RESUMO
Myocarditis occurs more frequently during clozapine (CLZ) administration than during treatment with other antipsychotic drugs (APs). In this observational study, we transversally screened outpatients for myocarditis by comparing a CLZ group of 132 subjects, with a non-CLZ group taking other APs (n = 371) only, and in 21 CLZ-treated patients and 18 subjects treated with other APs who had been followed for more than one year. The protocol included a) assessment of symptoms such as dyspnea, tachycardia, chest discomfort, fever, cough, and edema, b) blood pressure and heart auscultation; c) a standard electrocardiogram after a 5-minute rest, d) white cell count, and qualitative determination of troponin I, creatine-kinase-MB and myoglobin, and e) a cardiologist evaluation of subjects with suspected myocarditis. Only one case of myocarditis was detected, providing an approximation of the frequency of myocarditis of 1.6% in the first month of treatment. This was a 30-year-old man with schizophrenia who developed symptoms at day 6 after starting a treatment with 200 mg of CLZ a day without titration. Myocarditis was not observed during prolonged CLZ or other AP administration. These results support the proposal of starting CLZ treatment with a low dose and the feasibility of a simple protocol for myocarditis detection in psychiatry primary care.
El desarrollo de miocarditis ocurre con más frecuencia durante el tratamiento con clozapina (CLZ) que durante el uso de otros antipsicóticos (APs). En el presente estudio observacional evaluamos la presencia de miocarditis mediante un protocolo transversal comparando 132 sujetos tratados con CLZ con 371 pacientes tratados con otro AP, y en 21 sujetos tratados con CLZ y 18 pacientes tratados con otro AP en un protocolo longitudinal mayor 1 año de duración. La evaluación incluyó: a) detección de síntomas como disnea, taquicardia, malestar torácico, fiebre, tos y edema; b) presión arterial y auscultación cardiaca; c) electrocardiograma estándar luego de un reposo de 5 minutos; d) contaje de glóbulos blancos y determinación cualitativa de troponina I, creatin-kinasa-MB y mioglobina, y e) evaluación por un cardiólogo en sujetos sospechosos para miocarditis. Detectamos un solo caso de miocarditis, lo que permite una aproximación sobre la frecuencia de miocarditis de 1,6 % durante el primer mes de tratamiento. Se trató de un sujeto masculino con esquizofrenia que desarrolló síntomas durante el día 6 después de haber iniciado el tratamiento con CLZ a la dosis de 200 mg por día sin titulación. No se detectaron sujetos sospechosos de miocarditis durante el tratamiento prolongado con CLZ u otro AP. Estos resultados sustentan la recomendación de comenzar el tratamiento con clozapina a dosis bajas, y la factibilidad de utilizar un protocolo sencillo para detectar miocarditis en la atención psiquiátrica primaria.
Assuntos
Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Miocardite/induzido quimicamente , Estudos Transversais , Estudos LongitudinaisRESUMO
Myocarditis occurs more frequently during clozapine (CLZ) administration than during treatment with other antipsychotic drugs (APs). In this observational study, we transversally screened outpatients for myocarditis by comparing a CLZ group of 132 subjects, with a non-CLZ group taking other APs (n = 371) only, and in 21 CLZ-treated patients and 18 subjects treated with other APs who had been followed for more than one year. The protocol included a) assessment of symptoms such as dyspnea, tachycardia, chest discomfort, fever, cough, and edema, b) blood pressure and heart auscultation; c) a standard electrocardiogram after a 5-minute rest, d) white cell count, and qualitative determination of troponin I, creatine-kinase-MB and myoglobin, and e) a cardiologist evaluation of subjects with suspected myocarditis. Only one case of myocarditis was detected, providing an approximation of the frequency of myocarditis of 1.6% in the first month of treatment. This was a 30-year-old man with schizophrenia who developed symptoms at day 6 after starting a treatment with 200 mg of CLZ a day without titration. Myocarditis was not observed during prolonged CLZ or other AP administration. These results support the proposal of starting CLZ treatment with a low dose and the feasibility of a simple protocol for myocarditis detection in psychiatry primary care.
Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Miocardite/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available. METHODS: Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36). RESULTS: Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; -0.7, 7.1); other atypical APDs (4.9%; -0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; -7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy. CONCLUSIONS: Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation.
Assuntos
Antipsicóticos/efeitos adversos , Cardiomiopatias/epidemiologia , Clozapina/efeitos adversos , Hiponatremia/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatias/induzido quimicamente , Estudos Transversais , Feminino , Humanos , Hiponatremia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Venezuela/epidemiologia , Adulto JovemRESUMO
Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20 mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.
Assuntos
Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Adulto , Antioxidantes/administração & dosagem , Antipsicóticos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Melatonina/administração & dosagem , Pessoa de Meia-Idade , Projetos Piloto , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Tardive Dyskinesia (TD) is a movement disorder associated with the clinical administration of antipsychotics. It is believed that TD is due, among other factors, to an increase in the oxidative damage produced by free radicals. Antioxidants, like vitamin E, have been used in the treatment of TD but there is no evidence of their effectiveness. Melatonin (MEL) is 6 to 10 times more effective, as an antioxidant, than vitamin E and it has been used with an apparent higher effectiveness in the treatment of TD, although the results have not been conclusive. A randomized, double blind, placebo controlled design was used to determine the effectiveness of MEL (20mg/day) during 12 weeks in 7 patients with TD. Six patients with TD were treated with placebo. The Abnormal Involuntary Movement Scale (AIMS) was chosen to assess the severity of TD initially and after 4, 8 and 12 weeks. The psychiatric evaluation was done following the Brief Psychiatric Rating Scale. In two patients treated with MEL a significant improvement (more than 60%) of the values of AIMS was detected. In the remainder five, as well as in the patients treated with placebo, no difference was observed during the 12 weeks. When compared the AIMS score in all the MEL-treated patients with the values in the placebo-treated patients, no significant differences were detected during the 12 weeks of the study. However, the significant clinical improvement observed in two patients must be considered before reaching a final conclusion on the usefulness of MEL in TD.
La Discinesia Tardía (DT) es un trastorno de los movimientos asociado al uso crónico de antipsicóticos que parece producirse, entre otros factores, por un incremento en los procesos oxidativos. La vitamina E se ha utilizado en su tratamiento, pero no hay evidencia de su efectividad. Como la melatonina (MEL) es 6 a 10 veces más efectiva como antioxidante que la vitamina E, se ha utilizado con una aparente mayor efectividad, aunque los resultados no han sido concluyentes. Se realizó un estudio doble ciego, al azar y controlado con placebo, para determinar la efectividad de la administración de la MEL durante 12 semanas en 7 pacientes con DT. Seis pacientes con DT fueron tratados con placebo. La Escala de Movimientos Involuntarios Anormales (AIMS) se usó para evaluar la evolución de los movimientos al inicio y a las 4, 8 y 12 semanas de tratamiento. La evaluación clínica psiquiátrica se hizo con la Escala Breve de Evaluación Psiquiátrica. En dos pacientes tratados con MEL se observó una mejoría clínica superior al 60% pero en los restantes, así como en los tratados con placebo los valores de la AIMS no variaron significativamente en el transcurso de las 12 semanas. Cuando se compararon los valores de la AIMS de la totalidad de los pacientes tratados con MEL, con los del grupo placebo, no se detectó ninguna diferencia significativa. Sin embargo, la mejoría clínica significativa de dos de los pacientes estudiados debe considerarse para llegar a una conclusión sobre la utilidad de la MEL en la DT.
