Clinical and metabolic factors associated with weight gain in patients with schizophrenia spectrum disorders in the use of atypical antipsychotics

Orientador: Paulo DalgalarrondoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: Os antipsicóticos atípicos são, atualmente, o pilar para a terapêutica medicamentosa dos transtornos psicóticos do espectro da esquizofrenia. Entretanto, é frequente a ocorrência de efeitos adversos metabólicos, dentre eles o ganho de peso e suas complicações. A gênese do ganho de peso secundário ao uso de antipsicóticos ainda não está bem estabelecida, mas há indícios da influência de fatores relacionados ao controle de apetite e saciedade e de fatores inflamatórios. Objetivos: descrever aspectos sintomatológicos de pacientes com transtornos do espectro da esquizofrenia em uso de risperidona, olanzapina ou clozapina; verificar possíveis diferenças nas concentrações de adipocinas e marcadores inflamatórios entre os pacientes que ganharam ou não peso; avaliar qualidade de vida, autoimagem corporal, compulsão alimentar e sua possível associação com ganho ponderal. Método: Estudo transversal, realizado no ambulatório de psicóticos e egressos do Hospital das Clínicas da Universidade Estadual de Campinas (HC ¿ UNICAMP), durante o período de março de 2014 a junho de 2015. Os pacientes que participaram do estudo foram divididos em dois grupos, os que ganharam peso e os que não ganharam peso com uso de antipsicóticos. Eles responderam um questionário sociodemográfico e os seguintes instrumentos: Escala para Avaliação da Sintomatologia Psicótica ¿ PANSS, Escala de compulsão alimentar periódica ¿ Binge eating scale, Escala adaptada de Imagem Corporal, Escala de qualidade de vida em esquizofrênicos ¿ QLS-BR e Questionário Internacional de Atividade Física ¿ IPAQ. Foram dosadas as seguintes adipocinas: TNF?, IL1?, IL6, IL10, adiponectina e leptina. Foi realizada a bioimpedância de tais pacientes, além do cálculo de IMC. Resultados: Foram incluídos no estudo 52 sujeitos, dos quais 29 (55,8%) não ganharam peso e 23 (44,2%) ganharam peso. Após o uso da medicação 16 (30,8%) dos sujeitos estavam eutróficos, 25 (48,15%) com sobrepeso e 10 (19,2%) obesos. Os indivíduos eram em sua maioria homens (37 - 71,2%) e a média de idade foi 33,79 + 12,0 anos (IC 95%- 30,45- 37,13). As variáveis que se associaram negativamente com o ganho de peso foram: tempo de uso de medicação, tempo de doença, uso de clozapina e adiponectina. Escolaridade do chefe da família, binge eating, qualidade de vida, qualidade das relações familiares e concentrações de leptina foram mais elevadas entre os que ganharam peso. Conclusões: Concentrações mais elevadas de leptina e menores de adiponectina se associaram significativamente com ganho de peso. Outros fatores inflamatórios, assim como atividade física, não apresentaram tal associação. Ao contrário do esperado, pacientes com maior ganho de peso pontuaram melhor em qualidade de vida e seus familiares possuíam maior escolaridadeAbstract: Atypical antipsychotics (AA) are currently the mainstay for the pharmacological therapy of psychotic disorders. However, the occurrence of adverse effects is frequent, including weight gain and metabolic changes. The genesis of weight gain is not well established, but studies point to factors related to appetite control and to inflammatory markers. Aims: : to determine whether there were differences in the levels of adipokines and inflammatory markers amongpatients who gained weight using AA and those who did not; to assess possible associations of weight gain with quality of life, body self-image and binge eating. Subjects/Methods: This is a cross-sectional study, conducted with psychotic outpatients using AA (risperidone, olanzapine or clozapine); subjects were divided into two groups, those who gained weight and those who did not. The instruments used were: sociodemographic questionnaire; scale of psychotic symptoms (PANSS); Binge Eating Scale; adapted scale of body image; scale of Quality of Life for patients with Schizophrenia (QLS-BR); and the International Physical Activity Questionnaire (IPAQ). The following adipokines were measured: TNF?, IL1?, IL6, IL10, adiponectin and leptin. Results: There were included 52 subjects, among which 23 (44.2%) had gained weight. Subjects were mostly men (37; 71.2%) and the mean age was 33.8 + 12.0 years. Variables associated with not gaining weight gain were: duration of drug treatment, time since the first symptoms, use of clozapine and adiponectin levels. Variables associated with weight gain were: higher education of the household head, presence of food cravings, better quality of life and family relationships and higher leptin levels. Conclusions: higher concentrations of leptin and lower of adiponectin seemed to be important in the genesis of weight gain. Differently from what was expected, better quality of life, better relationship between patients and relatives, and higher degree of education of the householder were associated with weight gainMestradoSaude MentalMestra em Ciências Médica

Quality of life of asthmatic children and adolescents: relation to maternal coping

