies used in children and young people with TS. METHODS: PubMed / MEDLINE, Cochrane Library, ScienceDirect, SciELO and Lilacs were used from September 2020 to April 2021 to search for randomized clinical trials with pharmacological, behavioral, physical or alternative interventions for tics in children and young people with ST. RESULTS: 13 clinical trials were included, of which six pharmacological, six behavioral and one of other conformation. The global score on the Yale Global Tic Severity Scale showed evidence in favor of Habit Reversal Training (HRT) and Comprehensive Behavioral Intervention for Tics (CBIT). Evidence from two studies suggests that antipsychotic medications improve tic scores. Evidence from other interventions has shown no conclusive benefit. CONCLUSIONS: The present study identified benefits with the use of antipsychotics. The study also found that HRT and CBIT showed improvement in reducing the severity of tics, in addition to not having any adverse effects. These therapies showed significant clinical improvement, but there is no comparison between the use of these isolated approaches in relation to their use associated with medications. In view of the different forms of therapy, further studies are needed to identify the effectiveness and the profile of adverse effects of these interventions.

INTRODUÇÃO: A Síndrome de Tourette (ST) é um distúrbio do neurodesenvolvimento caracterizado por tiques motores e/ou vocais por mais de 12 meses. A ST afeta cerca de 0,8% dos pacientes pediátricos e associa-se a grande comprometimento funcional e sofrimento psíquico. O presente estudo tem como objetivo listar e comparar a eficácia das terapias utilizadas em crianças e jovens com ST. MÉTODOS: PubMed/MEDLINE, Cochrane Library, ScienceDirect, SciELO e Lilacs foram usados desde setembro de 2020 até abril de 2021 para a busca de ensaios clínicos randomizados com intervenções farmacológicas, comportamentais, físicas ou alternativas para tiques em crianças e jovens com ST. RESULTADOS: 13 ensaios clínicos foram incluídos, dos quais seis farmacológicos, seis comportamentais e um de outra conformação. A pontuação global na Yale Global Tic Severity Scale, apresentou evidências a favor do Treinamento de Reversão de Hábito (TRH) e Intervenção Comportamental Abrangente para Tiques (ICAT). As evidências de dois estudos sugerem que medicamentos antipsicóticos melhoram os escores de tiques. Evidências de outras intervenções não mostraram nenhum benefício conclusivo. CONCLUSÕES: O presente estudo identificou benefícios com o uso do antipsicóticos. O estudo também identificou que a TRH e a ICAT apresentaram melhora na redução da gravidade dos tiques, além de não apresentarem efeitos adversos. Essas terapias mostraram importante melhora clínica, mas não há comparação entre o uso dessas abordagens isoladas em relação ao seu uso associado com medicamentos. Diante das diferentes formas de terapia, mais estudos são necessários para identificar a eficácia e o perfil de efeitos adversos dessas intervenções.

Anorexia nervosa e o efeito no quadro clínico com o uso dos antipsicóticos / Anorexia nervosa and the effect on the clinical framework with the use of antipsychotics / Anorexia nervosa y el efecto sobre el marco clínico con el uso de antipsicóticos

Introdução:aanorexia nervosa caracteriza-se por um transtorno alimentar com quadro clínico típico de restrição dietética e desnutrição. Objetivo:verificar a eficácia do uso dos fármacos antipsicóticos olanzapina, quetiapina, risperidonano aumento ponderal de pacientes com tal patologia.Metodologia:utilizou-se de 9 Ensaios Clínicos Randomizados anexados na plataforma Medical Literature Analysis and Retrieval System Online/PubMed, sendo todos analisados a partir de critérios de inclusão e exclusão feitos aos pares para a realização de uma Revisão Sistemática de Literatura.Os artigos foram avaliados através do sistema Grading of Recommendatons AssessmentDevelopment and Evaluaton/GRADE. Resultadose discussão:Percebeu-se a prevalência da olanzapina sobre o aumento do peso entre os pacientes com anorexia comparado ao placebo. Pouca eficácia sobre o ganho ponderal com relação a quetiapina. A risperidona não demonstroualteração do peso ao utilizá-ladurante o tratamento da anorexia nervosa.Conclusões:Os achados sugeriram que aolanzapina, apresentou oefeito mais significativo sobre o ganho de peso em um menor intervalo de tempo (AU).

Introduction:Anorexia nervosa is characterized by an eating disorder with a typical clinical of food restriction and malnutrition. Objective:to verify the effectiveness of the use of the antipsychotic drugs olanzapine, quetiapine, risperidone in the weight gain of patients with this pathology. Methodology:9 Randomized Clinical Trials (RCT) were used attached to the Medical Literature Analysis andRetrieval System Online/PubMed/MEDLINE platform, all of which were analyzed based oninclusion and exclusion criteria made in pairs to carry out a Systematic Literature Review. Results and discussion:It was noticed the prevalence of olanzapine on weight gain among patients with anorexia compared to placebo. Little diligence on weight gain with regard to quetiapine. Risperine showed no weight change when used during the treatment of anorexia nervosa. Conclusions:The findings suggest that olanzapine had the most significant effect on weight gain in a short period (AU).

