Glucose Metabolism in Patients With Schizophrenia Treated With Atypical Antipsychotic Agents: A Frequently Sampled Intravenous Glucose Tolerance Test and Minimal Model Analysis

Harvard University, Cambridge, Massachusetts, United States
Archives of General Psychiatry (Impact Factor: 14.48). 01/2005; 62(1):19-28. DOI: 10.1001/archpsyc.62.1.19
Source: PubMed


While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.
To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.
A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.
Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis.
Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness.
The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine<olanzapine<risperidone), with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone (clozapine vs risperidone, t(33) = -4.29; P<.001; olanzapine vs risperidone, t(33) = -3.62; P = .001 [P<.001]). The homeostasis model assessment of insulin resistance also differed significantly among groups (F(33) = 4.92; P = .01) (clozapine>olanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine<olanzapine<risperidone) with significant differences between clozapine and risperidone (t(30) = -2.59; P = .02) and olanzapine and risperidone (t(30) = -2.34, P = .03).
Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects. Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences.

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Available from: Mary Weber, Sep 19, 2015
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    • "The introduction of the atypical antipsychotics (AAP) improved the compliance of patients with schizophrenia due to the reduced incidence of the extrapyramidal symptoms, but AAP treatment could be associated with increased appetite with concomitant weight gain and obesity that in turn can induce type 2 diabetes with diabetic ketoacidosis (Henderson et al. 2000; Basson et al. 2001; Newcomer 2005). Recent findings suggest that AAPs can induce insulin resistance and type 2 diabetes in the absence of obesity (Newcomer et al. 2002; Henderson et al. 2005; Teff et al. 2013). Since the diabetogenic potential of AAPs is linked partly to their muscarinic receptor blocking property (Matsui-Sakata et al. 2005) and darifenacin, a muscarinic receptor subtype 3 antagonist inhibits glucose-stimulated insulin release from pancreatic beta-cells causing immediate impairment in glucose tolerance (Hahn et al. 2011), we hypothesized that acute olanzapine administration can impede the activation of MIS mechanism similar to as could be seen in after administration of atropine. "
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    ABSTRACT: Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats. Then, under anaesthesia, the carotid artery and jugular vein was prepared and cannulated to obtain samples for blood glucose and hormone determination as well as for insulin/glucose infusion, respectively. Basal insulin sensitivity and MIS was determined by homeostasis model assessment (HOMA) calculation and by rapid insulin sensitivity test, respectively. In fasted animals, olanzapine increased blood glucose and plasma insulin and reduced basal insulin sensitivity, but it failed to modify other hormone levels. Postprandial leptin and glucose-dependent insulinotropic polypeptide (GIP) levels increased, and ghrelin level decreased significantly (p < 0.05) both in vehicle- and olanzapine-treated groups, but plasma insulin increased only in vehicle-treated animals. Furthermore, decrement in ghrelin level was attenuated in olanzapine-treated animals compared to controls. There was no significant change in the first meal size and duration or in the total amount of food consumed. Olanzapine had no effect on the MIS. We demonstrated that olanzapine can induce insulin resistance without weight gain in healthy rats. Furthermore, the MIS was preserved after acute olanzapine treatment. The blunted postprandial ghrelin and insulin response could contribute to the effect of olanzapine on feeding behaviour. Pharmacological induction of MIS may improve the olanzapine-induced insulin resistance.
    Full-text · Article · Feb 2015 · Archiv für Experimentelle Pathologie und Pharmakologie
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    • "An increasing amount of evidence suggests a possible increase in cardiovascular events in patients with schizophrenia treated with atypical antipsychotic drugs, and this is hypothesized to be secondary to lipid (Allison et al. 1999a, b, 2009; Ruetsch et al. 2005), as well as to glucose metabolism dysregulation (Henderson et al. 2005; Zhang et al. 2014). Serum paraoxonase is a HDL-associated hydrolase with a broad range of substrates (paraoxon, phenylacetate, dihydrocoumarin) and inhibits LDL oxidation. "
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    ABSTRACT: Introduction Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment. Methods The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined. Results PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46 ± 1.06 U/ml, p < 0.001; risperidone 50.57 ± 1.54 U/ml, p < 0.01; control 52.27 ± 1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group. Conclusions In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP.
    Full-text · Article · May 2014 · Psychopharmacology
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    • "Atypical antipsychotics are considered to be better tolerated than typical antipsychotic agents and are currently the mainstay of schizophrenia treatment. However, atypical antipsychotics have been associated with long-term adverse effects on patients' weight, serum glucose levels, and serum lipids [25-28]. In order to develop a patient-individualized switching strategy, decision making should be based on key patient illness characteristics, specifically on the patient's symptomatology, comorbidities, and side effects experienced with previous antipsychotics [16]. "
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    ABSTRACT: Patients under antipsychotic treatment for schizophrenia commonly exhibit poor adherence to treatment, high rates of treatment discontinuation, and frequent treatment changes. The ETOS study aimed to identify the reasons leading physicians to decide to switch antipsychotic treatment in outpatients with schizophrenia and to evaluate the outcome of this switch. ETOS was an observational 18-week (four visits) study in outpatients 18 to 65 years old, diagnosed with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders - 4th edition criteria at least 6 months prior to enrolment, who were initiated on a new antipsychotic monotherapy treatment within the 2 weeks prior to enrollment. A total of 574 patients were recruited by 87 hospital- and office-based physicians. Ethical approval was obtained prior to study initiation (NCT00999895). The final analysis included 568 patients, 39.0 +/- 11.2 years old with mean disease duration of 11.7 years. The male-to-female ratio was 53:47. The main reason for switching antipsychotic treatment was lack of tolerability (n = 369, 65.0%), followed by lack of efficacy (n = 249, 43.8%). Following treatment switch, 87.9% of patients (n = 499) showed meaningful clinical benefit by achieving a Clinical Global Impression-Clinical Benefit score of <=4 at the final visit. By the end of the study, total Positive and Negative Syndrome Scale, Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Simpson-Angus Scale scores demonstrated significant mean decreases of 31.69, 0.70, 1.14, and 11.30, respectively (all p < 0.0001). Treatment adherence remarkably improved. In the ETOS study, switch of antipsychotic monotherapy for reasons relating to lack of efficacy and/or tolerability was associated with significantly improved clinical benefit and significant increase of patients' adherence to treatment.
    Full-text · Article · Dec 2013 · Annals of General Psychiatry
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