clozapine and Hyperglycemia

Topics: Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyskinesias; Haloperidol; Humans; Hyperglycemia; Hyperprolactinemia; Olanzapine; Pirenzepine; Quetiapine Fumarate; Risperidone; Thioridazine; Weight Gain

Diabetes or hyperglycemia associated with the use of atypical anti-psychotic agents is a subject of growing concern among health care providers and the patients who use the drugs. Although much attention has been relegated to this topic in the mental health literature, there has been little attention devoted to it in the diabetes literature. The purpose of this report is to review the problem of diabetes mellitus associated with atypical anti-psychotic use from an endocrinology perspective. This paper will specifically present (a) a review of the increased prevalence of diabetes in the setting of schizophrenia, (b) a compilation and critical assessment of the existing publications that have documented the association of hyperglycemia and atypical anti-psychotic use, (c) a discussion of the potential mechanisms through which antipsychotics may lead to disturbances in glucose homeostasis, and (d) recommendations for the effective monitoring and treatment of affected patients.

Topics: Adult; Aged; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus; Humans; Hyperglycemia; Middle Aged; Odds Ratio; Olanzapine; Risperidone

Hyperglycaemia is known occasionally to occur with conventional neuroleptics, but has more recently been associated with atypical antipsychotics especially clozapine and olanzapine. This article examines more closely this association. A review of relevant published literature from 1970 to date was undertaken following Medline and Embase searches in June 2000. Hyperglycaemia with clozapine was widely reported: spontaneous reports of either hyperglycaemia or ketoacidosis were described in a total of 17 people. In a five-year naturalistic study, 30.5% of patients taking clozapine were eventually diagnosed with Type 2 diabetes. With olanzapine, a total of 10 cases of hyperglycaemia and 5 cases of ketoacidosis have been published. Reports of hyperglycaemia with other atypicals are relatively scarce. The association of hyperglycaemia or ketoacidosis with clozapine and olanzapine appears to be a true drug-induced effect. Risk factors may include male gender, age of around 40 years and being non-Caucasian. The management of hyperglycaemia depends on the causative agent. With clozapine, treatment with oral hypoglycaemics has been successful. With olanzapine, other atypical antipsychotics may be considered. Blood glucose monitoring is essential for all patients starting clozapine or olanzapine.

Topics: Adult; Age Factors; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Racial Groups; Sex Factors

The available literature suggests that patients with schizophrenia are at risk for diabetes mellitus and taking antipsychotic medication further increases the chance of developing non-insulin-dependent hyperglycemia. Case reports, chart reviews, and some results from clinical drug trials implicate a relationship between glucose levels and treatment with clozapine or olanzapine in patients with schizophrenia, although a few cases of hyperglycemia have also been reported in patients taking risperidone and quetiapine. These studies indicate that hyperglycemia is not dose dependent, is reversible on cessation of treatment with clozapine or olanzapine, and reappears on reintroduction of these therapies. The postulated underlying mechanisms involved in this process in patients with schizophrenia include (1) a decreased sensitivity to insulin that is independent of atypical medication, (2) an increased insulin resistance related to atypical medications, (3) the effects of atypical medications on serotonin receptors, and (4) overuse of insulin due to weight gain. These mechanisms are discussed in detail, and recommendations for the administration of atypical antipsychotics are offered. Overweight, ethnicity, family or personal history of diabetes mellitus or hypertension, and weight gain during the course of treatment have all been identified as risk factors in the development of hyperglycemia in patients with schizophrenia. However, it is difficult to statistically assess the true incidence of diabetes within each type of antipsychotic medication group with the exclusive dependence on available case studies and without proper epidemiologic research.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Comorbidity; Diabetes Mellitus; Female; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prevalence; Risk Factors; Schizophrenia; United States