Introducción: La anorexia nerviosa se caracteriza por un trastorno alimentario con un cuadro clínico típico de restricción alimentaria y desnutrición. Objetivo: verificar la efectividad del uso de los medicamentos antipsicóticos olanzapina, quetiapina, risperidonaem el aumento de peso de pacientes con esta patología.Metodología: Se utilizaron 9 Ensayos Clínicos Aleatorizados (RCT) adjuntos a la plataforma Medical Literature Analysis and Retrieval System Online / PubMed (MEDLINE), todos fueron analizados en base a criterios de inclusión y exclusión realizados en pares para realizar una Revisión Sistemática de la Literatura. Resultados y discusión:Se notó la prevalencia de la olanzapina en la ganancia de peso entre pacientes con anorexia en comparación con el placebo. Poca diligencia en la ganancia de peso con respecto a la quetiapina. Risperine no mostró cambios de peso cuando se usó durante el tratamiento de la anorexia nerviosa. Conclusiones:Los hallazgos sugieren que la olanzapina tuvo el efecto más significativo sobre el aumento de peso en un lapso de tiempo más corto (AU).

A influência dos aspectos subjetivos na adesão ao tratamento do transtorno bipolar: uma revisão sistemática / The influence of subjective aspects on adherence to the treatment of bipolar disorder: a systematic review

OBJETIVO: Evidenciar a influência dos aspectos subjetivos na adesão ao tratamento do transtorno bipolar. MÉTODOS: Foi realizada revisão sistemática com base nas diretrizes PRISMA. A identificação dos estudos foi realizada por meio da busca nos bancos de dados PubMed, Scopus e SciELO, com base nos descritores "Bipolar Disorder" AND "Treatment Adherence and Compliance" AND "Mental Health". A busca contemplou todos os artigos publicados até o ano 2020, sem restrição de idioma. RESULTADOS: Foram localizados 743 artigos, 714 foram excluídos no processo de seleção, 29 foram lidos na íntegra e 11 foram elegíveis para a composição da amostra. A influência dos aspectos subjetivos na adesão ao tratamento foi associada (1) às atitudes resultantes das percepções do sujeito sobre o transtorno e o tratamento e (2) as atitudes por influência de pessoas próximas. Os estudos apontam para a ocorrência de atitudes negativas em ambas as esferas, tendo a má adesão ao tratamento como desfecho. Na esfera da percepção do sujeito, evidenciam-se: presença de comportamentos intencionais e não intencionais; percepção de consequências; medo dos efeitos colaterais; sentimentos negativos; falta de compreensão sobre o transtorno e negação do diagnóstico. Na esfera da influência das pessoas próximas, destacam-se a baixa qualidade da aliança terapêutica e o suporte ineficaz oferecido pela família. CONCLUSÕES: Para melhorar a adesão ao tratamento do transtorno bipolar, é salutar que os esforços terapêuticos estejam centrados na experiência particular do sujeito, na sua satisfação e na colaboração pactuada com o tratamento.

OBJECTIVE: Evidence the influence of subjective aspects on adherence to the treatment of bipolar disorder. METHODS: A systematic review was performed based on the PRISMA guidelines. The identification of studies was performed by searching the PubMed, Scopus and Scielo databases based on the descriptors "Bipolar Disorder" AND "Treatment Adherence and Compliance" AND "Mental Health". The selection included all articles published up to the year 2020 and without language restrictions. RESULTS: A total of 743 articles were found, 714 were excluded from the selection process, 29 articles were read in full and 11 were eligible for sample composition. The influence of subjective aspects on treatment adherence was associated (1) with attitudes resulting from the subject's perceptions about the disorder and treatment and (2) attitudes influenced by people close to them. Studies point to the occurrence of negative attitudes in both spheres, with poor adherence to treatment as an outcome. In the sphere of the subject's perception, they show the presence of intentional and unintentional behaviors; perception of consequences; fear of side effects; negative feelings; lack of understanding about the disorder and denial of diagnosis. In the sphere of influence of those close to them, they highlight the low quality of the therapeutic alliance and the ineffective support offered by the family. CONCLUSIONS: To improve adherence to treatment for bipolar disorder, it is beneficial that therapeutic efforts are centered on the individual's particular experience, on their satisfaction and on the agreed collaboration with the treatment.

La reserpina aumenta la expresión de BDNF y PCNA, y disminuye la de caspasa-3, en células intersticiales (células de Leydig) de ratas / Reserpine increases BDNF and PCNA expression, but decreases caspase-3, in rat interstitial cells (Leydig cells)

