olanzapine and Glucose-Intolerance

Metabolic disturbances, obesity and life-shortening cardiovascular morbidity are major clinical problems among patients with antipsychotic treatment. Especially two of the most efficacious antipsychotics, clozapine and olanzapine, cause weight gain and metabolic disturbances. Additionally, patients with schizophrenia-spectrum disorders not infrequently consume alcohol. Glucagon-like peptide-1 (GLP-1) has shown to improve glycaemic control and reduce alcohol intake among patients with type 2 diabetes.. To investigate whether the beneficial effects of GLP-1 analogues on glycaemic control and alcohol intake, in patients with type 2 diabetes, can be extended to a population of pre-diabetic psychiatric patients receiving antipsychotic treatment.. Trial design, intervention and participants: The study is a 16-week, double-blinded, randomised, parallel-group, placebo-controlled clinical trial, designed to evaluate the effects of the GLP-1 analogue liraglutide on glycaemic control and alcohol intake compared to placebo in patients who are prediabetic, overweight (body mass index ≥27 kg/m(2)), diagnosed with a schizophrenia-spectrum disorder and on stable treatment with either clozapine or olanzapine.. The primary endpoint is the change in glucose tolerance from baseline (measured by area under the curve for the plasma glucose excursion following a 4 h 75 g oral glucose tolerance test) to follow-up at week 16. The secondary endpoints include changes of dysglycaemia, body weight, waist circumference, blood pressure, secretion of incretin hormones, insulin sensitivity and β cell function, dual-energy X-ray absorption scan (body composition), lipid profile, liver function and measures of quality of life, daily functioning, severity of the psychiatric disease and alcohol consumption from baseline to follow-up at week 16. Status: Currently recruiting patients.. Ethical approval has been obtained. Before screening, all patients will be provided oral and written information about the trial. The study will be disseminated by peer-review publications and conference presentations.. ClinicalTrials.gov: NCT01845259, EudraCT: 2013-000121-31.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clinical Protocols; Clozapine; Double-Blind Method; Glucagon-Like Peptide-1 Receptor; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Olanzapine; Prediabetic State; Research Design; Schizophrenia

This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters.. Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up.. Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG.. These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dyslipidemias; Early Medical Intervention; Female; Glucose Intolerance; Humans; Male; Middle Aged; Obesity; Olanzapine; Psychotic Disorders; Schizophrenia; Weight Reduction Programs

There have been innumerable advances in the pharmacotherapy of schizophrenia, but problems have emerged hand-in-glove, such as the presence of treatment-emergent glucose intolerance and frank diabetes mellitus (DM).. Medication-naïve patients with schizophrenia (n = 99) underwent baseline fasting and 2 h post-prandial plasma glucose measurements repeated after 6 weeks after randomization to receive olanzapine, risperidone or haloperidol. The results were compared with a matched healthy control group.. A significant difference (P = 0.002) in baseline 2 h post-prandial blood sugar (PPBS) was noted between the control group and the treatment group along with a significant increase in weight (P < 0.001), fasting blood sugar (P = 0.01) and 2 h PPBS (P < 0.001) from baseline to endpoint between the groups. A statistical significance in the incidence of DM at endpoint by the WHO criteria (10.1%) was also noted.. Male patients with schizophrenia are liable to develop DM. Antipsychotic treatment leads to the development of DM in a significant 10.1% within 6 weeks.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glucose Intolerance; Haloperidol; Humans; Male; Olanzapine; Prospective Studies; Schizophrenia

