olanzapine and Hyperglycemia

Multiple drugs are known to induce metabolic malfunctions, among them second-generation antipsychotics (SGAs). The pathogenesis of such adverse effects is of multifactorial origin.. We investigated whether SGAs drive dysbiosis, assessed whether gut microbiota alterations affect body weight and metabolic outcomes, and looked for the possible mechanism of metabolic disturbances secondary to SGA treatment in animal and human studies.. A systematic literature search (PubMed/Medline/Embase/ClinicalTrials.gov/PsychInfo) was conducted from database inception until 03 July 2018 for studies that reported the microbiome and weight alterations in SGA-treated subjects.. Seven articles reporting studies in mice (experiments = 8) and rats (experiments = 3) were included. Olanzapine was used in five and risperidone in six experiments. Only three articles (experiments = 4) in humans fit our criteria of using risperidone and mixed SGAs. The results confirmed microbiome alterations directly (rodent experiments = 5, human experiments = 4) or indirectly (rodent experiments = 4) with predominantly increased Firmicutes abundance relative to Bacteroidetes, as well as weight gain in rodents (experiments = 8) and humans (experiments = 4). Additionally, olanzapine administration was found to induce both metabolic alterations (adiposity, lipogenesis, plasma free fatty acid, and acetate levels increase) (experiments = 3) and inflammation (experiments = 2) in rodents, whereas risperidone suppressed the resting metabolic rate in rodents (experiments = 5) and elevated fasting blood glucose, triglycerides, LDL, hs-CRP, antioxidant superoxide dismutase, and HOMA-IR in humans (experiment = 1). One rodent study suggested a gender-dependent effect of dysbiosis on body weight.. Antipsychotic treatment-related microbiome alterations potentially result in body weight gain and metabolic disturbances. Inflammation and resting metabolic rate suppression seem to play crucial roles in the development of metabolic disorders.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Gastrointestinal Microbiome; Humans; Hyperglycemia; Metabolic Diseases; Olanzapine; Risperidone; Weight Gain

Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP).. Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency.. RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI.. Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.

Topics: Administration, Oral; Antipsychotic Agents; Benzodiazepines; Delayed-Action Preparations; Dyslipidemias; Humans; Hyperglycemia; Hyperprolactinemia; Injections; Medication Adherence; Movement Disorders; Olanzapine; Pain; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Weight Gain

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

To explore the clinical characteristics of hyperglycemia in patients treated with olanzapine.. Retrospective, epidemiologic survey of spontaneously reported adverse events related to olanzapine therapy. Government-affiliated drug evaluation center.. Two hundred thirty-seven patients with olanzapine-associated diabetes or hyperglycemia.. One hundred ninety-six cases from January 1994-May 15, 2001, were identified with the United States Food and Drug Administration's MedWatch Drug Surveillance System, and 41 cases published through May 15, 2001, were identified with MEDLINE or through meeting abstracts.. Of the 237 cases, 188 were new-onset diabetes, 44 were exacerbations of preexistent disease, and 5 could not be classified. Mean patient age for newly diagnosed cases was 40.7+/-12.9 years and male:female ratio was 1.8. Seventy-three percent of all cases of hyperglycemia appeared within 6 months of start of olanzapine therapy. Eighty patients had metabolic acidosis or ketosis, 41 had glucose levels of 1000 mg/dl or greater, and 15 patients died. When olanzapine was discontinued or the dosage decreased, 78% of patients had improved glycemic control. Hyperglycemia recurred in 8 of 10 cases with rechallenge.. Number of reports, temporal relationship to start of olanzapine therapy, relatively young age, and improvement on drug withdrawal suggest that olanzapine may precipitate or unmask diabetes in susceptible patients.

Topics: Benzodiazepines; Diabetes Mellitus; Humans; Hyperglycemia; Olanzapine; Pirenzepine; Retrospective Studies

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

Olanzapine has been associated with insulin resistance and new-onset diabetes mellitus. A 27-year-old African-American man developed new-onset severe hyperglycemia-glucose 1240 mg/dl, with ketonuria and acidosis, but no weight gain-2 years after starting olanzapine. Although his diabetes was stabilized with insulin, his family had difficulty monitoring his therapy, and insulin was discontinued. Subsequent monotherapy with pioglitazone stabilized the patient's glucose levels, allowing him to continue taking olanzapine. Health care professionals should be aware of links between olanzapine and diabetes mellitus and of the potential for delayed recognition of complications associated with diabetes in patients who are psychotic. Insulin poses additional problems because families of patients with schizophrenia have to deal with compliance and risk of accidental or suicidal overdose. This case and others described in the literature illustrate such dilemmas and highlight the need to further study links connecting diabetes, insulin resistance, and olanzapine. Further research to determine proportionality and risk differences among various atypical antipsychotics also is warranted.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetic Ketoacidosis; Humans; Hyperglycemia; Ketone Bodies; Male; Olanzapine; Pirenzepine

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

Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemia; Lipid Metabolism; Lipoproteins, HDL; Male; Middle Aged; Olanzapine; Piperazines; Prediabetic State; Predictive Value of Tests; Randomized Controlled Trials as Topic; Schizophrenia; Thiazoles; Time Factors; Treatment Outcome

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

Topics: Benzodiazepines; Blood Glucose; C-Peptide; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Olanzapine; Reference Values; Risperidone; Selective Serotonin Reuptake Inhibitors

In order to estimate the degree of glucose tolerance impairment, oral glucose tolerance test was conducted in the group of 15 schizophrenic patients taking olanzapine, the group of 15 schizophrenic patients taking risperidone and in the group of 14 healthy volunteers. In the olanzapine group the tolerance was impaired in 33% of the patients, contrary to the risperidone group in which impairment amounted to 20% of the patients. The authors discuss possible mechanisms responsible for impaired glucose tolerance in patients taking newer antipsychotic drugs.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Insulin Resistance; Male; Middle Aged; Olanzapine; Risk; Risperidone

