Glucose Intolerance with Atypical Antipsychotics

Drug Epidemiology Unit, Medical Products Agency, Uppsala, Sweden.
Drug Safety (Impact Factor: 2.82). 02/2002; 25(15):1107-16. DOI: 10.2165/00002018-200225150-00005
Source: PubMed


Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance.
To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs.
All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed.
Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77).
Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.

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Available from: Staffan Haegg, Mar 19, 2015
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    • "However, several SGAs are known to be associated with a high risk of metabolic adverse effects such as weight gain, hyperlipidemia and hyperglycemia [2,3]. Glucose dysregulation [4], glucose intolerance [5] and increased cholesterol levels [6] can occur in patients taking SGAs and there is a high prevalence of metabolic syndrome, especially in women (52%) compared with men (36%) with schizophrenia [7]. Additionally, obese and overweight patients with schizophrenia are at a higher risk of metabolic adverse effects than those with normal-weight [8]. "
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    ABSTRACT: There is a strong association between weight gain and metabolic events in patients with schizophrenia receiving many of the second-generation antipsychotic agents. We explored the relationship between body mass index (BMI) and metabolic events in patients with schizophrenia receiving long-acting injectable paliperidone palmitate (PP) in a long-term trial. We conducted a post hoc analysis of data from a PP study that included a 33-week open-label transition (TR) and maintenance phase; a variable duration, randomized, double-blind (DB), placebo-controlled phase and a 52-week open-label extension (OLE) phase. Overall, 644 patients received PP continuously from study entry through discontinuation or study completion and were grouped by baseline BMI (kg/m2): underweight (BMI <19; n = 29, 4.5%), normal-weight (BMI 19- < 25; n = 229, 35.6%), overweight (BMI 25- < 30; n = 232, 36.0%) and obese (BMI >=30; n = 154, 23.9%). Metabolic treatment-emergent adverse events (TEAEs) and changes in related laboratory results from TR baseline were analyzed. PP exposure was similar across BMI groups; overall mean (SD) dose/month was 70.3 (17.17) mg eq. [109.6 (26.78) mg]; median duration of exposure was 204 days (6 to 1009 days). Occurrences of metabolic TEAEs overall by group were 0% (underweight), 14.9% (normal-weight), 14.7% (overweight), and 24.0% (obese). The most common (>=2%) metabolic TEAE were weight gain and elevated blood levels of glucose, lipids, and insulin. Mean BMI and weight increased in normal-weight and overweight groups at DB endpoint, and in underweight, normal-weight and overweight groups at OLE endpoint (p <=0.05). No consistent trend for increased metabolic-related laboratory values by baseline BMI group was observed. Homeostatic model assessments for insulin resistance indicated preexisting insulin resistance at baseline, with minimal changes at OLE endpoint across baseline BMI groups. Occurrences of metabolic-related TEAEs trended with greater BMI status in patients with schizophrenia treated with PP; consistent trends in metabolic-related laboratory values were not observed.Trial registration: This study is registered at (NCT 00518323).
    BMC Psychiatry 02/2014; 14(1):52. DOI:10.1186/1471-244X-14-52 · 2.21 Impact Factor
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    • "Among the 13 large sample retrospective studies based on prescription or safety monitoring databases, eight compared the risk of developing DM directly or indirectly between AAP and conventional antipsychotics as groups. Seven of these reports (Sernyak et al., 2002; Koro et al., 2002; Gianfrancesco et al., 2002; Kornegay et al., 2002; Hedenmalm et al., 2002; Buse et al., 2003 and Fuller et al., 2003) suggested that certain atypical agents or atypicals as a group had a significantly increased risk of new-onset DM (or increased odds ratio for the casecontrol studies) compared to conventional antipsychotics. In evaluating the risk for newonset DM among individual atypical agents, 8 of these 13 studies compared the risk among individual atypical agents or relative to conventional agents or non-users of antipsychotics. "
    Topics in the Prevention, Treatment and Complications of Type 2 Diabetes, 11/2011; , ISBN: 978-953-307-590-7
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    • "One possible explanation for the unchanged values of FBS in our study is the exclusion of underlying diabetic condition from the study. One study reviewed reports available in WHO database and recognized male gender, an underlying diabetic condition, increase in weight and concomitant use of valproic acid, SSRIs or buspirone as the potential risk factors for developing glucose intolerance for clozapine, olanzapine and risperidone when grouped together (compared with typical antipsychotics) (26). "
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    ABSTRACT: Metabolic side effects of the second generation (atypical) antipsychotics have been a forefront of attention since their availability. One common concern is the development of hyperglycemia and insulin resistance. The aim of this study was to evaluate the effect of early initiation of omega-3 fatty acids supplementation on glucose-insulin homeostasis in a group of psychiatric patients under treatment with olanzapine and sodium valproate or lithium combination. In a double-blind design, eligible participants with schizophrenia, bipolar I, and schizoaffective disorders who were initiated on olanzapine combination with sodium valproate or lithium were randomly assigned to receive omega-3 or identical placebo capsules for 6 weeks. Fasting blood sugar (FBS), insulin and HbA(1c) were measured at the baseline and at the end of the 6(th) week. Homeostatic model assessment of insulin resistance (HOMA-IR), as a measure of insulin resistance, was also determined at the same times. At the end of the study, no significant difference was observed between the two arms in terms of FBS, fasting insulin, HbA(1c) and HOMA-IR. However, trends toward decreasing both fasting insulin levels (p=0.06) and HOMA-IR (p=0.07) were noted in the group receiving omega-3. No significant changes in the outcome variables were observed from the baseline to the final measurements in both groups. This study noted that adding omega-3 fatty acids at the commencement of olanzapine combination therapy with valproate or lithium could not favorably influence glucose-insulin homeostasis. However, trends toward a decrease in insulin levels (p=0.06) and HOMA-IR (p=0.07) observed in patients receiving omega-3 suggest a possible beneficial role of this supplement in this population and, therefore, warrant further evaluation.
    Iranian Journal of Psychiatry 03/2010; 5(1):18-22.
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