Olanzapine is commonly used to treat schizophrenia. However, long-term administration of olanzapine causes metabolic side effects, such as insulin resistance (IR), which seriously affects patients' quality of life. Both diagnostic and prognostic markers are urgently needed to increase patient compliance. We applied isobaric tags for relative and absolute quantitation (iTRAQ) labeling combined with 2D LC/MS/MS technology to identify the differentially expressed proteins in olanzapine-induced IR rats. A total of 3194 proteins were identified from rat adipose tissues, and 270 differentially expressed proteins were screened out with a ratio threshold >1.5-fold or <0.67-fold. Based on a bioinformatics analysis and literature search, we selected six candidates (MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz) from a set of 270 proteins and verified these proteins by western blot; the expression of these proteins coincided with the LC-MS/MS results. Finally, the biological roles of FABP4 and apoA-IV, which are two novel IR-related proteins identified in the present study, were verified in 3T3-L1 cells. These data suggest that these two proteins acted on olanzapine-induced IR via the IRS-1/AKT signaling pathway. Our results provide a dataset of potential targets to explore the mechanism in olanzapine-induced IR and reveal the new roles of FABP4 and apoA-IV in olanzapine-induced IR. SIGNIFICANCE: The proteomic analysis of this study revealed the target associated with olanzapine-induced IR and provided relevant insights into the molecular functions, biological processes, and signaling pathways in these targets. Protein MYH1, MYL2, Cp, FABP4, apoA-IV, and Ywhaz may be potential biomarkers, and protein FABP4 and apoA-IV were considered as promising targets in olanzapineinduced IR. Therefore, if the performance of the proposed biomarkers is further confirmed, these proteins can provide powerful targets for exploring the mechanism of olanzapine-induced IR.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Apolipoproteins A; Biomarkers; Cell Line; Computational Biology; Fatty Acid-Binding Proteins; Female; Gene Expression Regulation; Glucose Intolerance; Insulin Resistance; Olanzapine; Proteomics; Rats; Rats, Sprague-Dawley; Signal Transduction; Tandem Mass Spectrometry

Topics: Animals; Antipsychotic Agents; Biomarkers; Cytokines; Disease Models, Animal; Energy Metabolism; Female; Glucose Intolerance; Inflammation Mediators; Insulin Resistance; Locomotion; Metabolic Diseases; Mice; Motor Activity; Olanzapine; Probiotics

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.

Topics: Adipose Tissue; Adiposity; Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dyslipidemias; Female; Glucose Intolerance; Insulin Resistance; Male; Mice; Olanzapine; Pregnancy; Prenatal Exposure Delayed Effects; Sex Factors

Second generation antipsychotic drugs are routinely used as treatment for psychotic disorders. Many of these compounds, including olanzapine, cause metabolic side-effects such as impaired glucose tolerance and insulin resistance. Individual antidiabetic drugs can help control elevated glucose levels in patients treated with antipsychotics, but the effects of combining antidiabetics, which routinely occurs with Type 2 diabetes mellitus patients, have never been studied. Presently, we compared the effects of the three different antidiabetics metformin (500mg/kg, p.o.), rosiglitazone (30mg/kg, p.o.) and glyburide (10mg/kg, p.o.) on metabolic dysregulation in adult female rats treated acutely with olanzapine. In addition, dual combinations of each of these antidiabetics were compared head-to-head against each other and the individual drugs. The animals received two daily treatments with antidiabetics and were then treated acutely with olanzapine (10mg/kg, i.p.). Fasting glucose and insulin levels were measured, followed by a 2h glucose tolerance test. Olanzapine caused a large and highly significant glucose intolerance compared to vehicle treated rats. Rosiglitazone decreased glucose levels non-significantly, while both metformin and glyburide significantly decreased glucose levels compared to olanzapine-only treated animals. For antidiabetic dual-drug combinations, the rosiglitazone-metformin group showed an unexpected increase in glucose levels compared to all of the single antidiabetic drugs. However, both the metformin-glyburide and rosiglitazone-glyburide groups showed significantly greater reductions in glucose levels following olanzapine than with single drug treatment alone for metformin or rosiglitazone, bringing glucose levels down to values equivalent to vehicle-only treated animals. These findings indicate that further study of antidiabetic dual-drug combinations in patients treated with antipsychotic drugs is warranted.

Topics: Animals; Benzodiazepines; Disease Models, Animal; Drug Therapy, Combination; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Glyburide; Hypoglycemic Agents; Insulin; Metformin; Olanzapine; Rats; Rats, Sprague-Dawley; Rosiglitazone; Selective Serotonin Reuptake Inhibitors; Thiazolidinediones; Time Factors

The second generation antipsychotic drugs are effective treatments for psychotic disorders. Many of these compounds, including the drug olanzapine, have been associated with metabolic side-effects, including weight gain, impaired glucose tolerance and insulin resistance, which increase the risk of developing cardiometabolic disorders. Rodent models of olanzapine-induced metabolic side-effects have been used to study the physiology of these effects, but only at a single time point after drug treatment. The purpose of the present study was to examine longitudinal changes with chronic antipsychotic drug treatment. Adult female rats were treated with either olanzapine (15 mg/kg) or vehicle for five consecutive days each week, followed by a 48 h washout period. Animals were then challenged with either olanzapine (15 mg/kg) or vehicle, and fasting glucose and insulin values were recorded, as well as glucose clearance in the glucose tolerance test. Treatment with olanzapine was continued for 10 weeks, with weekly tests of metabolic indices. Rats treated acutely with olanzapine showed both glucose dysregulation and insulin resistance; for the group treated during the week with olanzapine, these effects did not change by the end of ten weeks of treatment. However, in the group of animals challenged only once per week with olanzapine, the metabolic side-effects markedly intensified with the passage of time, whereby glucose intolerance and insulin resistance increased significantly compared to both baseline values and all other treatment groups. This previously unreported sensitization phenomenon represents a novel finding that may have clinical implications for patients receiving intermittent antipsychotic drug dosing or with variable adherence to treatment.

Topics: Animals; Benzodiazepines; Blood Glucose; Drug Administration Schedule; Female; Glucose Intolerance; Insulin; Insulin Resistance; Olanzapine; Rats; Rats, Sprague-Dawley; Treatment Outcome

The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents.. We compared the effects of 3 distinct classes of antidiabetic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metabolic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assessment of insulin resistance equation.. Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels.. We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by antidiabetic treatments.. The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Female; Glucose Intolerance; Glyburide; Hypoglycemic Agents; Insulin Resistance; Metformin; Olanzapine; Rats; Rosiglitazone; Thiazolidinediones

This study consisting of two subprojects was undertaken to evaluate the effects of hyperprolactinemia on cardiovascular disease (CVD) risk parameters such as anthropometric measures, insulin sensitivity and blood lipids in patients with schizophrenia or related psychoses on long term treatment with antipsychotics.. In subproject Ι, 45 patients receiving the 2nd generation antipsychotics risperidone, clozapine or olanzapine were compared regarding prolactin (PRL), body mass index (BMI), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and blood lipids. In subproject Π, 24 patients receiving 1st or 2nd generation antipsychotics were investigated with diurnal profile of PRL and oral glucose tolerance test (OGTT).. Elevated PRL levels were found in about 45% of the patients and occurred more often in patients receiving risperidone or haloperidol, compared to patients receiving clozapine or olanzapine. In contrast, in subproject Ι, insulin and HOMA-IR were higher and high density lipoprotein cholesterol was lower in patients receiving clozapine or olanzapine, compared with patients receiving risperidone. However, PRL levels did not correlate to BMI, insulin, HOMA-IR or lipids in any of these three treatment groups. In subproject Π, OGTT showed impaired glucose tolerance in 25% and new-onset diabetes in 4% of the 24 patients investigated. Additionally, the PRL (median 24 h) levels correlated positively to the 2 h glucose level at OGTT (rs=0.42, p=0.04).. Our findings point to that hyperprolactinemia due to 1st and 2nd generation antipsychotics may decrease insulin sensitivity, whereas other mechanisms probably underlie insulin resistance induced by PRL-sparing antipsychotics such as clozapine and olanzapine.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Clozapine; Female; Glucose Intolerance; Humans; Hyperprolactinemia; Insulin Resistance; Lipids; Male; Middle Aged; Olanzapine; Prolactin; Psychotic Disorders; Risperidone; Schizophrenia; Young Adult