The association of hyperglycaemia and weight gain with the use of atypical antipsychotics has been documented. However, there is still not enough data from India. The fact that Indian patients usually have a lower body weight compared to European and American counterparts makes it difficult to extrapolate available data to the Indian context. The purpose of this study is: (a) To compare the prevalence of hyperglycaemia in schizophrenic patients taking olanzapine with those taking typical antipsychotics, and (b) to follow-up non-diabetic, non-obese schizophrenics on a stable regimen of antipsychotic monotherapy and determine the proportion of patients who develop weight gain, diabetes or impaired glucose tolerance; comparing the effects of olanzapine versus typical antipsychotics. Fifty-five schizophrenic patients attending psychiatry outpatients' department and on stable antipsychotic monotherapy for at least 6 weeks were included in the study. Those with a family or personal history of diabetes were excluded. There were 28 cases on olanzapine and 27 on either haloperidol or trifluoperazine. Fasting blood glucose estimation and body-mass Index (BMI) were recorded at baseline, at 6 weeks, and at 12 weeks. The two groups were comparable with respect to age, genderwise composition, and duration of illness. There was no significant difference in baseline glycaemic status or BMI. At the end of 12 weeks, olanzapine was not associated with any significant change in body weight, BMI or plasma fasting glucose. Duration of use of antipsychotic emerged as the only statistically significant risk factor for developing hyperglycaemia across both groups.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus; Female; Haloperidol; Humans; Hyperglycemia; India; Male; Obesity; Olanzapine; Prospective Studies; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors; Trifluoperazine

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

The goal of this study was to evaluate the effect of olanzapine or risperidone treatment on beta-cell function in healthy volunteers. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d; n = 17), risperidone (4 mg/d; n = 13), or placebo (n = 18) for 15-17 d. Insulin secretion was quantitatively assessed at baseline and the end of the study period using the hyperglycemic clamp. Weight increased significantly (P < 0.01) in the olanzapine (2.8 +/- 1.7 kg) and risperidone (3.1 +/- 2.1 kg) treatment groups. An increase ( approximately 25%) in the insulin response to hyperglycemia and a decrease ( approximately 18%) in the insulin sensitivity index were observed after treatment with olanzapine and risperidone. The change in insulin response was correlated (r = 0.5576; P = 0.019) with a change in body mass index. When the impact of weight change was accounted for by multivariate regression analyses, no significant change in insulin response or insulin sensitivity was detected after treatment with olanzapine or risperidone. We found no evidence that treatment of healthy volunteers with olanzapine or risperidone decreased the insulin secretory response to a prolonged hyperglycemic challenge. The results of this study do not support the hypothesis that olanzapine or risperidone directly impair pancreatic beta-cell function.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Insulin; Insulin Secretion; Male; Middle Aged; Olanzapine; Pirenzepine; Reference Values; Risperidone; Single-Blind Method; Weight Gain

Antipsychotic (AP) medications, such as olanzapine (OLZ), are used in the treatment of schizophrenia and a growing number of 'off-label' conditions. A single dose of OLZ causes robust increases in blood glucose within minutes of treatment. The purpose of the current study was to investigate whether interventions that increase circulating ketone bodies (fasting, β-hydroxybutyrate (βHB), ketone esters or a ketogenic diet (KD)) would be sufficient to protect against the acute metabolic side effects of OLZ. We demonstrate that fasting or the short-term consumption of a KD protects against OLZ-induced hyperglycaemia, independent of alterations in whole-body insulin action, and in parallel with a blunted rise in serum glucagon. Interestingly, the effects of fasting and KDs were not recapitulated by acutely increasing circulating concentrations of ketone bodies through treatment with βHB or oral ketone esters, approaches which increase ketone bodies to physiological or supra-physiological levels, respectively. Collectively, our findings demonstrate that fasting and the short-term consumption of a KD can protect against acute AP-induced perturbations in glucose homeostasis, whereas manipulations which acutely increase circulating ketone bodies do not elicit the same beneficial effects. KEY POINTS: Antipsychotic medications cause rapid and robust increases in blood glucose. Co-treatment approaches to offset these harmful metabolic side effects have not been identified. We demonstrate that fasting or the consumption of a short-term ketogenic diet, but not treatment with β-hydroxybutyrate or oral ketone esters, protects against acute antipsychotic-induced hyperglycaemia. The protective effects of fasting and ketogenic diets were paralleled by reductions in serum glucagon, but not improvements in whole-body insulin action.

Topics: 3-Hydroxybutyric Acid; Animals; Antipsychotic Agents; Blood Glucose; Diet, Ketogenic; Esters; Fasting; Glucagon; Hyperglycemia; Insulin; Ketone Bodies; Ketones; Mice; Olanzapine

Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, before treatment with OLZ either at the beginning of the light cycle, or 7 or 24 h following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 h following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio was maintained in high-fat fed, and AMPK β1-deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 wk of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ-induced perturbations in lipolysis, liver triglyceride accumulation, or whole body substrate oxidation. Collectively, our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism.

Topics: Animals; Blood Glucose; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Motor Activity; Olanzapine

Olanzapine is a second-generation antipsychotic (SGA) used in the treatment of schizophrenia and a number of off-label conditions. Although effective in reducing psychoses, acute olanzapine treatment causes hyperglycemia. Pharmacological agonists of the glucagon-like peptide 1 (GLP1) receptor have been shown to offset weight gain associated with chronic SGA administration. It is not known whether GLP1 receptor agonism would mitigate the acute metabolic side effects of SGAs. Within this context, we sought to determine whether pharmacological targeting of the GLP1 receptor would be sufficient to protect against acute olanzapine-induced impairments in glucose and lipid homeostasis. Male C57BL/6J mice were treated with olanzapine and/or the GLP1 receptor agonists liraglutide and exendin 4, and the blood glucose response was measured. We found that liraglutide or exendin 4 completely protected male mice against olanzapine-induced hyperglycemia in parallel with increases in circulating insulin (liraglutide, exendin 4) and reductions in glucagon (liraglutide only). In additional experiments, female mice, which are protected from acute olanzapine-induced hyperglycemia, displayed hyperglycemia, increases in glucagon, and reductions in insulin when treated with olanzapine and the GLP1 receptor antagonist exendin 9-39 compared with olanzapine treatment alone. Although in some instances the pharmacological targeting of the GLP1 receptor attenuated indexes of olanzapine-induced lipolysis, increases in liver triglyceride accumulation were not impacted. Our findings provide evidence that signaling through the GLP1 receptor can remarkably influence acute olanzapine-induced hyperglycemia, and from the standpoint of protecting against acute excursions in blood glucose, GLP1 receptor agonists should be considered as an adjunct treatment approach.

Topics: Animals; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Hyperglycemia; Hypoglycemic Agents; Lipolysis; Liraglutide; Liver; Male; Mice; Mice, Inbred C57BL; Olanzapine; Selective Serotonin Reuptake Inhibitors; Triglycerides

Olanzapine is a second-generation antipsychotic (SGA) used frequently in the treatment of schizophrenia and a growing list of off-label conditions. Though effective in reducing psychoses, acute olanzapine treatment causes rapid increases in blood glucose that are believed to be mediated by increases in liver glucose output, skeletal muscle insulin resistance, and beta cell dysfunction. Further, the acute lipidemic response to olanzapine has been largely unexplored. While females have been reported to be more susceptible to olanzapine-induced weight gain, there is little known about the impact of sex on the acute response to SGAs. The purpose of this study was to determine if the acute effects of SGAs on glucose and lipid metabolism display a sexually dimorphic response in C57BL/6 J mice and examine potential mechanisms mediating this effect. Age matched male and female C57BL/6 J mice were treated with olanzapine (5 mg/ kg, IP) or vehicle control and blood glucose was measured at baseline, 15, 30, 60, 90, and 120 min post-treatment and tissues and serum harvested. These experiments were repeated, and mice underwent an insulin (0.5 IU/kg) or pyruvate tolerance test (2 g/kg) following 60 min of olanzapine treatment. Females were protected against olanzapine-induced increases in blood glucose and pyruvate intolerance compared to male mice, and this occurred despite the development of severe insulin resistance. In male mice olanzapine increased the glucagon:insulin ratio whereas in females this ratio was reduced. When challenged with exogenous glucagon (1 mg/kg IP), females were less responsive than males. Male and female mice displayed similar increases in whole body fatty acid oxidation, serum fatty acids and liver triglyceride accumulation. Our findings provide evidence that while there are no apparent sex differences in the lipid metabolism response to olanzapine, that females are protected from acute olanzapine-induced excursions in blood glucose. This is likely due in part to reductions in the glucagon:insulin ratio and glucagon responsiveness which could impact olanzapine induced increases in liver glucose production.

Topics: Acute Disease; Animals; Blood Glucose; Female; Glucose Tolerance Test; Hyperglycemia; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Olanzapine; Severity of Illness Index; Sex Characteristics

Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK β1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK β1 suppresses these effects. Female AMPK β1

Topics: AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Biphenyl Compounds; Blood Glucose; Female; Gene Deletion; Gene Expression Regulation, Enzymologic; Glucose Tolerance Test; Hyperglycemia; Mice; Olanzapine; Pyrones; Pyruvic Acid; Thiophenes

Atypical antipsychotics, such as olanzapine, are commonly prescribed to patients with schizophrenic symptoms and other psychiatric disorders. However, weight gain and metabolic disturbance cause adverse effects, impair patient compliance and limit clinical utility. Thus, a better understanding of treatment-acquired adverse effects and identification of targets for therapeutic intervention are believed to offer more clinical benefits for patients with schizophrenia. Beyond its nutritional effects, studies have indicated that supplementation of chromium brings about beneficial outcomes against numerous metabolic disorders. In this study, we investigated whether olanzapine-induced weight gain and metabolic disturbance involved chromium dynamic mobilization in a female Sprague-Dawley rat model, and whether a dietary supplement of chromium improved olanzapine-acquired adverse effects. Olanzapine medicated rats experienced weight gain and adiposity, as well as the development of hyperglycemia, hyperinsulinemia, insulin resistance, hyperlipidemia, and inflammation. The olanzapine-induced metabolic disturbance was accompanied by a decrease in hepatic Akt and AMP-activated Protein Kinase (AMPK) actions, as well as an increase in serum interleukin-6 (IL-6), along with tissue chromium depletion. A daily intake of chromium supplements increased tissue chromium levels and thermogenic uncoupling protein-1 (UCP-1) expression in white adipose tissues, as well as improved both post-olanzapine weight gain and metabolic disturbance. Our findings suggest that olanzapine medicated rats showed a disturbance of tissue chromium homeostasis by inducing tissue depletion and urinary excretion. This loss may be an alternative mechanism responsible for olanzapine-induced weight gain and metabolic disturbance.

Topics: Adipose Tissue, White; Adiposity; Administration, Oral; AMP-Activated Protein Kinases; Animals; Antipsychotic Agents; Chlorides; Chromium Compounds; Female; Gene Expression Regulation; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Inflammation; Insulin Resistance; Interleukin-6; Liver; Muscle, Skeletal; Olanzapine; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Uncoupling Protein 1; Weight Gain

Despite benefits, atypical antipsychotics produce troublesome metabolic adverse effects particularly hyperphagia, weight gain, dyslipidemia, hyperglycemia and insulin resistance which further develop metabolic and cardiac complications. The animal models studied for antipsychotic-induced weight gain only focused on metabolic alteration in antipsychotics treated animals but none has considered psychosis as a predisposing factor which mimics the clinical condition. The present study was aimed to rule out the impact of pharmacologically induced psychosis-like phenotype on metabolic alterations induced by antipsychotics. Female BALB/c mice (weighing 18-23 g) exhibiting schizophrenia-like behavior after 5 days of MK-801 treatment (0.1 mg/kg, i.p.) were administered olanzapine (3 and 6 mg/kg, per oral) and risperidone (2 and 4 mg/kg, per oral) for six weeks. Acute as well as chronic treatment with olanzapine and risperidone treatment significantly reduced locomotion, increased feed intake and body weight in a time-dependent manner, which confirms the face validity of the animal model. Olanzapine (6 mg/kg) treatment significantly altered glucose and lipid homeostasis which was further accompanied by elevated levels of proinflammatory cytokines, ghrelin and leptin. These metabolic and biochemical alterations have demonstrated construct validity. Further, no significant difference was observed in the metabolic parameters in control and schizophrenic mice treated with olanzapine which confers that antipsychotic-induced metabolic alterations are independent of psychosis. Our study concluded that six-week olanzapine (6 mg/kg) treatment in control mice induced most of the clinically relevant physiological, biochemical and metabolic alterations (clinically relevant), that is independent of pharmacologically-induced psychosis.

Topics: Animals; Antipsychotic Agents; Body Weight; Female; Ghrelin; Hyperglycemia; Leptin; Mice; Mice, Inbred BALB C; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Weight Gain

Olanzapine is a second-generation antipsychotic used in the management of schizophrenia and various off-label conditions. The acute metabolic responses of olanzapine recapitulate many of the side effects associated with obesity. Obesity rates are high in the schizophrenic population, but it is unknown whether pre-existing obesity-associated metabolic dysfunction augments the acute side effects of olanzapine. To address this question, we compared the responses to olanzapine in lean and high-fat diet-induced (HFD) obese mice. Four weeks of HFD (60%kcal from fat) led to obese, hyperglycemic, and insulin resistant mice. Olanzapine-induced hyperglycemia and systemic insulin resistance were exacerbated in HFD-induced obese mice. Olanzapine also profoundly inhibited insulin signalling in skeletal muscle and liver, which appears to be exacerbated by obesity. The greater olanzapine-induced hyperglycemia may also result from increased hepatic glucose output in obese mice as pyruvate challenge led to significantly higher blood glucose concentrations, with associated increases in hepatic content of gluconeogenic enzymes. Olanzapine also suppressed RER while acutely increasing oxygen consumption in obese mice. A single olanzapine treatment reduced physical activity for up to 24h, regardless of obesity. Considering obesity is very common in the schizophrenic population, these data suggest that previous research may be under-estimating the severity of olanzapine's acute side effects.

Topics: Animals; Blood Glucose; Diet, High-Fat; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle, Skeletal; Obesity; Olanzapine

Olanzapine is a widely prescribed antipsychotic drug. While effective in reducing psychoses, treatment with olanzapine causes rapid increases in blood glucose. We wanted to determine if a single bout of exercise, immediately prior to treatment, would attenuate the olanzapine-induced rise in blood glucose and if this occurred in an IL-6 dependent manner. We found that exhaustive, but not moderate exercise, immediately prior to treatment, prevented olanzapine-induced hyperglycemia and this occurred in parallel with increases in serum IL-6. To determine if IL-6 was involved in the mechanisms through which exhaustive exercise protected against olanzapine-induced hyperglycemia several additional experiments were completed. Treatment with IL-6 (3 ng/g bw, IP) alone did not protect against olanzapine-induced increases in blood glucose. The protective effects of exhaustive exercise against olanzapine-induced increases in blood glucose were intact in whole body IL-6 knockout mice. Similarly, treating mice with an IL-6 neutralizing antibody prior to exhaustive exercise did not negate the protective effect of exercise against olanzapine-induced hyperglycemia. Our findings provide evidence that a single bout of exhaustive exercise protects against acute olanzapine-induced hyperglycemia and that IL-6 is neither sufficient, nor required for exercise to protect against increases in blood glucose with olanzapine treatment.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Hyperglycemia; Interleukin-6; Male; Mice, Inbred C57BL; Mice, Knockout; Olanzapine; Physical Conditioning, Animal

Olanzapine (OLZ) is an antipsychotic drug used in the treatment of schizophrenia. Although effective in reducing psychoses, OLZ causes acute increases in blood glucose. The acute effects of OLZ on hyperglycemia are likely caused by reductions in insulin secretion, insulin resistance, and increased hepatic glucose production. 5AMP-activated protein kinase (AMPK) is an energy sensor activated during exercise that can increase insulin sensitivity and insulin-independent glucose uptake in muscle. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is a pharmacologic agent that, among other effects, can activate AMPK in vivo. Conversely, hypothalamic activation of AMPK has been suggested to mediate the hyperglycemic effects of OLZ. The purpose of this investigation was to determine whether cotreatment with AICAR could prevent acute OLZ-induced hyperglycemia in lean and obese C57BL6/J mice. OLZ (5 mg/kg, i.p.) caused rapid increases in blood glucose, a blunted insulin response, and pyruvate intolerance, all of which were prevented with AICAR cotreatment in both lean and obese mice. AICAR did not affect OLZ-induced changes in whole-body substrate oxidation or energy expenditure. Peripheral injection of AICAR, but not OLZ, activated AMPK signaling in the hypothalamus. The results of the current study provide evidence that AICAR prevents OLZ-induced hyperglycemia, despite increasing hypothalamic AMPK signaling. These protective effects were associated with the preservation of whole-body insulin action and reductions in markers of liver glucose production.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Blood Glucose; Glucose; Homeostasis; Hyperglycemia; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Olanzapine; Pyruvic Acid; Ribonucleosides; Signal Transduction

To determine if glucagon is involved in mediating the increase in blood glucose levels caused by the second-generation antipsychotic drug olanzapine.. Olanzapine treatment increased serum glucagon and lead to rapid increases in blood glucose concentrations in WT mice. Gcgr. Gcgr

Topics: Animals; Benzodiazepines; Blood Glucose; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Homeostasis; Hyperglycemia; Insulin; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Olanzapine; Receptors, Glucagon

The patient was 32-year-old man, who received olanzapine for schizophrenia and developed polyuria and thirst without drinking soft-drinks after 4 months. Five months after the initiation of treatment, he developed diabetic ketoacidosis (blood glucose: 490 mg/dL, HbA1c: 15.5%). He was diagnosed with type 1 diabetes (glutamic acid decarboxylase (GAD)-Ab: 5.6 U/mL, IA-2 Ab: 5.9 U/mL, fasting C-peptide: 0.12 ng/mL) and was put on intensive insulin therapy. At four months after the onset of 1A diabetes, he experienced a honeymoon phase that was sustained until the 40th month of treatment. We hypothesize that the administration of olanzapine to a patient with pre-type 1A diabetes induced marked hyperglycemia and accelerated the onset of type 1A diabetes.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Humans; Hyperglycemia; Insulin; Male; Olanzapine; Prediabetic State; Schizophrenia

Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dose-dependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapine-induced acute hyperglycemia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Corticosterone; Epinephrine; Glucagon; Histamine; Hyperglycemia; Injections, Intravenous; Insulin; Male; Models, Biological; Olanzapine; Propranolol; Rats, Wistar

To evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies.. We conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66 years. Site-level results were pooled using meta-analytic methods.. Among 725,489 patients, 55% were aged 66+years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1-2 per 1000 person years), but more frequent in patients with pre-existing diabetes (6-12 per 1000 person years). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53-0.90].. Risk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Diabetes Complications; Female; Humans; Hyperglycemia; Male; Meta-Analysis as Topic; Middle Aged; Olanzapine; Proportional Hazards Models; Retrospective Studies; Risk; Risperidone; Schizophrenia; Young Adult

Patients with schizophrenia receive medication to alleviate various symptoms, but some efficacious second generation antipsychotics, particularly olanzapine, can cause obesity, dyslipidemia, and diabetes mellitus. It has been generally considered that olanzapine contributes to the development of diabetes by inducing obesity and subsequent insulin resistance. In this study, we examined the effect of olanzapine and risperidone, another second generation antipsychotic, on a hamster pancreatic β cell line, and found that both evoked mild endoplasmic reticulum (ER) stress, as evidenced by mild activation of the ER stress sensor molecule PERK. Surprisingly, only olanzapine induced marked apoptosis. Phosphorylation of the α subunit of eukaryotic initiation factor 2, an event immediately downstream of PERK activation, was not observed in cells treated with olanzapine, protein synthesis continued despite PERK activation, and ER stress was thereby sustained. Secretion of insulin was markedly inhibited, and both proinsulin and insulin accumulated inside olanzapine-treated cells. Inhibition of protein synthesis and knockdown of insulin mRNA, which result in less unfolded protein burden, both attenuated subsequent olanzapine-induced apoptosis. Given clinical observations that some patients taking olanzapine exhibit hyperlipidemia and hyperglycemia without gaining weight, our observations suggest that damage to pancreatic β cells may contribute to the undesirable metabolic consequences of olanzapine treatment in some cases.

Topics: Animals; Antipsychotic Agents; Apoptosis; Benzodiazepines; Cell Line; Cricetinae; Diabetes Mellitus; eIF-2 Kinase; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; HEK293 Cells; Hep G2 Cells; Humans; Hyperglycemia; Hyperlipidemias; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Olanzapine; Phosphorylation; Proinsulin; Protein Biosynthesis; Risperidone; RNA, Messenger; Schizophrenia; Unfolded Protein Response

Atypical antipsychotic drugs such as olanzapine are known to induce metabolic disturbance. We have already shown that olanzapine induces hepatic glucose production through the activation of hypothalamic adenosine 5'-monophosphate-activated protein kinase (AMPK). However, it is unclear how olanzapine activates hypothalamic AMPK. Since olanzapine is known to antagonize several receptors, including histaminergic, muscarinic, serotonergic, dopaminergic and adrenergic receptors, we examined the effect of each receptor antagonist on blood glucose levels in mice. Moreover, we also investigated whether these antagonists activate hypothalamic AMPK.. Male 6-week-old ICR mice were used. Blood glucose levels were determined by the glucose oxidase method. AMPK expression was measured by Western blotting.. Central administration of olanzapine (5-15 nmol i.c.v.) dose-dependently increased blood glucose levels in mice, whereas olanzapine did not change blood insulin levels. Histamine H1 receptor antagonist chlorpheniramine (1-10 μg i.c.v.), dopamine D2 receptor antagonist L-sulpiride (1-10 μg i.c.v.) and α1-adrenoceptor antagonist prazosin (0.3-3 μg i.c.v.) also significantly increased blood glucose levels in mice. In contrast, the blood glucose levels were not affected by muscarinic M1 receptor antagonist dicyclomine (1-10 μg i.c.v.) or serotonin 5-HT2A receptor antagonist M100907 (1-10 ng i.c.v.). Olanzapine-induced hyperglycemia was inhibited by the AMPK inhibitor compound C, and AMPK activator AICAR (10 ng to 1 μg i.c.v.) significantly increased blood glucose levels. Olanzapine (15 nmol), chlorpheniramine (10 μg), L-sulpiride (10 μg) and prazosin (3 μg) significantly increased phosphorylated AMPK in the hypothalamus of mice.. These results suggest that olanzapine activates hypothalamic AMPK by antagonizing histamine H1 receptors, dopamine D2 receptors and α1-adrenoceptors, which induces hyperglycemia.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Central Nervous System; Dopamine D2 Receptor Antagonists; Hyperglycemia; Hypothalamus; Male; Mice; Mice, Inbred ICR; Olanzapine; Receptors, Adrenergic, alpha-1; Receptors, Dopamine D2; Receptors, Histamine H1