Assuntos
Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Transtornos dos Movimentos/tratamento farmacológico , Antioxidantes/administração & dosagem , Antipsicóticos/efeitos adversos , Método Duplo-Cego , Melatonina/administração & dosagem , Projetos Piloto , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Depression has been associated to inflammatory and oxidative events. Previous report has shown renal oxidative stress in patients with depression. In order to analyze if depressive status is related to renal oxidative and inflammatory events, Sprague Dawley rats were submitted to forced swimming test (FST) and the renal oxidative metabolism, monocyte-macrophage infiltration and Angiotensin II (Ang II) expression were determined. Rats were submitted to FST daily (30 min) for 15 days. Motor activity was analyzed before FST. Kidney sections were homogenized to measure nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity by enzymatic and biochemical methods. Renal frozen sections were studied for superoxide anion (O2-), monocyte/macrophage infiltration and Ang II expression by histochemical and immunofluorescence methods. In addition, three groups of FST rats were treated with losartan, sertraline or water for 18 days with further renal O2-analysis. In the FST group, struggle time, motor activity, food intake and body weight gain were found decreased. Increased number of glomerular, interstitial and tubular O2-positive cells was observed in FST rats. High renal content of nitrite/nitrate (NO), MDA and decreased amount of GSH were found in FST rats. Values of renal ED-1 or Ang II positive cells in FST rats remained similar to controls; however, AT1 receptor blocking (losartan) and sertraline reduced both depressive-like behavior and renal O2-expression. These data suggests that depression-like behavior in rats is involved in kidney oxidative stress probably mediated by AT1 receptors.
Assuntos
Depressão/patologia , Depressão/fisiopatologia , Rim/metabolismo , Estresse Oxidativo/fisiologia , Angiotensina II/metabolismo , Animais , Modelos Animais de Doenças , Glutationa/metabolismo , Rim/patologia , Macrófagos/metabolismo , Masculino , Malondialdeído/metabolismo , Monócitos/metabolismo , Atividade Motora/fisiologia , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismo , Natação/psicologia , Fatores de TempoRESUMO
BACKGROUND: Few studies on the association between atypical antipsychotic drug (AAP) administration and metabolic dysfunction have concurrently evaluated the general population (GP), other psychotropic drug treatments and drug-free psychiatric patients. METHODS: We assessed the frequency of the metabolic syndrome (MS) according to the National Cholesterol Education Program criteria (NCEP) and its constituting variables in a GP sample (n=271) and in patients receiving, for at least three consecutive months, antiepileptic drugs (n=93), olanzapine (n=162), clozapine (n=105), typical antipsychotics (n=117), other AAP (n=58), other psychotropic drugs (n=185), and drug-free individuals (n=636). Subjects were clinically classified as schizophrenia, bipolar or other axis I disorders (DSM-IV-RT), and as first-degree relatives of each diagnostic group. RESULTS: The MS was detected in 26.6% of the GP (95% confidence interval: 21.5-31.8). No diagnostic or treatment group had a significantly higher age-adjusted frequency than the GP (p>0.05). Treatment duration did not significantly affect the results. However, significant differences were observed in the frequency of abnormal MS constituting variables in comparison to the GP. For example, schizophrenia patients and their relatives, bipolar subjects and olanzapine- and clozapine-treated patients had higher abnormal waist circumference values. In addition, bipolar patients and their relatives and subjects treated with olanzapine and other AAPs had higher frequencies of abnormal glucose levels. Neither schizophrenia nor bipolar patients in the diagnostic categories nor the olanzapine or the clozapine groups displayed higher proportions of abnormal triglycerides, high density cholesterol or blood pressure levels than the GP. CONCLUSIONS: While we did not demonstrate an increased frequency of the MS in AAP-treated subjects, our results confirm that specific metabolic variables must be monitored in psychiatric patients. Besides they stress the importance, in epidemiological studies, of concurrently comparing the figures recorded in AAP-treated patients with those obtained in the local GP, other drug treatment groups and drug-free subjects when referring to the magnitude of the metabolic effects of specific antipsychotic agents.