Olanzapine and highly palatable diets can alter metabolism and brain function. We investigated the interaction of chronic treatment (4 months) with olanzapine and a cafeteria diet on metabolic parameters, memory tasks (spatial and aversive), the elevated plus maze and locomotor activity induced by d-amphetamine. Male Wistar rats were separated into the following groups: standard diet vehicle, standard diet and olanzapine, cafeteria diet vehicle and cafeteria diet and olanzapine. Olanzapine was administered in the drinking water (approximately 1.5 mg/kg/day), and after 3 days of treatment, the rats exhibited an expected anxiolytic effect and reduced amphetamine-induced hyperlocomotion. After 4 months of treatment, cafeteria diet vehicle and cafeteria diet olanzapine rats exhibited an increased body weight and heavier fat pads compared with the standard diet groups. Olanzapine increased only the epididymal and mesenteric fat pads. The cafeteria diet and olanzapine group showed greater glucose intolerance compared with all other groups. The cafeteria diet altered the effects of chronic olanzapine on the performance in the water maze and inhibitory avoidance tasks. Chronic olanzapine treatment failed to affect amphetamine-induced locomotion and to produce anxiolytic effects in the elevated plus maze task, regardless of the diet. Our results suggest that chronic olanzapine caused an increase in fat pads, which is putatively involved in the etiology of many metabolic diseases. Rats on the cafeteria diet were overweight and exhibited glucose intolerance. We did not observe these effects with olanzapine treatment with the standard diet. Moreover, the chronic treatment regimen caused tolerance to the antipsychotic and anxiolytic effects of olanzapine and seemed to potentiate some of the metabolic effects of the cafeteria diet. The cafeteria diet also modified the effects of chronic treatment with olanzapine on cognitive tasks, which may represent an undesirable effect of poor diets in psychiatric patients.

Topics: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzodiazepines; Diet; Dietary Fats; Eating; Fast Foods; Glucose Intolerance; Humans; Male; Maze Learning; Motor Activity; Obesity; Olanzapine; Rats; Rats, Wistar

The aim of this study was to model in mice the association between metabolic syndrome and the administration of atypical antipsychotic (AAP). Two dosages (4 and 8 mg/kg per day) of olanzapine (OL) were infused in 36 female mice for 30 days by osmotic mini-pumps. This study was also designed to further extend the implications raised in other experiments by our model of AAP-induced metabolic dysregulation. Through the use of the osmotic mini-pumps, this model is aimed to circumvent the shorter (than in humans) half-life of AAPs in rodents and to chronically administer OL by a reliable and less disturbing method. Indirect calorimetry was used to evaluate metabolic rate (MR) and respiratory exchange ratio together with weight and caloric intake. Serum insulin, leptin, and glucose tolerance (oral glucose tolerance test) were assessed. Pancreatic beta cells insulin levels, periuterine and liver fat content were also analyzed. Olanzapine-infused mice exhibited a reduction of overall MR (kilojoule per hour) and resting MR and respiratory exchange ratio, with periuterine fat significantly enlarged. All metabolic alterations were detected at the highest dose, with major effects found on weight gain and hyperphagia. Impaired glucose metabolism, associated with hyperinsulinemia and hyperleptinemia were found. Insulin resistance was evidenced by the raise of HOMA-IR index. Increased insulin and lipid storage were detected at pancreatic and hepatic levels respectively. These findings illustrate the development of a cluster of risk factors (metabolic syndrome) and, for the first time, a decrease of energy expenditure (MR) due to chronic OL infusion.

Topics: Animals; Benzodiazepines; Body Weight; Dyslipidemias; Energy Metabolism; Female; Glucose Intolerance; Infusion Pumps, Implantable; Infusions, Intravenous; Insulin Resistance; Metabolic Syndrome; Mice; Olanzapine; Time Factors

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Drug Administration Schedule; Eating; Female; Glucagon-Like Peptide 1; Glucose Intolerance; Glucose Tolerance Test; Intra-Abdominal Fat; Liraglutide; Olanzapine; Rats; Rats, Sprague-Dawley; Subcutaneous Fat, Abdominal; Weight Gain

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

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