RESUMO
INTRODUCTION: Excessive body weight gain (BWG), hyperglycemia and dyslipidemia are important side effects of olanzapine. We assessed the effects of rosiglitazone on BWG, the insulin resistance index (HOMA-IR), lipids, glycated hemoglobin and fibrinogen in olanzapine-treated schizophrenia patients. METHODS: Thirty patients taking olanzapine (10-20 mg daily for 8 months) were randomly allocated to rosiglitazone (n=15; 4 to 8 mg daily) or placebo (n=15) in a 12-week double-blind protocol. Anthropometric and biochemical variables were evaluated at baseline, weeks 6 and 12. RESULTS: The rosiglitazone and placebo groups gained 3.2+/-4.5 and 2.2+/-2.3 kg, respectively (p=0.65). Insulin and the HOMA-IR significantly decreased after rosiglitazone (p<0.05). Rosiglitazone did not improve the lipid profile, fibrinogen and Hb1c levels. DISCUSSION: The positive impact of rosiglitazone was limited to improved glycemic control. It cannot be recommended for metabolic control during olanzapine treatment.
Assuntos
Antipsicóticos/efeitos adversos , Benzodiazepinas/efeitos adversos , Hipoglicemiantes/uso terapêutico , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Adulto , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Fibrinogênio/metabolismo , Hemoglobinas/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Olanzapina , Projetos Piloto , Rosiglitazona , Esquizofrenia/tratamento farmacológico , Estatística como AssuntoRESUMO
Excessive body weight gain (BWG) is a common side effect of some typical and atypical antipsychotic drugs (APs). Convergent evidence suggests a hierarchy in the magnitude of BWG that may be induced by diverse agents, being very high for clozapine and olanzapine; high for quetiapine, zotepin, chlorpromazine, and thioridazine; moderate for risperidone and sertindole; and low for ziprazidone, amisulpiride, haloperidol, fluphenazine, pimozide, and molindone. BWG may be related to increased appetite that is due to drug interaction with the brain monoaminergic and cholinergic systems and to the metabolic/endocrine effects of hyperprolactinemia. Subjects with schizophrenia and bipolar disorders manifested a significantly high prevalence of diabetes, even before the introduction of atypical APs. However, clozapine and olanzapine appear to display a high propensity to induce glucose dysregulation and dyslipidemia. Sudden BWG, insulin resistance, increased appetite, and related endocrine changes also may be involved in the development of glucose intolerance and dyslipidemia in predisposed individuals. Patients should be informed of these side effects in order to prevent excessive BWG, and their blood glucose and lipids should be monitored before treatment and then at regular intervals. Nutritional advice must be given and regular physical exercise recommended. An appropriate selection of APs ought to be based on drug efficacy for specific patients and assessment of relevant risk factors such as propensity to gain weight; family or personal history of diabetes or hyperlipidemia; and elevated fasting serum glucose, lipid, or insulin levels. At present, there is no standardized pharmacological treatment for AP-induced BWG. Some studies have assessed the effects of agents such as amantadine, orlistat, metformin, nizatidine, and topiramate on AP-induced BWG. Further studies will provide tools to identify patients at high risk for obesity and metabolic abnormalities during AP administration. Excessive body weight gain (BWG), glucose intolerance, and dyslipidemia during treatment with antipsychotic drugs (APs) were reported in the late 1950s [14,101]. However, after 1990, interest in these problems increased noticeably, mainly because of the high propensity of some new atypical APs to induce these side effects (Fig.1). The APs are currently used in diverse mental disorders. Hence, excessive BWG and metabolic dysfunction are not exclusive of subjects with schizophrenia. In the case of bipolar disorders, AP-induced BWG may be additive to that induced by mood stabilizers [14,48,101]. The clinical features [2,14,24,133,139,140] and mechanisms [14,34,68,87,93,101,130] of BWG and metabolic dysfunction have been previously reviewed. In this article, we focus on a unified theory to explain these side effects, based on the interaction of APs with brain neurotransmitters involved in appetite regulation. This review comprises the following sections: 1) the clinical features of AP-induced BWG; 2) the effects of APs on carbohydrate and lipid metabolism in humans and experimental animals; 3) mechanisms involved in BWG, glucose, and lipid dysregulation; 4) strategies for prevention and treatment of these side effects; and 5) research perspectives in the field. The following sources were consulted: MEDLINE, Cochrane database system, and PsychINFO. Numerous articles referred to in leading articles also were consulted. The literature on this subject has increased so rapidly that it was impossible to include all the data recently published. For the first two sections, references that illustrate current controversies in the field were selected.
Assuntos
Antipsicóticos/efeitos adversos , Doenças Metabólicas/induzido quimicamente , Obesidade/etiologia , Aumento de Peso/efeitos dos fármacos , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Metabolismo dos Carboidratos , Sistema Endócrino/efeitos dos fármacos , Sistema Endócrino/metabolismo , Humanos , Metabolismo dos Lipídeos , Doenças Metabólicas/metabolismo , Neurotransmissores/metabolismoRESUMO
1. To test the hypothesis that lithium-induced body weight gain is related to an unbalance in the reproductive hormones, lithium carbonate (900 mg/day) or placebo was administered to healthy men for 1 month. 2. Body weight, skin folds and the serum levels of thyrotropic hormone, tetraiodothyroxine, prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone (T5), dehydroepiandrosterone sulfate (DHEAS), estradiol (E2), cortisol, the ratios E2/T5 and T5/DHEA-S, and blood lipids were evaluated before and during treatment. 3. Body weight, skin folds, hormones and lipids serum levels were not significantly affected by the treatment with Li. These results agree with previous reports of lack of effects of 1 month-Li administration on appetite and body weight in normal male subjects (Chen et al., 1992), and question the appropriateness of studying Li-induced obesity in healthy volunteers, given the short-term administration and low doses of Li that must be used.