OBJECTIVE: To evaluate the quality of life of asthmatic children and adolescents, its relation with sociodemographic and clinical variables, and maternal coping strategies. METHODS: Cross-sectional study in which children and adolescents with asthma answered a quality of life questionnaire, and their mothers did the same with a coping scale. RESULTS: Out of the 42 children and adolescents investigated, 74% were classified as having mild/severe persistent asthma; 19%, mild persistent asthma; and 7%, intermittent asthma. A total of 69% of the participants showed impaired quality of life with mean scores ranging between 4.7 and 3.5, with greater harm in the domain of symptoms (score=3.6). There was a significant association between maternal schooling and the general index of quality of life, whereas maternal coping strategies were not associated with the severity of asthma. A large number of strategies used by mothers to cope with their children's crises were related to the management of stressors or to religious practices, and the latter presented negative correlation with the children's quality of life general index, showing that mothers whose children had worse quality of life used more religious coping. CONCLUSIONS: Asthmatic children, particularly those with moderate/severe persistent asthma, showed significant alterations as to quality of life. The high percentage of mothers using religious strategies, particularly in face of more severe clinical conditions, seem to indicate that they feel powerless to act, thus requiring concrete and useful orientation to low income families.OBJETIVO: Avaliar a qualidade de vida de crianças e adolescentes asmáticos, sua relação com variáveis sociodemográficas e clínicas e estratégias de enfrentamento materno. MÉTODOS: Estudo transversal no qual crianças e adolescentes com asma responderam a um questionário de qualidade de vida, e suas mães a uma escala de enfrentamento. RESULTADOS: Foram estudadas 42 crianças e adolescentes com idades entre 7 e 15 anos, sendo 74% classificados como tendo um quadro de asma persistente moderada/grave, 19% como persistente leve e 7% asma intermitente; 69% dos entrevistados apresentaram prejuízo na qualidade de vida, com escores médios variando de 4,7 a 3,5 e maior prejuízo no domínio sintomas (escore=3,6). Houve associação significativa entre escolaridade materna e índice geral de qualidade de vida, mas não entre gravidade da asma e tipo de enfrentamento materno. Grande parte das estratégias utilizadas pelas mães para enfrentar as crises do filho estava direcionada ao manejo de estressores ou práticas religiosas, estas com correlação negativa com o índice geral de qualidade de vida da criança, sinalizando que mães cujos filhos tinham pior qualidade de vida usavam mais enfrentamentos religiosos. CONCLUSÕES: Crianças asmáticas, especialmente com asma persistente moderada/grave, apresentaram alterações significativas em sua qualidade de vida. A alta porcentagem de uso de estratégias religiosas por parte das mães, especialmente frente a quadros mais graves, parece indicar que elas se sentem impotentes para atuar, necessitando de orientações concretas e factíveis para uma população de baixa renda.OBJETIVO: Evaluar la calidad de vida de niños y adolescentes asmáticos, su relación con variables sociodemográficas, clínicas y estratégicas de enfrentamiento materno. MÉTODOS: Estudio transversal en el que niños y adolescentes con asma contestaron un cuestionario de calidad de vida (PAQLQ-A) y sus madres a una escala de enfrentamiento (EMEP). RESULTADOS: Se estudiaron 42 niños y adolescentes con edad de 7-15 años y, entre ellos, el 74% fueron clasificados como teniendo un cuadro de asma persistente moderada/grave, el 19% como persistente y el 7% asma intermitente; el 69% de los entrevistados presentaron perjuicio en la calidad de vida, con escores medianos variando de 4,7 a 3,5 y mayor perjuicio en el dominio de síntomas (escore=3,6). Hubo asociación significativa entre escolaridad materna e índice general de calidad de vida, pero no hubo asociación entre gravedad del asma y tipo de enfrentamiento materno. Gran parte de las estrategias utilizadas por las madres para enfrentar las crisis de los hijos estaba dirigida al manejo de estresores o prácticas religiosas. Estas últimas con correlación negativa con el índice general de calidad de vida del niño, señalizando que madres cuyos hijos tenían peor calidad de vida usaban más enfrentamientos religiosos. CONCLUSIONES: Niños asmáticos, especialmente con asma persistente moderada/grave, presentaron alteraciones significativas en su calidad de vida. El alto porcentaje de uso de estrategias religiosas por parte de las madres, especialmente frente a cuadros más graves, parece indicar que ellas se sienten impotentes para actuar, necesitando de orientaciones concretas y factibles para una población de bajos ingresos.14515

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Qualidade de vida de crianças e adolescentes asmáticos: Sua relação com estratégias de enfrentamento materno

Objective: To evaluate the quality of life of asthmatic children and adolescents, its relation with sociodemographic and clinical variables, and maternal coping strategies. Methods: Cross-sectional study in which children and adolescents with asthma answered a quality of life questionnaire, and their mothers did the same with a coping scale. Results: Out of the 42 children and adolescents investigated, 74% were classified as having mild/severe persistent asthma; 19%, mild persistent asthma; and 7%, intermittent asthma. A total of 69% of the participants showed impaired quality of life with mean scores ranging between 4.7 and 3.5, with greater harm in the domain of symptoms (score=3.6). There was a significant association between maternal schooling and the general index of quality of life, whereas maternal coping strategies were not associated with the severity of asthma. A large number of strategies used by mothers to cope with their children's crises were related to the management of stressors or to religious practices, and the latter presented negative correlation with the children's quality of life general index, showing that mothers whose children had worse quality of life used more religious coping. Conclusions: Asthmatic children, particularly those with moderate/severe persistent asthma, showed significant alterations as to quality of life. The high percentage of mothers using religious strategies, particularly in face of more severe clinical conditions, seem to indicate that they feel powerless to act, thus requiring concrete and useful orientation to low income families

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population

Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Objective: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. Methods: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. Results: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. Interpretation: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals