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

Schizophrenia Program, Massachusetts General Hospital, Boston, MA, USA.
Archives of General Psychiatry (Impact Factor: 13.75). 01/2005; 62(1):19-28. DOI: 10.1001/archpsyc.62.1.19
Source: PubMed

ABSTRACT 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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    • "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.
    Psychopharmacology 05/2014; 231(24). DOI:10.1007/s00213-014-3624-0 · 3.99 Impact Factor
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    • "These findings are also supported by clinical reports, in which patients were matched for adiposity or for body mass index. Results from these studies demonstrated antipsychotic-induced impairment of glucose regulation independent of adiposity (Newcomer et al. 2002) and insulin resistance in non-obese patients who were treated with clozapine or olanzapine (Henderson et al. 2005). Taken together, these clinical and pre-clinical data strongly suggest that antipsychotic-induced insulin resistance is not dependent on weight gain. "
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    ABSTRACT: Schizophrenia doubles the odds of diabetes, and atypical antipsychotics (AAPs) also increase risk of diabetes. Indeed, little is known about the effects of AAPs on vascular dysfunctions associated with diabetes. This study aimed to determine the effects of risperidone (RISP) and paliperidone (PALI) on the vascular function of diabetic rats. Diabetes was induced by feeding with a high-fat diet followed by the administration of streptozotocin (35 mg·(kg body mass)(-1), by intraperitoneal injection). Rats received RISP or PALI (1.25 mg·kg(-1)·d(-1), per os) for 3 weeks. Endothelium-dependent relaxation, systolic blood pressure, lipid profile, insulin resistance, and adhesion molecules, vascular cell-adhesion-molecule-1 (VCAM-1), intracellular-adhesion-molecule-1 (ICAM-1), and E-selectin were investigated. RISP significantly worsened the impaired endothelium-dependent relaxation of diabetic aortic rings with upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin, and proinflammatory cytokines MPC-1 and TNF-α. RISP augmented the metabolic dysfunctions and reduced insulin sensitivity in the insulin tolerance test as well as HOMA-IR. PALI produced insignificant effects on vascular and metabolic aberrations. Our results suggest that RISP, but not PALI, aggravates the metabolic abnormalities and vascular dysfunction associated with diabetes, which may be mediated by upregulation of VCAM-1, ICAM-1, and E-selectin. Nevertheless, future investigation for the possible mechanisms underlying the difference noticed between the 2 AAPs is warranted.
    Canadian Journal of Physiology and Pharmacology 12/2013; 91(12):1119-26. DOI:10.1139/cjpp-2013-0185 · 1.55 Impact Factor
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    • "As in the general population, obesity may have an unfavorable impact on glucose homeostasis in patients using antipsychotics . However, several studies have shown elevated serum insulin levels following atypical antipsychotic medication independent of body mass index (BMI) (Melkersson et al. 2000; Arranz et al. 2004; Henderson et al. 2005). This finding suggests that antipsychotics may directly affect glucose homeostasis by mechanisms other than by weight gain alone. "
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    ABSTRACT: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c). We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor. A significant association of interaction between haplotype rs346074-rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants. This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics.
    Psychopharmacology 02/2011; 216(2):257-65. DOI:10.1007/s00213-011-2211-x · 3.99 Impact Factor
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