La reserpina es un antipsicótico e hipotensor arterial que reduce significativamente los niveles de monoaminas centrales, y también es utilizada para modelar los cuadros depresivos humanos en animales de laboratorio. Este trabajo estudió, en ratas Wistar machos adolescentes, cómo la reserpina afecta indicadores moleculares de la función testicular, la cual se ha visto alterada en humanos deprimidos. Una semana luego de finalizado el tratamiento con reserpina (4 dosis de 0,0 o 1,0 mg/Kg, cada 2 días) la respuesta ansiosa y depresiva fue evaluada en un laberinto en cruz elevado. Posteriormente, se sacrificaron los animales y disecaron los testículos, los cuales fueron fijados e incluidos en bloques de parafina de donde se obtuvieron cortes histológicos de 6 µm de espesor. Estos se utilizaron para medir el diámetro de los túbulos seminíferos y para medir por inmunohistoquímica el porcentaje de células intersticiales (células de Leydig) positivas a (1) Factor neurotrófico derivado del cerebro, (2) antígeno nuclear de células en proliferación (BDNF y PCNA, respectivamente, por sus siglas en inglés), y a (3) caspasa-3. Se obtuvo también un índice de positividad al receptor de andrógenos en las células intersticiales. La expresión del receptor de andrógeno fue evaluada utilizando una escala semicuantitativa de escores (0, 1, 2 y 3) y el resto de las moléculas por presencia o ausencia de expresión de cada antígeno investigado en 300 células por preparado. Los resultados comportamentales indicaron alteraciones en la respuesta de ansiedad y una significativa depresión motora (e.g., mayor latencia en conductas de escape del sector blanco) en los animales tratados con reserpina. No se observaron diferencias en los diámetros de los túbulos seminíferos ni en la expresión del receptor de andrógeno, mientras que sí se encontró mayor proporción de células intersticiales positivas a BDNF y PCNA, y menor proporción de células positivas a caspasa-3, en los animales tratados. Los resultados corroboran la capacidad de la reserpina para reproducir rasgos comportamentales de la depresión. La administración de la droga, sin embargo, no parece reproducir a nivel testicular los efectos deletéreos encontrados en humanos deprimidos, e incluso los resultados sugieren que la reserpina puede mejorar algunos aspectos de la funcionalidad testicular relacionadas con la actividad de las células intersticiales en ratas.

Reserpine, a drug that depletes central monoamines, has been used as an antipsychotic and arterial hypotensive, and to model depression in animals. The present study analyzed, in adolescent male rats, the effects of chronic reserpine treatment on molecular indexes of testicular function. A week after termination of the treatment (4 doses of 0,0 or 1,0 mg/Kg/every 48 h) the animals were tested for anxiety response and depression patterns in an elevated plus maze. They were then euthanized, their testes dissected, fixed and embedded in paraffin to obtain blocks. Histological sections (6 µm) were obtained and used to measure the diameter of seminiferous tubules and the expression in Leydig cells of Brain-derived neurotrophic factor (BDNF), Proliferating cell nuclear antigen (PCNA), Caspase-3 and androgen receptors, by immunohistochemistry. Behavioral results indicated significant alterations in anxiety responses and a significant motor depression (e.g., greater latency to escape from the white sector). There were no differences between groups in the diameter of seminiferous tubules nor in the androgen receptors positivity. Reserpine-treated animals, however, exhibited more BDNF and PCNA positive cells, and less positive Caspase-3 cells in Leydig cells, than control animals. The results corroborate the efficacy of reserpine to reproduce some of the behavioral components of depression. The drug, however, does not seem to exert in rats the same effects on testicular function that have been found in humans diagnosed with depression. Furthermore the drug seems to enhance some aspects of testicular function related to Leydig cells function in rats.

Tratamiento psicofarmacológico de pacientes con trastorno límite de la personalidad: aspectos farmacoclínicos con evidencia científica / Psychopharmacologic treatment of patients with borderline personality disorder: pharmacoclinic aspects with scientific evidence

Introducción: El trastorno de la personalidad (TLP) afecta al 1-2% de la población adulta y aproximadamente al 20% de los pacientes hospitalizados por causas psiquiátricas. La tasa de mortalidad por suicidio alcanza el 10%, y se destacan las conductas suicidas que alcanzan el 84% de los pacientes, siendo éstas muy prevalentes en la consultas en los servicios de emergencia. El tratamiento psicofarmacológico aplicado en estos pacientes es uno de los abordajes clínicos que más incertidumbre generan debido a la falta de protocolos terapéuticos que cubran todas las dimensiones centrales de la personalidad. Objetivos: El objetivo del presente artículo es realizar una revisión bibliográfica sobre la utilidad de antipsicóticos de segunda generación, estabilizadores del ánimo y antidepresivos para el tratamiento farmacológico aplicado a la clínica de pacientes con diagnóstico de trastorno límite de la personalidad, con especificación de la evidencia científica para cada grupo farmacológico. Material y Método: Revisión y comparación bibliográfica sobre el uso y utilización de 3 grupos psicofarmacológicos (antipsicóticos de segunda generación, estabilizadores del ánimo y antidepresivos)para el tratamiento de pacientes con diagnóstico de TLP, con especificación de los indicadores y resultados de trabajos de medicina basada en la evidencia. Resultados: Según la revisión sistemática en ensayos clínicos con antipsicóticos (primera y segunda generación), estabilizadores del estado de ánimo y antidepresivos se hallaron mayores beneficios con el uso de estabilizadores del estado de ánimo (topiramato, lamotrigina y valproato de sodio) y antipsicóticos de segunda generación (aripiprazol y olanzapina). La consistencia es baja ya que el tamaño muestral fue pequeño o fue realizado mediante reportes de casos. Asimismo, la duración de los estudios varió de 5 a 24 semanas (duración promedio 12 semanas) y analizaron datos de 1714 participantes, con muestras heterogéneas en los estudios (entre 16 y 314 participantes).Conclusión: Suponemos que se debería profundizar en el abordaje de los síntomas borderline, básicamente investigaciones longitudinales a largo plazo (superior al año) con mayor número de pacientes, instrumentos de evaluación validados y tener en cuenta diseños para la traslación de resultados en contexto asistencial