Atypical antipsychotic drugs such as Olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying the metabolic side-effects of these centrally acting drugs are still unknown to a large extent. We compared the effects of peripheral (intragastric; 3 mg/kg/h) versus central (intracerebroventricular; 30 µg/kg/h) administration of Olanzapine on glucose metabolism using the stable isotope dilution technique (Experiment 1) in combination with low and high hyperinsulinemic-euglycemic clamps (Experiments 2 and 3), in order to evaluate hepatic and extra-hepatic insulin sensitivity, in adult male Wistar rats. Blood glucose, plasma corticosterone and insulin levels were measured alongside endogenous glucose production and glucose disappearance. Livers were harvested to determine glycogen content. Under basal conditions peripheral administration of Olanzapine induced pronounced hyperglycemia without a significant increase in hepatic glucose production (Experiment 1). The clamp experiments revealed a clear insulin resistance both at hepatic (Experiment 2) and extra-hepatic levels (Experiment 3). The induction of insulin resistance in Experiments 2 and 3 was supported by decreased hepatic glycogen stores in Olanzapine-treated rats. Central administration of Olanzapine, however, did not result in any significant changes in blood glucose, plasma insulin or corticosterone concentrations nor in glucose production. In conclusion, acute intragastric administration of Olanzapine leads to hyperglycemia and insulin resistance in male rats. The metabolic side-effects of Olanzapine appear to be mediated primarily via a peripheral mechanism, and not to have a central origin.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Glucose; Glucose Clamp Technique; Glycogen; Hyperglycemia; Insulin; Insulin Resistance; Liver; Male; Olanzapine; Rats; Rats, Wistar

A 35-year-old woman, diagnosed as schizophrenia and treated with olanzapine for nearly 30 months, consulted our department because of severe hyperglycemia. The use of antipsychotics, switching from olanzapine to risperidone, and a one-month introduction of insulin therapy resulted in the decrease of pre-prandial blood glucose levels and the increase of insulin levels (269 to 128 mg/dL, 5.6 to 21.8 µU/mL). A higher level of insulin resistance as measured by HOMA-IR after the improvement of hyperglycemia (3.6 vs. 6.8) suggested that the long use of olanzapine reduced insulin secretion. Based on this case, impairment of pancreatic β-cells caused by olanzapine might be reversible.

Topics: Adult; Benzodiazepines; Drug Substitution; Female; Humans; Hyperglycemia; Insulin; Insulin Secretion; Olanzapine; Recovery of Function; Risperidone; Severity of Illness Index

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp.Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; C-Peptide; Disease Models, Animal; Glucose; Glucose Clamp Technique; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Time Factors

Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some individuals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a diverse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.

Topics: Animals; Anticonvulsants; Appetite Regulation; Benzodiazepines; Biomarkers; Body Weight; Diabetes Mellitus; Female; Hyperglycemia; Hyperphagia; Hypothalamic Area, Lateral; Intracellular Signaling Peptides and Proteins; Isoxazoles; Neurons; Neuropeptides; Nucleus Accumbens; Obesity; Olanzapine; Orexins; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Treatment Outcome; Weight Gain; Zonisamide

To report a case of rapidly occurring hyperglycemia that occurred in a geriatric patient 3 days after treatment with olanzapine.. An 89-year-old man was admitted for dementia with behavioral disturbance and psychosis and was started on olanzapine 2.5 mg twice daily. Due to paranoia and agitation, the dose was increased to 5 mg twice daily after 2 days. Subsequently, he developed hyperglycemia (fasting blood glucose 138 mg/dL) that resolved when olanzapine was stopped and recurred (fasting blood glucose 150 mg/dL) after 2 days of rechallenge with olanzapine 2.5 mg twice daily. In addition, his overall medical status worsened, as he developed concurrent acute renal failure and became more confused and lethargic. The hyperglycemia once again resolved with discontinuation of the drug.. We postulate that the rapid onset of hyperglycemia and the resulting medical sequelae were due to olanzapine. An objective causality assessment revealed that the adverse drug event was probable. There have been numerous case reports of hyperglycemia with olanzapine in the literature, but none reported hyperglycemia within days of initiation of the medication. Although weight gain often coincides with hyperglycemia in patients taking atypical antipsychotics, it does not seem to be a necessary causal factor. Recent data in animal studies have indicated that olanzapine and clozapine rapidly impair whole-body insulin sensitivity in a dose-dependent manner.. Clinicians treating elderly patients with olanzapine should be aware of the potential for rapidly developing hyperglycemia and monitor such patients accordingly.

Topics: Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Humans; Hyperglycemia; Male; Olanzapine; Psychotic Disorders

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

Concern is mounting that atypical antipsychotics cause disturbance in glucose regulation ranging from reversible hyperglycemia to diabetic ketoacidosis and death. It is difficult, however, to know what the level of risk of hyperglycemia might be for an individual patient on a particular medication of this class. We conducted a retrospective nonrandomized cohort analysis of glucose measurements in 18,764 patients receiving outpatient prescriptions for olanzapine, risperidone, or typical antipsychotics from 1 October 1998 to 30 June 2003 at six Veterans Affairs Medical Centers in the southeast United States. In patients without a random plasma glucose measurement > or =160 mg/dl before medication exposure (n=1394), treatment with index medications was associated with an incidence of new diabetes-level hyperglycemia of 78.7 cases per 1,000 individuals exposed per year. Olanzapine exposure was associated with a greater rate of developing at least one glucose measurement > or =200 mg/dl than risperidone (odds ratio=2.14, P=0.003). Olanzapine exposure was also associated with a greater rate of development of at least one fasting glucose measurement > or =126 mg/dl than risperidone. Typical antipsychotics were associated with risk intermediate between the two atypicals. These data indicate that patients with no previously observed glucose elevations develop diabetes-level hyperglycemia during antipsychotic treatment, particularly in patients receiving olanzapine.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Chlorpromazine; Cohort Studies; Female; Fluphenazine; Haloperidol; Hospitals, Veterans; Humans; Hyperglycemia; Incidence; Male; Middle Aged; Olanzapine; Perphenazine; Retrospective Studies; Risk Assessment; Risk Factors; Risperidone; Southeastern United States; Time Factors; Veterans

Topics: Adult; Anorexia Nervosa; Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Olanzapine

To report a case of fatal hyponatremia, marked hyperglycemia, and acute pancreatitis following simultaneous administration of paroxetine, fluphenazine, haloperidol and olanzapine.. A 44-year-old non-diabetic male was admitted unconsciously, with severe hyponatremia, hyperglycemia and bradypnea. The patient had a history of long-term treatment with paroxetine, fluphenazine, haloperidol and olanzapine. Upon arrival, the plasma sodium level was 104 mmol/l, and blood glucose was 940 mg/dl. The therapy consisted of ventilatory support and intensive correction of hyponatremia and hyperglycemia. 2 hours later, hypotension and refractory cardiac arrest occurred. The autopsy disclosed severe cerebral edema as cause of death, and a modest hemorrhagic pancreatitis.. Paroxetine is a selective serotonin reuptake inhibitor which stimulates antidiuretic hormone (ADH) release and may cause the syndrome of inappropriate ADH secretion with consecutive hyponatremia. Fluphenazine and haloperidol may contribute to this syndrome. Fluphenazine, and particularly olanzapine are associated with an increased incidence ofdiabetes. Olanzapine has been reported as a risk factor for acute pancreatitis. The Naranjo probability scale was not applicable because of almost immediate lethal outcome.. Polypharmacy increases the risk of various adverse reactions. Adverse effects of paroxetine and many anti-psychotic drugs, such as hyponatremia and hyperglycemia, should be monitored periodically to prevent complications. The role of olanzapine in the etiology of acute pancreatitis remains to be evaluated.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Brain Edema; Fatal Outcome; Fluphenazine; Haloperidol; Heart Arrest; Humans; Hyperglycemia; Hyponatremia; Inappropriate ADH Syndrome; Male; Mental Disorders; Olanzapine; Pancreatitis; Paroxetine; Polypharmacy; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Disease Progression; Humans; Hyperglycemia; Hyperlipidemias; Male; Olanzapine; Risperidone; Schizophrenia, Paranoid

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

The following is a case report analysis intended to draw attention to the need for better care coordination by describing the observed relationship of olanzapine to metabolic changes manifested as uncontrolled diabetes mellitus and weight gain. A 47-year-old male with bipolar I disorder/hallucinations presented to the Veterans Affairs Medical Center (VAMC) with suicidal ideations. He was referred to the psychiatry service where he was treated with olanzapine. He was followed exclusively by the psychiatry service for more than a year. During that time,weight issues and diabetes status were not addressed. Upon presenting to the primary care service a year and a half later, the patient was taking 40 mg per day of olanzapine and had gained 62 pounds, a 30% increase in body weight; glycosylated hemoglobin (A1c) was 11.1%. The patient was enrolled in a weight-loss clinic, and his diabetes medications were adjusted.Subsequently, olanzapine was discontinued because of weight gain and uncontrolled diabetes. Blood sugar and A1c were finally stabilized one month after discontinuation of olanzapine (A1c,6.9%). The patient experienced a relapse in his bipolar disorder,and olanzapine was restarted at 20 to 40 mg per day. His blood sugar became uncontrolled, he gained 13 pounds, and his A1c increased to 9.4%.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Olanzapine; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Contraindications; Diabetes Mellitus; Diagnosis, Differential; Dibenzothiazepines; Humans; Hyperglycemia; Japan; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Research Design; Risk Factors; Schizophrenia

Topics: Benzodiazepines; Humans; Hyperglycemia; Insulin Resistance; Olanzapine; Prospective Studies

Some reports of impaired glucose tolerance associated with olanzapine (OLZ) treatment have been published before OLZ was marketed in Japan. In Japan, we have been prohibited from using OLZ for patients with diabetes mellitus, since several cases with OLZ-associated impaired glucose tolerance including two deaths from diabetic coma have been reported. Here, we report four cases of OLZ-associated impaired glucose tolerance and review the points to consider in treatment with OLZ. Of our four cases, three cases were new-onset (non diabetes mellitus cases) and the other case was a diabetes mellitus-existent (diabetes mellitus case). In the non DM cases, the time to the onset of impaired glucose tolerance after initiating treatment with OLZ was 8-9 months, and the impaired glucose tolerance immediately improved after discontinuing treatment with OLZ and initiating treatment for diabetes mellitus. Therefore, it is necessary to continue long-term monitoring of the parameters of glucose metabolism for all patients treated with OLZ. Should impaired glucose tolerance develop during treatment with OLZ, treatment with OLZ should be discontinued immediately and treatment for diabetes mellitus should be started if necessary. Although the condition of diabetes mellitus was stable befor initiating treatment with OLZ in the DM case, hyperglycemia developed immediately after initiating treatment with OLZ and the condition remained unstable even after early treatment for diabetes mellitus. Therefore, it is necessary to check for a previous history of diabetes mellitus and hyperglycemia befor initiating treatment with OLZ. Correlations between weight gain and occurrence of impaired glucose tolerance are not clear, so it is necessary to monitor the occurrence of impaired glucose tolerance even in cases without weight gain.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Contraindications; Diabetes Mellitus; Disease Progression; Female; Glucose Intolerance; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Schizophrenia; Time Factors; Water Intoxication

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

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Incidence; Japan; Male; Middle Aged; Olanzapine; Schizophrenia; Severity of Illness Index

We report the case of a euglycaemic woman whose glucose control rapidly decompensated following olanzapine initiation leading to diabetic coma. Hyperglycaemia has been associated with chronic psychotic disorders and antipsychotics for many years. However, it is unusual to see such rapid and life-threatening changes associated with treatment. The case highlights that changes in antipsychotic treatment may be associated with large changes in glucose tolerance, and that it is possible to continue antipsychotic treatment with appropriate diabetic care.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 1; Diabetic Coma; Diabetic Ketoacidosis; Dose-Response Relationship, Drug; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Olanzapine; Psychotic Disorders

The increasing use of olanzapine for treating adolescent patients has brought with it greater awareness of the recognized side effects of this medication, especially weight gain. Of the reports of glucose dysregulation related to olanzapine therapy, only a few pertain to adolescents. We present five cases: two youths who consequently suffered from overt diabetes and three who responded with glucose dysregulation. According to the Naranjo probability scale, the relation of this phenomenon to olanzapine therapy is "probable." We consider the findings of the presented case series as justification for regular metabolic follow-up for apparently healthy adolescents receiving olanzapine therapy.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