Assuntos
Antipsicóticos/uso terapêutico , Família/psicologia , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Doenças Metabólicas/etiologia , Adulto , Fatores Etários , Idoso , Benzodiazepinas/uso terapêutico , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Colesterol/metabolismo , Clozapina/uso terapêutico , Planejamento em Saúde Comunitária , Intervalos de Confiança , Feminino , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Olanzapina , Estudos Retrospectivos , Resultado do Tratamento , Venezuela/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The role of leptin in atypical antipsychotic-induced metabolic dysfunction was explored by assessing the anthropometric and metabolic profile and the response to metformin (MET) of clozapine- (CLZ) treated schizophrenia patients according to their single nucleotide polymorphisms (SNPs) in the leptin promoter (LEP2548/GA) and leptin receptor (LEPR Q223R) genes. METHODS: Phase 1. Body mass index (BMI), waist circumference, serum glucose, HbA1C, lipids, leptin, cortisol, insulin resistance index (HOMA-IR), metabolic syndrome and the frequencies of SNPs were assessed in 56 CLZ-treated patients (78.6% males). Phase 2. Fifty two phase 1 subjects were randomly assigned to MET XR (n=23) (1000 mg/day) or placebo (n=29) for 14 weeks. Changes in anthropometric and biochemical variables were compared between the SNPs. RESULTS: Phase 1. The QQ group displayed the lowest triglyceride levels (p<0.05). No other significant difference was observed. Phase 2. Change in anthropometric variables did not differ between the genotypes in any treatment group. After MET, glucose levels significantly increased in the GG group (p<0.05), whereas the HOMA-IR and the low density cholesterol significantly decreased in the QQ- but not in the (QR+RR) group (p<0.05). No differences were observed after placebo. CONCLUSIONS: BW response to CLZ was not related to LEP- and LEPR-SNPs. The GG and (QR+RR) genotypes showed an unexpectedly opposite and blunted response to MET administration respectively.
Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Hipoglicemiantes/uso terapêutico , Leptina/genética , Doenças Metabólicas/induzido quimicamente , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Receptores para Leptina/genética , Esquizofrenia , Adulto , Glicemia/efeitos dos fármacos , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Genótipo , Humanos , Hidrocortisona/sangue , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Farmacogenética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Venezuela/epidemiologiaRESUMO
OBJECTIVES: Previous reports have shown that the depressive status in humans and experimental animals is associated with decreased immune response. Since monocyte chemotaxis and expression of CD11a are pivotal mechanisms in immune response, impairment of these events could explain the diminished immune response in depression. METHODS: To test this, rats were submitted to the forced swimming test (FST) for 3 and 15 days. Animals were sacrificed at days 4 (3 days' FST), 16 (15 days' FST) and 30 (15 days' FST and 15 days of recovery time). At these times, a blood sample was obtained for serum and leukocyte isolation. Mononuclear leukocytes were obtained by Histopaque gradient. Chemotaxis responsiveness was determined in Boyden chambers using zymosan-activated rat serum. Cellular CD11a expression and serum CD11a were determined by immunofluorescence and ELISA, respectively. RESULTS: Decreased chemotaxis was observed in FST animals at days 4 and 16 with total recovery at day 30. Diminished expression of cellular CD11a was observed at day 16 and remained decreased at day 30. There were no significant differences in serum CD11a content. CONCLUSION: Decreased chemotactic response and expression of CD11a found in this experimental model of depression could be important mechanisms to induce impairment immune response in experimental and clinical depression.
Assuntos
Antígeno CD11a/biossíntese , Quimiotaxia de Leucócito/imunologia , Tolerância Imunológica , Monócitos/imunologia , Animais , Antígeno CD11a/sangue , Antígeno CD11a/genética , Células Cultivadas , Quimiotaxia de Leucócito/genética , Transtorno Depressivo/imunologia , Transtorno Depressivo/metabolismo , Transtorno Depressivo/psicologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/genética , Imunidade Inata/genética , Masculino , Monócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Natação/psicologia , Fatores de TempoRESUMO
Autonomic and peripheral neuropathies are well-described complications in diabetes. Diabetes mellitus is also associated to central nervous system damage. This little-known complication is characterized by impairment of brain functions and electrophysiological changes associated with neurochemical and structural abnormalities. The purpose of this study was to investigate brain structural and ultrastructural changes in rats with streptozotocin-induced diabetes. Cerebral cortex, hypothalamus, and cerebellum were obtained from controls and 8 weeks diabetic rats. Light and electron microscope studies showed degenerative changes of neurons and glia, perivascular and mitochondrial swelling, disarrangement of myelin sheath, increased area of myelinated axons, presynaptic vesicle dispersion in swollen axonal boutoms, fragmentation of neurofilaments, and oligodendrocyte abnormalities. In addition, depressive mood was observed in diabetic animals. The brain morphological alterations observed in diabetic animals could be related to brain pathologic process leading to abnormal function, cellular death, and depressive behavioral.