Introduction: Personality disorder affects 1-2% of adult population and almost 20% of hospitalized patients for psychiatric causes. Mortality rate by suicide is almost 10%, and suicidal behaviour stand out in 84% of patients, being very prevalent in emergency service. Psicopharmacologic treatment applied to those patients is one of the approaches that more uncertainty generates because of the absence of therapeutic protocols that cover all the central dimensions of the personality. Objectives: to make a bibliographic review about second generation antipsychotics utility, mood stabilizers and antidepressants applied to patients with diagnosis of borderline personality disorder, with scientific evidence specification for each pharmacological group. Material and Method: Bibliographic review and comparison about use and utilization of three psicopharmacologic groups (second generation antipsychotics, mood stabilizers and antidepressant) for patients with borderline personality disorder treatment, with indicators specification and evidence-based medicine works results. Results: According to systematic review in clinical essays with antipsychotics (first and second generation), mood stabilizers and antidepressants, it was found more benefits with mood stabilizers (topiramate, lamotrigine and sodium valproate) and second generation antipsychotics (aripiprazole and olanzapine). The consistency is low because of the sample size or it was made with cases reports. Likewise, studies duration were between 5 and 24 weeks (average duration: 12 weeks) and 1714 data patients ́ were analysed, with heterogeneous sample (between 16 and 314). Conclusions: We assume we should deepen in borderline symptoms average with long term longitudinal studies (more than a year) with a bigger number of patients, validated evaluation instruments and take into account designs for results translation in an assistance context.

Atypical antipsychotics in the treatment of pathological aggression in children and adolescents: literature review and clinical recommendations / Antipsicóticos atípicos no tratamento da agressividade patológica em crianças e adolescentes: revisão da literatura e recomendações clínicas

Objective: To review the literature about the use of atypical antipsychotics in the treatment of pathological aggression in children and adolescents. Method: The databases MEDLINE, SciELO, and LILACS were searched for publications in Portuguese or English from 1992 to August 2011 using the following keywords: mental disease, child, adolescent, treatment, atypical antipsychotic, aggressive behavior, aggression, and violent behavior. Results: Sixty-seven studies of good methodological quality and clinical interest and relevance were identified. Studies including children and adolescents were relatively limited, because few atypical antipsychotics have been approved by the Food and Drug Administration (FDA). All the medications included in this review (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole and clozapine) have some effectiveness in treating aggression in children and adolescents, and choices should be based on clinical indications and side effects. Conclusions: There are few studies about the effectiveness and safety of atypical antipsychotics for the pediatric population, and further randomized controlled studies with larger groups of patients and more diagnostic categories, such as severe conduct disorder and oppositional defiant disorder, should be conducted to confirm the results reported up to date and to evaluate the impact of long-term use.

Objetivo: Realizar uma revisão sistemática da literatura científica sobre o uso de antipsicóticos atípicos (APAs) no tratamento da agressividade patológica em crianças e adolescentes. Método: Foi realizada busca eletrônica nas bases de dados MEDLINE, SciELO e LILACS, de 1992 a agosto 2011, considerando artigos publicados em língua inglesa e portuguesa. Foram utilizadas associações das seguintes expressões: mental disease, child, adolescent, treatment, atypical antipsychotic, aggressive behaviour, aggression e violent behavior. Resultados: Foram identificados 67 artigos de boa qualidade metodológica, de relevância e interesse clínico para o tema em foco. De modo geral, os estudos são relativamente limitados para esta faixa etária, resultado do fato de poucos APAs terem sido aprovados pela Food and Drug Administration (FDA). Dentre as medicações consideradas nesta revisão (risperidona, olanzapina, quetiapina, ziprazidona, aripiprazol e clozapina), todas elas podem ter alguma efetividade no tratamento da agressividade em crianças e adolescentes, ficando a escolha baseada na indicação clínica e perfil de efeitos colaterais. Conclusão: O número ainda limitado de estudos acerca da efetividade e segurança na população pediátrica demanda pesquisas futuras com grupos maiores de pacientes e com mais categorias diagnósticas (como, por exemplo, as formas graves de transtorno de conduta e transtorno desafiador de oposição), desenhadas de forma randomizada e controlada. Assim poderão ser confirmados os achados até o momento e o impacto do uso em longo prazo.

Implications and limitations of cellular reprogramming for psychiatric drug development

Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.