Assuntos
Peso Corporal/efeitos dos fármacos , Hormônios Esteroides Gonadais/sangue , Carbonato de Lítio/farmacologia , Adulto , Análise de Variância , Índice de Massa Corporal , Peso Corporal/fisiologia , Sulfato de Desidroepiandrosterona/sangue , Estradiol/sangue , Hormônio Foliculoestimulante/sangue , Humanos , Hidrocortisona/sangue , Lítio/sangue , Hormônio Luteinizante/sangue , Masculino , Prolactina/sangue , Radioimunoensaio , Valores de Referência , Reprodutibilidade dos Testes , Reprodução , Dobras Cutâneas , Testosterona/sangue , Hormônios Tireóideos/sangue , Tireotropina/sangue , Aumento de Peso/efeitos dos fármacosRESUMO
The efficacy of the antiviral agent Amantadine (AM, 5-100 mg/kg/sc, ip or intrahypothalamically, 12.5-100 micrograms bilaterally) in influencing body weight and food intake in drug-free rats, and in preventing neuroleptic-induced weight gain, was assessed in adult female rats. In drug-free rats, acute administration of systemic AM or directly injected in the lateral hypothalamus (LH) displayed a significant dose-dependent anorectic effect (p < 0.001). This effect could be mediated by the brain monoaminergic system, because systemic or local injections of AM increased dopamine and serotonin overflow in the nucleus accumbens and in the LH. Chronic administration of AM significantly decreased body weight gain in drug-free rats only at the dose of 100 mg/kg/sc. Similarly, obesity induced by the neuroleptic drug sulpiride (SUL, 20 mg/kg/ip for 21 days) was prevented by AM only at the dose of 100 mg/kg. AM did not prevent SUL-induced hyperprolactinemia, disruption of the vaginal cycle and a decrement in the weight of the uterus and ovaries at any dosage. This lack of efficacy of AM contrasts with that of bromocriptine, which completely prevented SUL-induced weight gain and hyperprolactinemia. The results show that despite a potent acute anorectic effect, AM displays a weak antagonistic action on SUL-induced obesity in rats, in contrast to the preliminary results obtained in humans. As AM metabolism differs in humans and rats, additional research is needed before its systematic testing in counteracting neuroleptic-induced obesity in patients with mental disorders.
Assuntos
Amantadina/uso terapêutico , Antipsicóticos/efeitos adversos , Obesidade/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Dopamina/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Estro/efeitos dos fármacos , Feminino , Hipotálamo/metabolismo , Núcleo Accumbens/metabolismo , Obesidade/induzido quimicamente , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Serotonina/metabolismo , Sulpirida/efeitos adversosRESUMO
Metabolic and endocrine abnormalities secondary to hyperprolactinemia, particularly hypogonadism, may be involved in the excessive body weight gain observed during treatment with antipsychotic drugs. The present study was conducted in healthy men in order to detect an endocrine imbalance secondary to antipsychotic drug administration, which, if sustained in the long term, might be involved in the development of obesity. Sulpiride (200 mg daily for 30 days) or placebo was nonblindly administered, and body weight gain was correlated with the serum levels of prolactin, luteinizing hormone, follicle-stimulating hormone, estradiol, free testosterone, thyrotropic hormone, free tetraiodothyroxine, cortisol, dehydroepiandrosterone sulphate (DHEA-S), and the ratios estradiol/testosterone and testosterone/DHEA-S; the blood lipids were also assessed. Body weight gain and the serum levels of prolactin were significantly increased by sulpiride; in addition, a significant positive correlation was observed between prolactin levels and body weight gain. Other endocrine parameters were not significantly affected by the drug. These short-term results show that in healthy men, body weight can be increased by antipsychotic drug administration; this effect may be related to hyperprolactinemia alone, since other endocrine parameters were normal at the time of treatment. A more prolonged treatment with antipsychotic agents might be required to observe the alterations in gonadal and adrenal steroids often detected in subjects with primary obesity.
Assuntos
Antipsicóticos/efeitos adversos , Peso Corporal/efeitos dos fármacos , Doenças do Sistema Endócrino/induzido quimicamente , Prolactina/sangue , Sulpirida/efeitos adversos , Adulto , Hormônios Esteroides Gonadais/sangue , Gonadotropinas Hipofisárias/sangue , Humanos , Lipídeos/sangue , Masculino , Estado Nutricional , Hormônios Tireóideos/sangueRESUMO
Weight gain is an undesirable side-effect of long-term lithium administration which notably interferes with treatment compliance. The mechanisms of this weight gain remain unclear, making its management in patients difficult. In this paper, studies describing the features of this weight gain in patients and in rats treated with chronic lithium administration are reviewed. The effects of lithium on body weight differ between patients and rats in a number of ways, including the observation that excessive weight gain is observed in both male and female patients, but only in female rats. Nevertheless, an animal model of lithium-induced weight gain may be able to provide useful insights into some of the specific mechanisms involved, particularly those related to interactions with gonadal steroid function. We discuss the effects of lithium on the endocrine system, neurotransmitters, metabolism, electrolyte regulation, and feeding behavior, which might underlie lithium's effects on body weight. Finally, suggestions for the management of weight gain in the clinical setting are presented. These include, in the long term, dietary control and physical activity and, in the short term, choosing among several drugs that have been tested either in patients or in animal models of obesity. If weight gain still cannot be controlled and treatment compliance is at risk, the mood stabilizers carbamazepine or valproic acid might be substituted for lithium treatment.