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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article we review the empirical literature on weight gain associated with neuroleptic drug use. Weight gain, which appears to be associated with an increase in appetite, is variable but likely to be larger initially and then plateau. Clozapine and low-potency phenothiazines are associated with the largest gains and molindone with weight loss, but the mechanism is not known. Amantadine and fenfluramine may reverse weight gain to some degree. Dietary fat seems to play an important role in obesity, and research is needed to increase the data base and elucidate possible mechanisms. Studies are also needed to evaluate preventive strategies and to determine which drugs are least likely to produce weight gain as well as which drugs could be added to a neuroleptic regimen to control weight.
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PMID:Weight gain associated with neuroleptic medication: a review. 748 76

Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.
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PMID:Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients. 819 52

Previous reports have shown that long-term administration of typical and atypical neuroleptics induced obesity in female but not in male rats. It has been suggested that impaired ovarian steroidogenesis related to neuroleptic-induced hyperprolactinemia is necessary to observe the body weight changes. This hypothesis was tested with clozapine, an atypical neuroleptic that produces in rats a shorter increase in serum prolactin levels than do other neuroleptics. The effects of clozapine on body weight and food intake were assessed in female and male rats under treatment with any of the following doses: 0.5, 1, 2.5, 5, 10, and 20 mg/kg IP for 21 days. Vaginal cycle under clozapine treatment, as an indirect indicator of ovarian steroidogenesis, was also assessed. Obesity was not observed in any group. By contrast, clozapine at the doses of 10 and 20 mg/kg significantly decreased body weight and feeding in male rats. Clozapine at the doses of 5 and 10 mg/kg IP induced permanent diestrus. The failure of clozapine to induce obesity in female rats, despite impaired vaginal cycle, can be considered indirect evidence that drug-induced hyperprolactinemia is not sufficient to observe neuroleptic-induced obesity in rats.
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PMID:Effects of long-term administration of clozapine on body weight and food intake in rats. 851 72

Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). Weight gain occurs no matter what the patient's age, sex, or race and is seen with both oral and depot drug formulations. Numerous studies have found that patients gain weight when treated with a conventional antipsychotic, such as chlorpromazine, fluphenazine, and haloperidol. The newer, novel antipsychotics offer advantages over conventional antipsychotics, especially a relative lack of extrapyramidal symptoms, but some still have the disadvantage of causing weight gain. Clozapine and olanzapine in particular appear to cause substantial weight gain, much more so than do most conventional neuroleptics and novel agents such as risperidone. Given the risks to health and treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.
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PMID:Weight gain associated with antipsychotic drugs. 1103 Apr 90

Controversy persists about links between psychotropic drug use, obesity, and consequent menstrual irregularities. Although these interrelationships have been suggested to possibly explain polycystic ovarian syndrome among women taking valproate, less is known about menstrual irregularities associated with weight gain caused by other psychotropics. Clozapine, sparing of prolactin-related menstrual effects yet often associated with weight gain, offers a model psychotropic from which to test such hypotheses. We studied outpatient premenopausal women from a clozapine clinic to preliminarily assess the association between menstrual cycle patterns and body mass index (BMI). Records were reviewed for 13 female premenopausal schizophrenic, bipolar, or schizoaffective outpatients who took clozapine with no conventional antipsychotics for >6 months. Mean 6-month menstrual cycle lengths were compared with BMIs and relative weight changes since starting clozapine. Subjects took clozapine (mean +/- SD dose 392.2 +/- 195.7 mg/day) for a mean +/- SD of 4.4 +/- 3.2 years, with a mean preclozapine weight increase of 27%. Twenty-three percent had menstrual irregularities in the preceding 6 months (mean +/- SD cycle length = 36.4 +/- 18.1 days), although no significant associations were observed between cycle length and (a) mean +/- SD BMI (32.0 +/- 8.4) (r = -0.09, p = 0.78) or (b) weight change since starting clozapine (r = -0.10, p = 0.75). The observed lack of association between clozapine-induced weight gain and menstrual disturbances would provisionally suggest that iatrogenic weight gain does not robustly explain the emergence of irregular menses among premenopausal women taking clozapine.
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PMID:A preliminary study of the relationship between clozapine-induced weight gain and menstrual irregularities in schizophrenic, schizoaffective, and bipolar women. 1204 36

