Phenothiazines and Diabetes in Hospitalized Women

Thonnard-Neumann, Ernst

doi:10.1176/ajp.124.7.978

Cited by 135 publications

(66 citation statements)

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“…The presence of a high-affinity antimuscarinic agent could block the parasympathetic pathway, resulting in a shift toward increased hepatic glucose output, mimicking the effects of parasympathetic neuropathy, which has been suggested to contribute to increased hepatic glucose production (40) and insulin resistance in obese type 2 diabetic subjects (41). In addition, it should be noted that the increased diabetes risk is not limited to the newer SGAs with antimuscarinic properties, since chlorpromazine, the first-generation antipsychotic introduced in the 1950s, also has affinity for muscarinic receptors (42), and has been associated with the development of diabetes in schizophrenic patients (43)(44)(45). Chlorpromazine is a moderately potent antagonist at human and rat muscarinic M 3 receptors (results not shown), and further studies are needed to characterize its effects on insulin release.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion From Perifused Rat Islets

et al. 2005

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Treatment with the atypical antipsychotics olanzapine and clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia, ketoacidosis, and diabetes, in some cases independent of weight gain. Because these events may be a consequence of their ability to directly alter insulin secretion from pancreatic ␤-cells, we determined the effects of several antipsychotics on cholinergic-and glucose-stimulated insulin secretion from isolated rat islets. At concentrations encompassing therapeutically relevant levels, olanzapine and clozapine reduced insulin secretion stimulated by 10 mol/l carbachol plus 7 mmol/l glucose. This inhibition of insulin secretion was paralleled by significant reductions in carbachol-potentiated inositol phosphate accumulation. In contrast, risperidone or ziprasidone had no adverse effect on cholinergic-induced insulin secretion or inositol phosphate accumulation. None of the compounds tested impaired the islet secretory responses to 8 mmol/l glucose alone. Finally, in vitro binding and functional data show that olanzapine and clozapine (unlike risperidone, ziprasidone, and haloperidol) are potent muscarinic M 3 antagonists. These findings demonstrate that low concentrations of olanzapine and clozapine can markedly and selectively impair cholinergicstimulated insulin secretion by blocking muscarinic M 3 receptors, which could be one of the contributing factors to their higher risk for producing hyperglycemia and diabetes in humans. Diabetes 54:1552-1558, 2005 R ecent reviews of clinical databases have revealed that olanzapine and clozapine carry a higher risk for producing hyperglycemia, ketoacidosis, and new-onset type 2 diabetes than other second-generation antipsychotics (SGAs) or haloperidol, a first-generation antipsychotic (1-6). The use of olanzapine and clozapine is often associated with notable weight gain and dyslipidemia, which are known risk factors in the development of diabetes. However, several reports have described cases of hyperglycemia following olanzapine and clozapine treatment that were not associated with weight gain (7,8). Furthermore, cases exist where switching to other SGAs, such as ziprasidone or risperidone, resulted in the reversal of olanzapine-or clozapine-associated hyperglycemia, suggesting that fundamental differences exist among the SGAs (9 -11).The mechanisms responsible for the increased diabetes risk of olanzapine and clozapine are not known, but in contrast to other SGAs, both compounds are potent muscarinic receptor antagonists (12). This led us to consider the possibility that disruption of the cholinergic processes regulating insulin secretion is one of the underlying mechanisms for impaired glucose regulation. Therefore, we investigated the effects of several antipsychotics on cholinergic-stimulated insulin secretion and the activation of phospholipase C using isolated rat pancreatic islets. Since the cholinergic activation of insulin release is mediated through muscarinic M 3 receptors on ␤-cells ...

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion From Perifused Rat Islets

et al. 2005

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“…An association between antipsychotic medication use and metabolic dysregulation has also been suspected for many years, based on a series of published case reports describing increased rates of diabetes (Charatan and Bartlett, 1995;Hiles, 1956;Dynes, 1969) in patients taking chlorpromazine, and on inpatient studies showing that the rate of diabetes in female psychiatric inpatients rose from roughly 4% to 17% between 1956and 1968, as antipsychotic use increased (Thonnard-Neumann, 1968. In the last decade it has become very clear that many secondgeneration antipsychotic (SGA) medications also have the propensity to cause significant weight gain in very short amounts of time and to adversely affect glucose metabolism.…”

Section: Introductionmentioning

confidence: 99%

Early treatment-related changes in diabetes and cardiovascular disease risk markers in first episode psychosis subjects