This study was undertaken to examine if patients exhibit more pronounced metabolic abnormalities after 8-year treatment with clozapine or olanzapine than before, and also to investigate whether there exist any differences between long-term clozapine and olanzapine therapies regarding metabolic side- effects.. Fifty psychiatric outpatients diagnosed with schizophrenia or schizoaffective disorder and on treatment with clozapine or olanzapine were studied during 8 years. Fasting blood or serum samples for glucose, lipids, prolactin and antipsychotic drug concentrations were analyzed. In addition, body mass index was calculated.. More patients treated with olanzapine compared with those treated with clozapine ended with their medication, in most cases because of diabetes mellitus and/or hyperlipidemia, during the 8-year follow-up. Also more patients treated with olanzapine compared with those treated with clozapine developed manifest diabetes mellitus during the 8-year period. Prolactin levels were higher in the patients treated with olanzapine compared with in those treated with clozapine at study start, but there were no differences in the other parameters between the treatment groups at study start. In the patients remaining on their medication all 8 years, the glucose level increased over time in the clozapine group, but not in the olanzapine group, whereas body mass index and lipids were unchanged over time in both treatment groups.. Our findings point to that both olanzapine and clozapine long-term treatments cause development of hyperglycemia and/or hyperlipidemia. Furthermore, olanzapine long-term treatment seems to more often lead to development of manifest diabetes mellitus than long-term treatment with clozapine.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Hyperlipidemias; Male; Metabolic Diseases; Middle Aged; Olanzapine; Psychotic Disorders; Schizophrenia

This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffective disorder.. This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance.. Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, or depressive symptoms. QTc significantly increased at week 2 but not at week 6.. The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Chronic Disease; Clozapine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Middle Aged; Morbidity; Olanzapine; Piperazines; Schizophrenia; Thiazoles; Time Factors

Adjunctive fluvoxamine inhibits clozapine metabolism and decreases plasma norclozapine (a toxic metabolite of clozapine) to clozapine ratios. This study aimed to demonstrate the effects of fluvoxamine on clozapine-related weight gain, hyperglycemia, and lipid abnormalities.. Sixty-eight treatment-resistant inpatients with a DSM-IV diagnosis of schizophrenia were randomly assigned to 2 treatment groups for 12 weeks. The monotherapy group (N = 34) received clozapine (< or = 600 mg/day). The coadministration group (N = 34) received fluvoxamine (50 mg/day) plus low-dose clozapine (< or = 250 mg/day). The study was conducted from August 1999 to October 2002.. The 2 groups were similar in demographic data; baseline body weight and body mass index (BMI); baseline serum glucose, triglyceride, and cholesterol levels; and steady-state plasma clozapine concentration. The monotherapy patients (but not the coadministration patients) had significantly higher (p < .05) body weight, BMI, and serum glucose and triglyceride levels after treatment than at baseline. At week 12, the monotherapy patients also had significantly higher glucose (p = .035), triglyceride (p = .041), and norclozapine (p = .009) (and numerically higher cholesterol) levels than the cotreatment patients. The changes in weight and serum glucose and triglyceride levels were significantly correlated (p = .026, p = .005, and p = .028, respectively) with the plasma concentration of norclozapine but not with plasma levels of clozapine.. These results suggest that fluvoxamine cotreatment can attenuate weight gain and metabolic disturbances in clozapine-treated patients. Plasma levels of norclozapine, but not clozapine, are associated with increases in weight and serum glucose and triglyceride levels. Of note, coadministration of fluvoxamine could increase plasma clozapine levels markedly and carry the risk of adverse events. If this combined treatment is applied, conservative introduction with reduced clozapine dosage and careful therapeutic drug monitoring of clozapine concentration is recommended.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Cholesterol; Clozapine; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Fluvoxamine; Humans; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Selective Serotonin Reuptake Inhibitors; Triglycerides; Weight Gain

The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial.. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period.. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22).. In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Haloperidol; Hospitalization; Humans; Hypercholesterolemia; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Prospective Studies; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Antipsychotics are widely used to manage mental illnesses. They have, however, been reported to cause various adverse events. Two studies were conducted to resolve clinical questions related to adverse events caused by antipsychotic medications in clinical practice. The first adverse event studied was clozapine-induced sialorrhea (CIS), a common adverse event. There is no established standard treatment for CIS because the underlying mechanism remains unclear. Therefore, this study aimed to identify the cause of CIS. Results of clinical and basic studies suggest that N-desmethylclozapine (NDMC), the active metabolite of clozapine, is the causative agent of CIS. Furthermore, the action of NDMC on salivary gland cells via muscarinic receptors is one of the proposed mechanisms of CIS. The second adverse event was hyperglycemia. Antipsychotics increase the incidence of hyperglycemia. However, the incidence of antipsychotic-induced hyperglycemia is difficult to predict because many factors are involved. This study aimed to examine the effect of antipsychotic treatment-associated factors on hyperglycemic progression after adjustment for the effect of background factors suggested to be associated with hyperglycemic progression. A national multicenter prospective observational study of 631 newly initiated patients showed that initiation of clozapine and zotepine treatment significantly increased the incidence of hyperglycemia. In addition, obesity has been shown to significantly increase the incidence of antipsychotic-induced hyperglycemia. Because these studies were conducted to resolve questions that arose in actual clinical practice, the study results obtained are considered to have clinical applicability.

Topics: Antipsychotic Agents; Clozapine; Humans; Hyperglycemia; Mental Disorders

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiepins; Female; Haloperidol; Humans; Hyperglycemia; Incidence; Japan; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia

Clozapine is an atypical antipsychotic used in refractory schizophrenia, also efficient in alleviating dyskinesia in Parkinson's disease. Despite its potency, this drug is associated with severe metabolic side effects, including increased risk for diabetes. We report the case of a 45-year-old overweight woman with Parkinson's disease who presented with rapid-onset hyperglycaemia within 2 months after starting clozapine for refractory dyskinaesia. She had a history of gestational diabetes. At presentation, her blood glucose level was 505 mg/dL and glycated haemoglobin 12.4%, with no catabolic symptoms. Clozapine was suspended and metformin was started, but adequate glycaemic control was achieved only with insulin therapy, along with exenatide and empagliflozin afterwards. We assume that clozapine acted as a trigger for rapid deterioration of glycaemic control through direct pathophysiological mechanisms, rather than an indirect slowly evolving weight gain-related metabolic syndrome pathway. Clinicians should be aware of this complication, enabling timely diagnosis and proper treatment.

Topics: Antipsychotic Agents; Blood Glucose; Clozapine; Female; Humans; Hyperglycemia; Middle Aged; Schizophrenia

Clozapine, an antipsychotic developed in 1958, is considered the gold standard and the treatment of choice in treatment-resistant schizophrenia despite its side effects and despite 40-70% of these patients not responding to clozapine. In the last decade, new antipsychotics, such as paliperidone palmitate (PP), have emerged as well as its long acting-injectable (LAI) formulations, available as PP-1-monthly (PP1M) and the newest PP-3-montlhy (PP3M). Despite paliperidone having shown a similar efficacy as others antipsychotics for the treatment of schizophrenia, and that PP3M has been shown to reduce relapses compared to oral formulations, no study has been carried out in treatment-resistant schizophrenia. The aim of our study was to carry out an exploratory evaluation of endocrine and hepatic profiles as well as the concomitant treatments associated to PP3M vs. clozapine, the gold standard, in patients with treatment-resistant schizophrenia. We designed a retrospective study. A total number of 33 patients previously diagnosed as schizophrenics treatment-resistant, who were prescribed clozapine followed by PP1M and PP3M when available, were selected. Demographic data, BMI, hepatic enzymes (glutamic oxaloacetic transaminase, glutamate-pyruvate transaminase and gamma-glutamyl transferase (GGT)], thyroid function (thyroid stimulating hormone), blood platelets and both white and red blood cells as well as the use of concomitant antipsychotics, benzodiazepines and biperiden were compared under treatment with clozapine and PP3M. Antipsychotics and benzodiazepines dosages were compared using by the defined daily dose (DDD) method and haloperidol or diazepam dose equivalents. All statistical analyses were performed using the paired Student t-test for repeated measures. Our data showed that patients under treatment with PP3M showed a significant decrease in BMI (P < 0.01), glucose (P < 0.01), cholesterol (P < 0.05) and triglycerides (P < 0.01) when compared with basal values under treatment with clozapine. Hepatic cholestasis enzyme, GGT, were significantly elevated (P < 0.05) under treatment with clozapine when compared to PP3M. Switching clozapine to PP3M led to a significant lower pharmacological exposure to antipsychotics, by both the DDD (P < 0.05) and haloperidol dose equivalents (P < 0.001) methods without increasing the dose of benzodiazepines while biperiden was more used under PP3M. Finally, antipsychotic monotherapy was higher and less polypharmacy was use