Recently there has been increased concern over the side effects of the atypical antipsychotic drugs, including diabetes, hyperlipidemia and obesity. The relationship between diabetes and antipsychotic drugs requires a careful analysis. Patients with schizophrenia are known to suffer from diabetes more often than the general population. In addition, a number of case reports indicate that the conventional antipsychotic as well as atypical antipsychotic drugs produce diabetes. Clozapine and olanzapine, in particular, have been implicated producing diabetes as well as diabetic ketoacidosis. Epidemiological surveys have supplemented the case reports, finding increased incidence of diabetes in patients treated with atypical antipsychotic agents, but these surveys have not yielded consistent results regarding the differential effects of the various atypical antipsychotic drugs. The mechanism by which antipsychotic agents produce diabetes is not elucidated. Weight gain and consequent alteration in triglycerides and cholesterol have been known to occur frequently with olanzapine and clozapine. The ensuing metabolic syndrome itself may cause insulin resistance and diabetes. In the absence of definitive scientific data on the differential effects of antipsychotic drugs in inducing diabetes, clinical prudence and careful monitoring of all patients on atypical antipsychotic drugs is necessary. Aripiprazole and ziprasidone have not been shown to increase weight or produce diabetes, but more information on the diabetogenic effects of ziprasidone and aripiprazole is needed. In order to assess the differential effects of atypical antipsychotic drugs in producing diabetes and the mechanisms by which they produce this reaction, further research is necessary.
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PMID:Side effects of atypical antipsychotic drugs. 1528 97

There is compelling evidence that patients with schizophrenia are prone to gain weight. In addition, atypical antipsychotic (AAP) drugs also induce weight gain. All antipsychotic drugs produce weight gain but the potential varies. Many studies overwhelmingly confirm that AAP drugs produce substantially more weight gain in comparison to conventional antipsychotic drugs. Clozapine and olanzapine have the most weight inducing potential. Even ziprasidone, which is considered to be weight neutral, and aripiprazole a dopamine modulator produce weight gain in some. The pathophysiology of weight gain is complicated. Many neurohormones, neuropeptides, gut hormones, as well as adipose tissue and hair root derived hormones interact with environmental factors to produce weight gain. Management of weight gain is a difficult problem. Basic to treatment is an understanding of the etiology. Drug induced obesity provides a unique opportunity to psychiatrists to understand this clinically important problem. In the absence of this knowledge, prevention is the best hope. Education, diet control and simple behavioral measures may prevent excessive weight gain. In those with weight gain, treatment can be attempted with pharmacotherapy with careful monitoring of the side effects.
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PMID:Atypical antipsychotic induced weight gain: pathophysiology and management. 1532 1

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.
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PMID:Dyslipidemia and atypical antipsychotic drugs. 1560 Mar 82

Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.
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PMID:Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. 1599 56

Weight gain, leading to further morbidity and poor treatment compliance, is a common adverse effect of treatment with clozapine. The C825T polymorphism in the human G protein beta3 subunit gene has been noted to be associated with obesity, hypertension and coronary artery disease. Clozapine increases the level of G protein beta3 subunit in the rat striatum. The aim of the present study was to investigate the relationship between G protein beta3 polymorphisms and clozapine-induced body weight change in a Chinese population during long-term treatment. One hundred and thirty-four schizophrenic patients, who were treated with clozapine continuously (13.4+/-0.5 months), were genotyped for G protein beta3 subunit C825T polymorphism. None of these patients received second-generation antipsychotics before clozapine treatment. Body weight was monitored at baseline before clozapine treatment and at the endpoint after clozapine treatment. Patients with the TT type experienced significantly more weight gain (16.2+/-2.5%) compared to those with CT (9.3+/-1.2%) or CC types (5.5+/-2.4%) after long-term clozapine treatment (P = 0.003). Further stratification by gender demonstrated that the effect of C825T polymorphism on weight gain remained significant both in males and females. These findings confirm the importance of genetic factors in body weight change induced by long-term clozapine treatment in patients with schizophrenia, and indicate a role for the G protein beta3 subunit in body weight regulation during long-term clozapine treatment.
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PMID:C825T polymorphism in the human G protein beta3 subunit gene is associated with long-term clozapine treatment-induced body weight change in the Chinese population. 1614 1


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