Graham

Cho

Brownley

et al. 2008

Schizophrenia Research

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Objective-To examine prospective changes in cardiovascular disease (CVD) and type-2 diabetes risk factors in young adult first episode psychotic (FEP) patients treated with second generation antipsychotic medications.Methods-At baseline, fasting serum and anthropometric measures were obtained from 45 FEP patients and 41 healthy adults (controls) of similar age, ethnicity and sex; sixteen of the FEP patients remained on the same antipsychotic medication and were available for a second blood draw at 24 weeks of treatment. Serum was assayed for glucose, insulin, triglycerides, total cholesterol and high and low density lipoproteins (HDL, LDL), adiponectin, leptin, interleukin 6, E-selectin and VCAM-1. Wilcoxon nonparametric tests were used to compare risk markers between the FEP and control group at baseline and to evaluate pre-post treatment changes within the FEP group.Results-At baseline, the distributions of risk marker values were similar between the two groups and the percentages of FEP patients and healthy controls who were overweight/obese, dyslipidemic, hyperglycemic, and hyperinsulinemic did not differ. At 24 weeks, compared to baseline, FEP patients showed significant increases in BMI (p=0.0002), glucose (p=0.0449), insulin (p=0.0161), cholesterol (p=0.0129), leptin (p=0.0215), and E-selectin (p=0.0195), and a decrease in adiponectin (p=0.0371).Conclusions-Among patients with first episode psychosis, 6-month treatment with second generation antipsychotics is associated with the exacerbation of pre-existing and emergence of new CVD and diabetes risk factors.

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“…Unfortunately, many studies have associated the treatment of patients with antipsychotic medication with the development of impaired glucose tolerance, insulin resistance, and type 2 diabetes (2)(3)(4), but the mechanism underlying this association is not known. However, before the advent of antipsychotic medication in the 1960s, studies indicated that patients with schizophrenia had higher rates of diabetes than the normal population (5). This suggests that environmental or genetic factors may also be important in the development of insulin resistance in psychiatric patients.…”

mentioning

confidence: 99%

Insulin Resistance Is Associated With Hypercortisolemia in Polynesian Patients Treated With Antipsychotic Medication

Poa¹,

Edgar²

2007

Diabetes Care

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OBJECTIVE -Type 2 diabetes is more prevalent in the indigenous Polynesian population of New Zealand (Maori) than in Europeans. The aim of this study was to determine whether insulin resistance in Maori psychiatric patients was associated with antipsychotic treatment and to investigate the mechanism of an association.RESEARCH DESIGN AND METHODS -Thirty adult Maori psychiatric patients receiving antipsychotic medication for Ͼ6 months and 30 healthy, age-, sex-, and BMI-matched control subjects were enrolled. Early morning fasting blood samples were analyzed for plasma levels of glucose, insulin, A1C, triglycerides, total cholesterol, IGF-1, cortisol, cortisol-binding globulin (CBG), and adiponectin.RESULTS -The patient group had significantly higher median fasting insulin plasma levels than the control group (P ϭ 0.002), which were independent of BMI, age, and sex. In addition, the patient group had significantly higher total cortisol (P ϭ 0.03) and lower CBG levels (P ϭ 0.004) than the control group, resulting in significantly higher levels of free cortisol (P ϭ 0.004). The patient group was also significantly more hypoglycemic (P ϭ 0.026) and hypertriglyceridemic (P ϭ 0.028) than the control group. There was no significant difference in BMI, waist circumference, A1C, total cholesterol, IGF-1, or adiponectin levels between the two groups.CONCLUSIONS -An increase in insulin resistance is seen in Maori psychiatric patients treated with antipsychotic medication. Therefore, Polynesian ethnicity should be considered in prescribing practice and general care of this group. In addition, the hypothalamic-pituitaryadrenal axis may have an important role in the mechanism by which this insulin resistance develops.

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Phenothiazines and Diabetes in Hospitalized Women

Cited by 135 publications

References 3 publications

Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion From Perifused Rat Islets

Inhibitory Effects of Antipsychotics on Carbachol-Enhanced Insulin Secretion From Perifused Rat Islets

Early treatment-related changes in diabetes and cardiovascular disease risk markers in first episode psychosis subjects

Insulin Resistance Is Associated With Hypercortisolemia in Polynesian Patients Treated With Antipsychotic Medication

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