Topics: Antipsychotic Agents; Clozapine; Drug Administration Schedule; Drug Resistance; Drug Substitution; Dyslipidemias; Female; Humans; Hyperglycemia; Male; Middle Aged; Obesity; Paliperidone Palmitate; Retrospective Studies; Schizophrenia; Spain

Clozapine is an antipsychotic known for its superior efficacy in treating drug-resistant Schizophrenia. However, Clozapine induces various side effects such as hyperglycemia, agranulocytosis, weight gain etc. The mechanisms of these Clozapine-induced side effects have remained largely elusive though an important role is ascribed to 5-HT

Topics: Animals; Antipsychotic Agents; Clozapine; Hyperglycemia; Male; Mice, Knockout; Receptor, Serotonin, 5-HT2A

Catecholamine (CA) neurons in the ventrolateral medulla (VLM) contribute importantly to glucoregulation during glucose deficit. However, it is not known which CA neurons elicit different glucoregulatory responses or whether selective activation of CA neurons is sufficient to elicit these responses. Therefore, to selectively activate CA subpopulations, we injected male or female Th-Cre+ transgenic rats with the Cre-dependent DREADD construct, AAV2-DIO-hSyn-hM3D(Gq)-mCherry, at one of four rostrocaudal levels of the VLM: rostral C1 (C1r), middle C1 (C1m), the area of A1 and C1 overlap (A1/C1), and A1. Transfection was highly selective for CA neurons at each site. Systemic injection of the Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor agonist, clozapine-N-oxide (CNO), stimulated feeding in rats transfected at C1r, C1m, or A1/C1 but not A1. CNO increased corticosterone secretion in rats transfected at C1m or A1/C1 but not A1. In contrast, CNO did not increase blood glucose or induce c-Fos expression in the spinal cord or adrenal medulla after transfection of any single VLM site but required dual transfection of both C1m and C1r, possibly indicating that CA neurons mediating blood glucose responses are more sparsely distributed in C1r and C1m than those mediating feeding and corticosterone secretion. These results show that selective activation of C1 CA neurons is sufficient to increase feeding, blood glucose levels, and corticosterone secretion and suggest that each of these responses is mediated by CA neurons concentrated at different levels of the C1 cell group.

Topics: Activation, Metabolic; Adrenal Medulla; Animals; Antipsychotic Agents; Behavior, Animal; Catecholamines; Clozapine; Feeding Behavior; Female; Humans; Hyperglycemia; Luminescent Proteins; Male; Medulla Oblongata; Nerve Tissue Proteins; Neurons; Organ Specificity; Pharmacogenomic Variants; Rats, Transgenic; Receptors, Drug; Recombinant Fusion Proteins; Red Fluorescent Protein; Spinal Cord Lateral Horn

Clozapine, an atypical antipsychotic agent, has been reported to cause acute hyperglycemia. However, the mechanism of clozapine-induced rapidly developing hyperglycemia is not well elucidated. To clarify the mechanism underlying clozapine-induced acute hyperglycemia, we investigated the effects of single intravenous administration of clozapine on the serum concentrations of glucose and several endogenous substances in rats. Male Wistar rats received an intravenous injection of saline (control) or clozapine 2.5, 5, 10 mg/kg. Blood samples were obtained periodically after clozapine administration to determine the serum concentrations of glucose, adrenaline, glucagon, insulin, corticosterone, and clozapine. The serum concentrations of glucose, adrenaline, and glucagon increased dose-dependently after the administration of clozapine at 2.5-10 mg/kg, and reached maxima at 5 mg/kg of clozapine. The serum concentration of corticosterone increased after the administration of clozapine, but no significant variation was observed with the dosage of clozapine. The concentration of serum insulin increased in a dose-dependent manner after clozapine administration. In conclusion, a single administration of clozapine increased the serum concentration of glucose in rats, and adrenaline and/or glucagon would be associated with clozapine-induced acute hyperglycemia.