Nitric oxide plasma/serum levels in patients with schizophrenia: a systematic review and meta-analysis / Níveis plasmáticos/séricos do óxido nítrico em pacientes com esquizofrenia: uma revisão sistemática e metanálise

For the last 40 years, schizophrenia has been considered to be the result primarily of a dysfunction in brain dopaminergic pathways. In this review, it is described and discussed findings concerning nitric oxide-mediated neurotransmission in schizophrenia. Studies were searched in PubMed, SciELO, and LILACS using the terms schizophrenia and nitric oxide plasma levels or nitric oxide serum levels, with no time limit. The reference lists of selected articles were also hand-searched for additional articles. From 15 potential reports, 10 were eligible to be included in the review and meta-analysis. These studies included a total of 505 patients with schizophrenia and 339 healthy volunteers. No significant difference was found between patients and healthy controls regarding total nitrite plasma/serum levels (effect size g = 0.285, 95%CI = -0.205 to 0.774, p = 0.254). However, when studies with patients under antipsychotic treatment were examined separately, there was a significant difference between patients and healthy volunteers (effect size g = 0.663, 95%CI = 0.365 to 0.961, p < 0.001), showing that patients under treatment have higher levels of plasma/serum nitric oxide than controls. These results suggest that antipsychotics increase nitric oxide plasma/serum levels and that the nitrergic pathway would be a fertile target for the development of new treatments for patients with schizophrenia.

Durante os últimos 40 anos, a esquizofrenia foi considerada, principalmente, como o resultado de disfunções dopaminérgicas no cérebro. Esta revisão descreve e discute algumas descobertas sobre a neurotransmissão mediada pelo óxido nítrico na esquizofrenia. A busca foi feita nas bases PubMed, SciELO e LILACS usando-se os termos schizophrenia e nitric oxide plasma levels ou nitric oxide serum levels, sem limites de tempo. As listas de referências dos artigos selecionados foram examinadas em busca de outras publicações pertinentes. Dentre 15 artigos passíveis de serem incluídos, 10 preenchiam os critérios estabelecidos para a revisão e metanálise. Esses estudos incluíram 505 pacientes com esquizofrenia e 339 voluntários saudáveis. Não foram encontradas diferenças significativas entre pacientes e voluntários saudáveis quanto aos níveis plasmáticos de nitrito total (effect size g = 0,285, IC 95% = -0,205 a 0,774, p = 0,254). No entanto, o exame separado dos estudos envolvendo pacientes em tratamento antipsicótico apresentou diferenças significativas entre pacientes e voluntários saudáveis (effect size g = 0,663, IC 95% = 0,365 to 0,961, p < 0,001), demonstrando que pacientes em tratamento possuem níveis plasmáticos mais altos de óxido nítrico. Esses resultados sugerem que os antipsicóticos podem aumentar os níveis plasmáticos de óxido nítrico e que a via nitrérgica (e sua estimulação) constituiria um alvo propício para o desenvolvimento de novos tratamentos para pacientes com esquizofrenia.

Estudo da interação de antipsicóticos atípicos e albumina sérica com base em modelos matemáticos e espectrofluorimétricos / Study of the interaction of atypical antipsychotics and serum albumin based on mathematical and spectrofluorimetric models

Os antipsicóticos são drogas utilizadas no tratamento de muitos transtornos psiquiátricos, sendo classificados em dois grupos: típicos e atípicos. Os típicos formam o grupo de drogas que bloqueiam especialmente os receptores de dopamina e, por isto, causam efeitos colaterais característicos, que se manifestam através de sintomas extrapiramidais e podem terminar em discinesia tardia. Os atípicos apresentam eficácia antipsicótica similar à dos antipsicóticos típicos, mas produzem menos efeitos colaterais extrapiramidais e não causam discinesia tardia. Os antipsicóticos se ligam às proteínas plasmáticas, principalmente a albumina, a qual representa cerca de 60% do total das proteínas no soro humano. Neste trabalho estudamos os processos de interação de duas drogas antipsicóticas atípicas, risperidona e sulpirida, com as albuminas séricas humana (HSA) e bovina (BSA), através da técnica de supressão da fluorescência intrínseca do triptofano. A partir dos espectros de fluorescência, a análise dos dados foi feita obtendo-se os gráficos e as constantes de Stern-Volmer. A análise da supressão da fluorescência foi feita a partir da média aritmética dos dados oriundos dos experimentos realizados em cada condição adotada. Como a molécula da sulpirida é fluorescente desenvolvemos uma modelagem matemática do processo de interação, que nos permitiu então obter os dados referentes à supressão da fluorescência da proteína. Os resultados mostraram que a risperidona e a sulpirida suprimem a fluorescência de ambas albuminas por um processo de quenching estático, formando complexos droga-albumina. A risperidona tem uma afinidade com a HSA cerca de 6,5 vezes maior do que a sulpirida, a 37 oC. As constantes de associação calculadas para a interação risperidona-HSA, através da Teoria de Stern-Volmer, foram 1,43 (± 0,05) x 105 M-1, a 37 °C, e 2,56 (± 0,09) x 105 M-1, a 25 ºC1; e para a sulpirida, 2,20 (± 0,08) x 104 M-1, a 37 ºC, e 5,46 (± 0,20) x 104 M-1, a 25 ºC...