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

A case history of a 31-year-old male schizophrenic patient is presented. The man was treated with olanzapine for three weeks before he died. After one week on a 10 mg daily dose of olanzapine, his fasting blood glucose was elevated to 11.3 mmol/L (203 mg/dL). In order to treat more aggressively his psychosis, the olanzapine dose was raised to 20 mg daily resulting in his fasting blood glucose climbing to 15.8 mmol/l (284 mg/dL). On the days preceding his death, he became progressively weaker, and developed polydipsia with polyuria. He had no personal or family history of diabetes mellitus and he was on no other medication at the time of his death. Postmortem blood, vitreous humor, and urine glucose concentrations were 53 mmol/L (954 mg/dL), 49 mmol/L (882 mg/dL), and 329 mmol/L (5922 mg/dL), respectively. Drug screen on urine and blood indicated only a small amount or olanzapine and no alcohols. Peripheral blood olanzapine concentration was within therapeutic limits, 45 ng/mL. Analysis of vitreous humor and urine revealed severe dehydration with small amounts of ketones. Death was attributed to hyperosmolar nonketotic diabetic coma, and olanzapine was felt most likely to be the cause. Another atypical neuroleptic, clozapine, has also been associated with the development and exacerbation of diabetes mellitus or diabetic ketoacidosis. We recommend including vitreous glucose and beta-hydroxybutyrate analysis as part of postmortem toxicology work up when the drug screen reveals the presence of either olanzapine or clozapine.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Benzodiazepines; Dehydration; Diabetes Complications; Fatal Outcome; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Male; Olanzapine; Piperazines; Pirenzepine; Schizophrenia, Paranoid; Thiazoles; Treatment Outcome

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: Antipsychotic Agents; Benzodiazepines; Humans; Hyperglycemia; Ketosis; Male; Middle Aged; Olanzapine; Pirenzepine

To provide evidence that olanzapine can cause glucose dysregulation by a mechanism other than weight gain.. I report a case of a diabetic patient who developed glucose dysregulation soon after initiation of olanzapine treatment, occurring in the absence of weight gain. I compare this case to previous case reports.. Our patient developed persistent hyperglycaemia within 3 weeks of initiating treatment with olanzapine. Weight recorded just prior to commencement and soon after discontinuation of olanzapine were not significantly different.. Controlled studies are necessary to elucidate the mechanism by which olanzapine can cause dysregulation of glucose homeostasis, and to develop guidelines for the use of olanzapine in patients with known diabetes as well as in patients with risk factors for diabetes.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Diabetes Complications; Diabetes Mellitus; Female; Humans; Hyperglycemia; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Olanzapine; Pirenzepine; Psychotic Disorders; Weight Gain

We describe here a case of olanzapine associated weight gain, hyperglycemia and neuroleptic malignant syndrome in a 64 year-old woman with a significant medical history. Eighteen weeks after initiating olanzapine, Mrs X lost glycemic control, exhibited signs and symptoms consistent with neuroleptic malignant syndrome and gained 8.9 kg. We suggest that utilization of olanzapine in the less medically stable geriatric patient be implemented with vigilant monitoring for such complications mentioned above.

Topics: Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Middle Aged; Neuroleptic Malignant Syndrome; Olanzapine; Pirenzepine; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Double-Blind Method; Female; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine; Schizophrenia

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Female; Humans; Hyperglycemia; Olanzapine; Pirenzepine

Olanzapine is an atypical antipsychotic that is becoming more widely used in children and adolescents. There have been reports of olanzapine-induced hyperglycemia and hypertriglyceridemia in adults. This case report describes the development of both hyperglycemia and hypertriglyceridemia in a male adolescent that resolved with discontinuation of olanzapine and without dietary changes or the use of insulin or oral hypoglycemics.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Humans; Hyperglycemia; Hypertriglyceridemia; Male; Mental Disorders; Olanzapine; Pirenzepine

Olanzapine, a serotonin-dopamine-receptor antagonist, is an atypical antipsychotic agent used to treat schizophrenia and other psychotic disorders. It is preferred over older antipsychotics because of its relatively low frequency of sedation, orthostatic hypotension, extrapyramidal symptoms, and anticholinergic side effects. A 45-year-old man with well-controlled type 2 diabetes mellitus experienced an abrupt worsening of his diabetes after 3 years of olanzapine therapy His hemoglobin A1c (HbA1c) level rose from a baseline of 5.9-6.2% to 12.5%. Discontinuation of olanzapine by means of a 3-month taper resulted in a reduction in HbA1c to pretreatment levels. Although cases of olanzapine-induced hyperglycemia have been documented in the literature, this complication has not been reported in a patient maintained on therapy for this duration. Clinicians should be aware of this possible complication in patients receiving long-term olanzapine therapy.

Topics: Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Humans; Hyperglycemia; Long-Term Care; Male; Mental Disorders; Middle Aged; Olanzapine; Pirenzepine; Selective Serotonin Reuptake Inhibitors

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

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Comorbidity; Depressive Disorder; Diabetes Mellitus; Humans; Hyperglycemia; Male; Middle Aged; Olanzapine; Pirenzepine

Two psychotic patients developed hyperglycaemia several weeks after starting olanzapine. In one case the elevated glucose concentrations returned to normal soon after withdrawal of olanzapine. In the second case severe ketoacidosis with lethal outcome occurred.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetic Ketoacidosis; Fatal Outcome; Female; Humans; Hyperglycemia; Male; Olanzapine; Paranoid Disorders; Pirenzepine; Selective Serotonin Reuptake Inhibitors

Topics: Adult; Antidepressive Agents; Benzodiazepines; Clomipramine; Dehydration; Depressive Disorder; Diabetes Mellitus, Type 2; Female; Humans; Hyperglycemia; Olanzapine; Pirenzepine; Syndrome

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; Male; Olanzapine; Pirenzepine; Psychotic Disorders; Recurrence