Topics: Animals; Antipsychotic Agents; Blood Glucose; Clozapine; Corticosterone; Epinephrine; Glucagon; Hyperglycemia; Insulin; Male; Rats, Wistar

Hundreds of hormones and ligands stimulate cyclic AMP (cAMP) signaling in different tissues through the activation of G-protein-coupled receptors (GPCRs). Although the functions and individual effectors of cAMP signaling are well characterized in many tissues, pleiotropic effects of GPCR agonists limit investigations of physiological functions of cAMP signaling in individual cell types at different developmental stages

Topics: Animals; Blood Glucose; Cells, Cultured; Clozapine; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Glucose; Green Fluorescent Proteins; Hepatocytes; Hyperglycemia; Integrases; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, G-Protein-Coupled; RNA, Untranslated; Signal Transduction

Chronic treatment with the atypical antipsychotics clozapine has been associated with an increased risk for deterioration of glucose homeostasis, leading to hyperglycemia and insulin resistance diabetes. The present study mainly aimed to investigate possible mechanisms underlying clozapine-induced hyperglycemia. Male Wistar albino rats were randomly divided into two groups (each consists of 12 rats). The first group received clozapine orally at a dose of 10mg/kg body weight daily for 6 weeks, while the other group received the drug vehicle only and served as the control group. At the end of the six weeks, hyperglycemia, hyperinsulinemia and insulin resistance, as indicated by Homeostatic model assessment of insulin resistance (HOMA-IR), were observed in the clozapine group as compared with the control group. This disturbance in glucose regulation was associated with non-significant changes in body weight, serum cortisol level, and hepatic glycogen content. The Clozapine group showed a significant increase in hepatic phosphorylase activity and in the gene expression level of hepatic glucose-6-phosphatse (G6Pase) enzymes compared to the control group. It can be concluded that clozapine-induced hyperglycemia and insulin resistance occur in a manner mostly independent of weight gain, and may be attributed to an increase in hepatic phosphorylase activity and increased expression level of G6Pase.

Topics: Animals; Antipsychotic Agents; Body Weight; Clozapine; Hyperglycemia; Insulin Resistance; Male; Rats; Rats, Wistar

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP1A2; Female; Genotype; Humans; Hyperglycemia; Pancreatitis; Schizophrenia, Paranoid

Although it is generally accepted that atypical antipsychotics differ in their risk for diabetic side effects, the underlying pharmacological mechanisms are unknown. Studies on the mechanisms of antipsychotic-induced hyperglycemia or insulin resistance are often confounded by the concomitant weight gain and dyslipidemia, known diabetic risk factors. To investigate whether antipsychotics can acutely cause metabolic effects before any change in body composition, we studied the effects of four atypical antipsychotics on whole-body insulin resistance. Using the hyperinsulinemic, euglycemic clamp technique in conscious rats, insulin and somatostatin were infused at a constant rate to provide constant hyperinsulinemia and to suppress pancreatic insulin secretion. Glucose was infused at a variable rate, adjusted to maintain euglycemia. At steady state, animals were administered vehicle (V) or antipsychotic and the glucose infusion rate was monitored as an index of insulin sensitivity. Clamp experiments using radiotracers and studies on glucose uptake into isolated skeletal muscle were conducted to differentiate between effects on hepatic glucose production (HGP) and on peripheral glucose uptake. Olanzapine (OLAN) and clozapine (CLOZ) acutely impaired whole-body insulin sensitivity in a dose-dependent manner (P<0.001 vs V), whereas ziprasidone and risperidone had no effect. CLOZ also induced profound insulin resistance after dosing 10 mg/kg/day for 5 days (P<0.05 vs V). Tracer studies indicated that acute changes mainly reflect increased HGP, consistent with the lack of effect on glucose uptake. OLAN and CLOZ can thus rapidly induce marked insulin resistance, which could contribute to the hyperglycemia and ketoacidosis reported for patients receiving those therapies.

Topics: Acute Disease; Animals; Antipsychotic Agents; Benzodiazepines; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Energy Metabolism; Glucose; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Metabolic Syndrome; Muscle, Skeletal; Olanzapine; Rats; Rats, Wistar; Somatostatin

Atypical antipsychotics have been related with hyperglycaemia, diabetes mellitus, weight gain and lipid alterations in some patients. This study analyzed whether continuous treatment with risperidone, olanzapine, or clozapine entails a risk of glucose or lipid metabolism alterations in schizophrenic patients.. Patients included in this study were schizophrenics who had received mono-therapeutic with clozapine, olanzapine or risperidone for a period of 1 to 3 years. Those schizophrenic patients who were diagnosed as diabetic during psychiatric treatment and those who showed fasting glycemia greater than or equal to 126 mg/dl in two consecutive measurements were considered cases. The remaining schizophrenic patients who were receiving treatment and did not show these alterations were considered controls.. In the adjusted analysis (multivariate logistic regression) of the effect of antipsychotic treatment on the presence of diabetes, which also assessed age and body-mass index, the adjusted odds ratio (OR) for olanzapine relative to risperidone was 2.22 (95% confidence interval [CI], 1.12-4.22), (p = 0.0228); and that for clozapine relative to risperidone was 2.87 (95% CI, 1.19, 6.93), (p = 0.0192). Both results reveal a significantly greater risk for the appearance of diabetes mellitus in patients treated with olanzapine or clozapine than in those treated with risperidone. There were significant differences in the risk of increase in triglycerides in patients receiving olanzapine (OR = 1.34; p = 0.0075) and clozapine (OR = 1.58; p = 0.0028).. The risk of the appearance of diabetes mellitus in patients treated with olanzapine is twice as high as that in patients treated with risperidone, and the risk in patients treated with clozapine is nearly triple as high as that found in patients treated with risperidone. Risperidone appears to be a safer antipsychotic drug in the long term, with regard to the risk of alterations in glucose and lipid metabolism.

Topics: Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Clozapine; Diabetes Mellitus; Female; Humans; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Olanzapine; Risk Factors; Risperidone; Schizophrenia

This retrospective study compared the prevalence of diabetes mellitus/hyperglycemia between patients receiving treatment with clozapine (n = 24) and patients receiving treatment with depot (n = 27) neuroleptics in a Department of Veterans Affairs outpatient mental health clinic in the Mid-Atlantic region. Of the clozapine cases without a history of diabetes/hyperglycemia, 27.7% developed diabetes after initiation of clozapine. There were no new cases of diabetes/hyperglycemia in the depot group after initiation of depot neuroleptic. All patients receiving neuroleptic treatment should be monitored for changes in weight, lipid, and glucose levels so that appropriate preventive and therapeutic measures can be promptly initiated.

Topics: Adult; Antipsychotic Agents; Body Weight; Clozapine; Delayed-Action Preparations; Diabetes Mellitus; Drug Monitoring; Female; Health Services Needs and Demand; Humans; Hyperglycemia; Male; Mass Screening; Mid-Atlantic Region; Middle Aged; Nurse's Role; Prevalence; Retrospective Studies; Risk Factors; Schizophrenia; United States; United States Department of Veterans Affairs; Veterans

Topics: Adult; Anti-Obesity Agents; Chronic Disease; Clozapine; Humans; Hyperglycemia; Lactones; Male; Obesity; Orlistat; Schizophrenia

The use of atypical antipsychotics has been associated with abnormalities of glucose metabolism in patients with schizophrenia. This study was designed to determine the proportion of undiagnosed hyperglycemia in patients receiving a broad range of atypical antipsychotics.. All outpatients treated at an urban Veterans Affairs medical center who received a prescription for clozapine, risperidone, olanzapine, quetiapine, or ziprasidone were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. Testing took place October 2000 to November 2002. Patients previously diagnosed as diabetic were excluded.. Of the 647 patients who received antipsychotic prescriptions and were not diagnosed as diabetic, 494 (76.4%) had a random glucose result, while 153 (23.6%) had an FPG result. Within the FPG group, 107 (69.9%) had a normal FPG level, while 46 (30.1%) had an abnormally elevated FPG. There were no differences between these 2 groups in terms of race/ethnicity, age, body mass index, or comorbid diagnoses. However, significantly more patients receiving clozapine were found to have occult hyperglycemia (p = .001); no significant differences in the percentage of patients with FPG levels > or = 100 mg/dL and those with FPG levels < 100 mg/dL were observed for any of the other medications.. Hyperglycemia is common in patients treated with atypical antipsychotics and thought to be euglycemic. Screening for elevated FPG is indicated for patients receiving atypical antipsychotics.

Topics: Ambulatory Care; Antipsychotic Agents; Blood Glucose; Clozapine; Comorbidity; Connecticut; Diabetes Mellitus; Drug Therapy, Combination; Female; Glucose Tolerance Test; Hospitals, Veterans; Humans; Hyperglycemia; Male; Mass Screening; Mental Disorders; Middle Aged; Sampling Studies; Schizophrenia

The introduction of new antipsychotics has resulted in the availability of drugs with improved safety and tolerability as well as proven efficacy compared to the older antipsychotics. New compounds might show new or different adverse effects that arise in the post-marketing phase when a greater number of patients are treated. One goal of the drug safety program in psychiatry AMSP ( Arzneimittelsicherheit in der Psychiatrie) is the detection and description of severe, new, or rare adverse drug reactions (ADRs). Between 1993 and 2000, 122,562 patients were monitored in 35 psychiatric institutions, 86,349 patients of which received antipsychotics. Hyperglycemia related to antipsychotics was observed in association with only two compounds so far: clozapine and olanzapine (clozapine 2 cases, olanzapine 7 cases). In 6 of 9 patients, weight gain preceded hyperglycemia. The relative frequency of these adverse drug related events was 0.013 % for clozapine and 0.075 % for olanzapine. The symptomatology included reversible hyperglycemia, worsening of existing diabetes, and new-onset diabetes. Control for glycemic dysregulation should be maintained in clinical practice with these drugs.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Outcome Assessment, Health Care; Product Surveillance, Postmarketing; Prospective Studies; Psychotic Disorders; Retrospective Studies; Risk Factors

Clozapine has been demonstrated to be superior to typical neuroleptics in reducing refractory symptoms in patients with schizophrenia, but it has also been associated with hyperglycemia and diabetes mellitus. This study was designed to investigate the proportion of undiagnosed impaired fasting glucose and diabetes mellitus in patients prescribed clozapine at 8 Department of Veterans Affairs (VA) medical centers.. All patients diagnosed by the VA in New England with ICD-9 schizophrenia from Oct. 1, 1999, to Sept. 30, 2000, who received a prescription for clozapine were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. All patients were also characterized as to whether they were diagnosed as diabetic prior to the screening FPG. Patients not previously diagnosed as diabetic were divided into 2 groups: normal FPG (< 110 mg/dL) and elevated FPG (>or= 110 mg/dL). Clinical and sociodemographic characteristics of the 2 groups were compared using chi-square and t tests.. Overall, 121 patients were not previously diagnosed as diabetic and received an FPG. Ninety-three (77%) had a normal FPG, and 28 (23%) had an elevated plasma glucose-including 17% with impaired fasting glucose and 6% with diabetes. Patients with hyperglycemia were significantly older (p =.007) and more commonly codiagnosed with bipolar disorder (p =.04).. Hyperglycemia was common in patients receiving clozapine who had not been previously diagnosed as diabetic. These patients should be considered a group at high risk to develop diabetes mellitus and deserve both close monitoring and early intervention at the first sign of the onset of either diabetes or impaired glucose tolerance.

Topics: Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Diabetes Mellitus; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Male; Middle Aged; New England; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Benzodiazepines; Cholesterol; Clozapine; Humans; Hyperglycemia; Hyperlipidemias; Olanzapine; Pirenzepine; Schizophrenia; Triglycerides

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Black People; Blood Glucose; Clozapine; Diabetic Ketoacidosis; Drug Interactions; Fatal Outcome; Humans; Hyperglycemia; Male; Risk Factors

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.

Topics: Adverse Drug Reaction Reporting Systems; Antipsychotic Agents; Bayes Theorem; Benzodiazepines; Chlorpromazine; Clozapine; Diabetes Mellitus; Glucose Intolerance; Haloperidol; Humans; Hyperglycemia; Olanzapine; Pirenzepine; Risk Factors; Risperidone; World Health Organization

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Clozapine; Humans; Hyperglycemia; Olanzapine; Pirenzepine

Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs--risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2-100 microM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC(50)'s estimated to be 35 and 20 microM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.

Topics: Animals; Antimetabolites; Antipsychotic Agents; Biological Transport; Clozapine; Deoxyglucose; Dose-Response Relationship, Drug; Glucose; Hyperglycemia; Neurons; PC12 Cells; Rats; Risperidone; Structure-Activity Relationship; Tritium

Topics: Antipsychotic Agents; Black People; Clozapine; Diabetes Mellitus, Type 2; Dyskinesia, Drug-Induced; Humans; Hyperglycemia; Netherlands Antilles; Risk Factors

1. This case report of a Chinese male schizophrenic patient describes new side effects that have not been documented previously for patients treated with clozapine. At certain doses of clozapine, the patient showed direct adverse reactions, which include a combination of hyperglycemia, hyperlipemia, and periodic paralysis. 2. In a four-year study of this patient who had no previous episodes of diabetes in his or his family history, the authors found that these symptoms disappeared upon withdrawal of clozapine and relapsed with re-treatment of the drug. This study indicates that hyperglycemia, hyperlipemia, and periodic paralysis may need to be monitored on patients treated with clozapine.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Clozapine; Humans; Hyperglycemia; Hyperlipidemias; Male; Paralysis; Schizophrenia; Triglycerides

This report describes a 48-year-old caucasian male with schizophrenia who developed hepatitis, hyperglycemia, pleural effusion, eosinophilia, hematuria and proteinuria early in clozapine treatment which resolved on drug discontinuation. The literature on similar cases is reviewed.

Topics: Antipsychotic Agents; Blood Cell Count; Chemical and Drug Induced Liver Injury; Clozapine; Eosinophilia; Hematuria; Humans; Hyperglycemia; Male; Middle Aged; Pleural Effusion; Proteinuria; Schizophrenia, Paranoid; Tomography, X-Ray Computed

The authors describe the case of a patient with treatment-resistant schizophrenia who became pregnant after switching from conventional neuroleptic medications to clozapine, an atypical antipsychotic medication that does not cause hyperprolactinemia. Gestational diabetes, possibly exacerbated by clozapine, complicated management of her pregnancy. Comprehensive community support and psychiatric rehabilitation, combined with a positive response to clozapine, contributed to satisfying the patient's goal of having a healthy baby and being able to take the baby home to live with her and her husband.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Humans; Hyperglycemia; Pregnancy; Pregnancy Complications; Schizophrenia

To describe a patient with neutropenic fever complicated by hyperglycemia, lactic acidosis, and fatal myocardial failure associated with clozapine therapy.. A 37-year-old Ashkenazic Jewish man was admitted for agranulocytosis and fever, which developed after 11 weeks of clozapine monotherapy for drug-resistant schizophrenia. Complete blood counts and a routine serum chemical analysis had been normal before the treatment was initiated, and remained within normal limits during the first 10 weeks of the treatment. On the day of admission, the patient deteriorated rapidly and developed extreme hyperglycemia, severe lactic acidosis, recurrent cardiac arrest, cardiogenic shock, and coma. He died 36 hours later despite intensive treatment.. Clozapine intake reduced fatal aganulocytosis, associated with hyperglycemia, lactic acidosis, and heart failure. White blood cell count monitoring was insufficient to predict these adverse effects.. Clozapine should be avoided in high-risk patients (e.g., the elderly, women, Ashkenazic Jews).

Topics: Acidosis, Lactic; Adult; Agranulocytosis; Antipsychotic Agents; Clozapine; Fatal Outcome; Heart Arrest; Humans; Hyperglycemia; Jews; Leukocyte Count; Male; Risk Factors

Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis.. We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus.. The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms.. Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.

Topics: Adult; Blood Glucose; Clozapine; Comorbidity; Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Hyperglycemia; Male; Middle Aged; Psychotic Disorders; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Topics: Adult; Anxiety Disorders; Buspirone; Clozapine; Drug Interactions; Drug Therapy, Combination; Gastrointestinal Hemorrhage; Humans; Hyperglycemia; Male; Schizophrenia, Paranoid

Topics: Adult; Clozapine; Diabetes Mellitus, Type 1; Humans; Hyperglycemia; Male; Schizophrenia