Antipsychotics are drugs used to treat many psychiatric disorders. They are classified into two groups: typical and atypical. The typical group act blocking dopamine receptors in particular and it causes characteristic side effects with extrapyramidal symptoms, and can lead to tardive dyskinesia. The atypical group presents similar efficacy to typical group, but they produce less extrapyramidal side effects and does not cause tardive dyskinesia. Antipsychotics bind to plasmatic proteins, mainly to albumin, which represents about 60% of total human serum proteins. In this study we studied the interactions of two atypical antipsychotic drugs, risperidone and sulpiride, with human serum albumin (HSA) and bovine (BSA) through the technique of intrinsic tryptophan fluorescence quenching. From the fluorescence spectra, a data analysis was made to obtain Stern-Volmer plots and constants. Quenching analysis was performed used from using arithmetic means of data from experiments for each adopted condition. As sulpiride molecule is fluorescent, a mathematical modeling for interaction process was made. It allows us then to obtain the data referents to fluorescence quenching of protein. Results showed that risperidone and sulpiride quench the fluorescence for both albumins by static quenching process, forming complexes drug-albumin. The risperidone affinity to HSA is about 6.5 higher than supiride, at 37 oC. Stern-Volmer constants for interaction risperidone-HSA were 1.43 (± 0.05) x 105 M-1, at 37oC, and 2.56 (± 0.09) x 105 M-1, at 25 oC; and for sulpiride were 2.20 (± 0.08) x 104 M-1, at 37 oC, and 5.46 (± 0.20) x 104 M-1, at 25 oC. As the quenching ratio for BSA was higher than HAS, we suggested that the primary site for risperidone on albumin is closer of the domain of trypthophan 134 of BSA than the domain of trypthophan 212 of HAS. The same is suggested for the primary site of supiride at 37oC.

Efecto neurofarmacológico del zumo de Morinda citrifolia / Neuropharmacological properties of Morinda citrifolia juice

Morinda citrifolia Linn. (Rubiaceae) (Noni) is a plant, to which several therapeutic properties have assigned, but its neuropsicopharmacological effects have been poor studied. The aim of this work was to characterize the neuropharmacological properties of its juice, in male mice, by means of a battery of behavioral tests: Irwin test, exploratory behavior, barbiturate sleeping time and amphetamine-induced stereotypes. Doses of 450, 900 and 1800 mg/kg were administered, according to the juice dry weight. The results obtained from the different tests suggest the presence of non identified chemical compounds with sedative activity, specifically of neuroleptic type.

Morinda citrifolia Linn. (Rubiaceae) (Noni) es una planta que presenta diversas propiedades terapéuticas, pero sus efectos neuropsicofarmacológicos han sido poco estudiados. El objetivo del presente trabajo, fue caracterizar el perfil neurofarmacológico de su jugo, en ratones machos, por medio de una batería de pruebas de comportamiento: prueba de Irwin, conducta exploratoria, tiempo de sueño barbitúrico y estereotipias anfetamina-inducidas. Dosis de 450, 900 y 1800 mg/kg fueron administrada, de acuerdo con el peso de jugo seco. Los resultados obtenidos de las diferentes pruebas sugieren la presencia de compuestos químicos no identificados con actividad sedante, especialmente de tipo neuroléptica.

The impact of antipsychotic drugs on food intake and body weight and on leptin levels in blood and hypothalamic ob-r leptin receptor expression in wistar rats

OBJECTIVES: The aim of our study was to investigate the impact of typical and atypical antipsychotic drugs on leptin concentration in blood and changes in the receptor expression in the hypothalamus of male Wistar rats. METHODS: From the age of 13 to 18 weeks, three groups of 20 animals were fed an average dose of 3.5 + 0.03 mg/ kg body weight (BW) haloperidol; 30.6 + 0.22 mg/kg BW clozapine; or 14.9 + 0.13 mg/kg BW ziprasidone in ground food pellets containing 15 percent fat. Twenty control animals received no drugs. Blood samples were taken at week 14, 16, and 19. Locomotor activity and exploratory behavior were measured using the alcove test at weeks 15 and 17. The expression of the hypothalamic leptin receptor in rat brains was determined by using a Western blot. RESULTS: Rats medicated with haloperidol and ziprasidone showed a significantly decreased percentage weight gain and food consumption. We observed no differences in the alcove test, but locomotor activity was significantly reduced in the haloperidol group. Except for rats in the clozapine and ziprasidone groups, after 2 weeks of drug application, we found no changes in the leptin blood concentrations among the four groups or animals within each group. Moreover, we did not find specific differences in hypothalamic leptin receptor expression among the groups. CONCLUSION: We concluded that in male Wistar rats during this treatment period, the tested drugs did not act directly on the leptin regulatory system. We recommend further studies using long-term treatment of different rat strains.

Control de la agresividad con olanzapina en pacientes post tec / Aggressiveness control using olanzapine in post tbi patients

Estudio caso-control con uso de olanzapina en pacientes portadores de Daño Orgánico Cerebral (DOC) con síntomas psiquiátricos significativos. Se estudiaron 21 casos y 10 controles. Se realizó un estudio prospectivo doble ciego sobre uso de olanzapina versus placebo en pacientes portadores de DOC post TEC con trastornos conductuales, fundamentalmente, agresividad, agitación psicomotora y conducta suicida. Se demuestra que la olanzapina es un fármaco de utilidad para el control de la irritabilidad en pacientes portadores de un DOC post TEC. También fue útil en el control del insomnio, la tristeza, la labilidad emocional y la verborrea.

Case-Control study, using Olanzapine in patients having Organic Brain Damage (OBD) with significant psychiatric symptoms. Twenty one cases and 10 controls were studied. A prospective double-blind study was conducted on the use of olazapine versus placebo in patients suffering from post TBI OBD with behaviourial disorders, mainly aggressiveness, psychomotor agitation and suicidal behaviour. It is shown that olazapine is a useful drug for the control of irritability in patients suffering from post TBI OBD. It was also useful in the control of insomnia, sadness, emotional weakness and verbosity.

Regional brain metabolism in schizophrenia: The influence of antipsychotics.

BACKGROUND: Schizophrenia has been associated with a plethora of metabolic changes in the brain that vary with duration and type of psychoses. Additionally, it has been observed that antipsychotics can further alter cerebral glucose metabolism. These changes resulting from antipsychotics have been postulated to be reflective of the duration and mechanism of action of the medication. AIMS: We aimed to examine the influence of antipsychotics on brain metabolism in individuals with schizophrenia in a naturalistic setting. SETTINGS AND DESIGN: A cross-sectional study was carried out by the psychiatry department of a tertiary care hospital in collaboration with the Radiation Medicine Centre. MATERIALS AND METHODS: Eighteen male patients with schizophrenia in different phases of treatment underwent an 18F-deoxyglucose positron emission tomography scan in a resting state 12 hours after the last dose of antipsychotic. Statistical Analysis: The types and duration of treatment were then compared with the regional glucose uptake in 14 predetermined regions of interest. The relative Uptake Values were further compared using SPSS 11.0. RESULTS: An immediate increase followed by a decrease in cortical uptake was noted while the basal ganglia uptake remained high, albeit with a decreasing trend. Typical antipsychotics were associated with lower frontal cortical and higher basal ganglia and cerebellar uptake as compared to atypical antipsychotics. CONCLUSION: The differential influence of the type and duration of antipsychotic on glucose uptake suggests a possible trend towards long-term side effects with typical medications that were not noted on clinical examination. This however needs to be confirmed with larger, controlled studies.

Novos antipsicóticos para o tratamento da esquizofrenia / New antipsychotics for the treatment of schizophrenia

CONTEXTO: Os antipsicóticos de segunda geração representam o grande avanço na terapêutica da esquizofrenia das últimas décadas, porém nos últimos anos foram sintetizados novos antipsicóticos que estão abrindo maiores perspectivas no campo do tratamento da esquizofrenia. Alguns desses medicamentos já foram lançados, enquanto outros estão em fase de testes. OBJETIVO: Apresentar uma síntese do conhecimento dos novos antipsicóticos de segunda geração. MÉTODOS: Busca por meio do PubMed e literatura específica fornecida pelos fabricantes dos medicamentos. RESULTADOS E CONCLUSÕES: São apresentadas as principais características farmacológicas, de eficácia, segurança e tolerabilidade dos seguintes antipsicóticos: Asenapina, ACP-103, Bifeprunox, Paliperidona, Risperidona de Ação Prolongada e Sertindol.

BACKGROUND: The second generation antipsychotics represent the great achievement in the treatment of schizophrenia of the last decades. However in the last years some new antipsychotics were synthesized and such new compounds may represent great perspectives for the field of the treatment of schizophrenia. Some of these compounds are in use while others are still on evaluation through clinical trials. OBJECTIVE: Summarize the current knowledge of new antipsychotics. METHODS: PubMed search as well literature provided by the manufactures. RESULTS AND CONCLUSIONS: We present the main pharmacological characteristics as well as profiles of efficacy, security and tolerability of the following compounds: Asenapine, ACP-103, Bifeprunox, Paliperidone, Long Acting Injectable Risperidone and Sertindole.

Haloperidol and clozapine differentially regulate signals pstream of glycogen synthase kinase 3 in the rat frontal cortex

Glycogen synthase kinase 3 (GSK3) was recently suggested to be a potential target of psychotropics used in psychiatric illnesses such as schizophrenia and bipolar disorder. Relevant studies have found that antipsychotic drugs regulate GSK3 activity via an increase in either inhibitory serine phosphorylation or amount of GSK3 after acute or subchronic treatment. Recent evidence shows that GSK3 is regulated by dopaminergic or serotonergic systems implicated in the pathophysiology and treatment mechanisms of schizophrenia and bipolar disorder. Therefore, antipsychotics may regulate GSK3 via antagonizing dopaminergic or serotonergic activity. However, the signaling pathway that is involved in GSK3 regulation by dopaminergic or serotonergic systems has not been well established. Haloperidol is a typical antipsychotic with potent dopamine D(2) receptor antagonism. Clozapine is an atypical antipsychotic with potent serotonin 5HT(2) receptor antagonism. We injected rats with haloperidol or clozapine and examined the phosphorylation and amount of GSK3alpha/beta and its well-known upstream regulators Akt and Dvl in the rat frontal cortex by Western blotting. Both haloperidol and clozapine induced Ser21/9 phosphorylation of GSK3GSK3alpha/beta. Haloperidol increased the Ser473 phosphorylation of Akt transiently, whereas clozapine maintained the increase for 1 h. Haloperidol did not affect the phosphorylation and amount of Dvl, whereas clozapine increased both phosphorylation and the amount of Dvl. Our results suggest that GSK3 activity may be regulated by both typical and atypical antipsychotics and that Akt or Dvl, depending on the D(2)- or 5HT(2)- receptor antagonism properties of typical and atypical antipsychotics, mediate the regulation differently.

Effect of Withania somnifera on forced swimming test induced immobility in mice and its interaction with various drugs.

The objective of the present study was to evaluate the antidepressant action of Withania somnifera (WS) as well as its interaction with the conventional antidepressant drugs and to delineate the possible mechanism of its antidepressant action using forced swimming model in mice. Effect of different doses of WS, fluoxetine and imipramine were studied on forced swimming test induced mean immobility time (MIT). Moreover effect of WS 100 mg/kg, i.p. was observed at different time intervals. Effect produced by combination of sub therapeutic doses of WS with imipramine (2.5 mg/kg, i.p.) as well as fluoxetine (2.5 mg/kg, i.p.) were also observed. Effect of WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) were observed in mice pretreated with reserpine (2 mg/kg, i.p.) and clonidine (0.15 mg/kg, i.p.). Effects of prazosin (3 mg/kg, i.p.) or haloperidol (0.1 mg/kg, i.p.) pre-treatment were also observed on WS induced decrease in MIT. WS produced dose dependent decrease in MIT. Maximum effect in MIT was observed after 30 min of treatment with WS 100 mg/kg, i.p. Combination of WS (37.5 mg/kg, i.p.) with imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) also produced significant decrease in the MIT. Clonidine and reserpine induced increase in MIT, was significantly reversed by treatment with WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.). Pre-treatment with prazosin but not haloperidol, significantly antagonized the WS (100 mg/kg, i.p.) induced decrease in MIT. It is concluded that, WS produced significant decrease in MIT in mice which could be mediated partly through a adrenoceptor as well as alteration in the level of central biogenic amines.

[Comparison of the effects of typical antipsychotics and olanzapine on fasting blood sugar of psychiatric patients]

Low extrapyramidal symptoms, weight gain, increased fasting blood sugar and cholestrole are some of the side effects of antipsychotic drugs that can be dangerous for patients. Atypical antipsychotics like olanzapine have little extrapyramidal side effects, but they may induce weight gain and increase FBS. In this simple randomized double blind chincal trial, 80 admitted patients of psychiatric wards of Noor hospital were randomly divided in two groups, 40 in each. Patients who had past history of diabetes melltus and family history of DM in the first degree relations and/or had undergone diabetogenic drugs thrapy from 15 days before this research or had fatness [BMI > 28] were excluded from study. These two groups were statistically matched for age, sex and diagnosis. Primaly FBS was measured 24 to 48 hours after admission and secondary FBS is measured 1 month after the beginning of the treatment. Mean FBS increased in both groups. In typical antipsychotics group, the mean of primary FBS was 89.3 +/- 11.1 and the mean of secondary FBS was 94.9 +/- 12.6. Paired t-test showed that this difference is statistically significant [t = 206, p=0.01] and in olanzapine group the mean of primary and secondary FBS were 94.9 +/- 14.35 and 101.8 +/- 22.4 respectively. Paired t-test showed that this difference is statistically significant too [t = 2.44, p= 0.01]. Medium and high potent typical antipsychotics and olanzapine showed significant changes in FBS, however, the differences were not meaningful between these two groups [t = 0.38, p = 0.7]. Although both typical antisychotic [medium and high potent] and olanzapine show significant difference in increasing FBS but the difference between these two, groups for increasing FBS were not meaningful. Therefore, case reports are not sufficient for assessing the effects of olanzapine on fasting blood sugar

Psychopharmacological profile of hydro-alcoholic extract of Euphorbia neriifolia leaves in mice and rats.

The leaf extract of E. neriifolia significantly reduced apomorphine-induced stereotypy in mice at all doses (100, 200, 400 mg/kg body weight) in mice and rats and was devoid of catalepsic effect thereby, suggesting specific dopaminergic receptor modulating activity. The extract (400 mg/kg) potentiated pentobarbitone-induced hypnosis. It showed protection against maximal electro-shock-induced convulsion at 400 mg/kg. E. neriifolia leaf extract had anxiolytic action at 400 mg/kg by increasing the percentage of time spent in open arm in elevated plus-maze. The extract did not reverse scopolamine-induced amnesia on elevated plus-maze. It increased transfer latency at 200 and 400 mg/kg and also in combination with scopolamine. These results indicated anti-anxiety, anti-psychotic and anti-convulsant activity of E. neriifolia leaf extract in mice and rats. Phytochemical study showed the presence of steroidal saponin, reducing sugar, tannins, flavonoids in the crude leaf extract