clozapine 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

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased

Topics: Adipocytes; Animals; Biomarkers; Body Weights and Measures; Chromium; Clozapine; Disease Models, Animal; Fatty Acid-Binding Proteins; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation; Glucose Intolerance; Immunohistochemistry; Insulin; Kidney Diseases; Liver; Mice; Mice, Obese; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Retinal Diseases; Sterol Regulatory Element Binding Protein 1

Clozapine (CLZ), an antipsychotic with a unique mechanism of action, is known to be superior to any other antipsychotic for schizophrenia. However, CLZ is also known to be associated with the development of lethal side effects, which include agranulocytosis and glucose intolerance (GI). Regular measurement and registration of blood test results have been mandatory for all CLZ users; however, these risks may still prevent therapists from prescribing CLZ. While CLZ-induced agranulocytosis has been well documented, CLZ-induced GI in the real world has not been fully investigated. Therefore, in this study, we used data registered in monitoring systems to investigate background factors associated with new-onset GI after CLZ administration and changes in HbA1c levels during CLZ treatment. Data of all patients with schizophrenia who were using CLZ from July 29, 2009 to January 20, 2016 were used for the analysis. Of the 3,746 patients enrolled in the study, 92 (2.5%) had GI at baseline; of the remaining 3,654 patients, 428 (11.7%) developed new-onset GI. Multivariate logistic regression analysis revealed that the development of new-onset GI was significantly associated with older age, higher baseline HbA1c levels, and longer treatment duration. In patients with GI at baseline, HbA1c levels were maintained or improved over 18 months, while in the other patients, CLZ administration gradually elevated HbA1c levels. The findings of this study suggest that, although adequate monitoring and intervention is required, CLZ induction and maintenance therapy may be safe, even for patients with impaired glucose tolerance.

Topics: Adult; Antipsychotic Agents; Clozapine; Female; Glucose Intolerance; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Japan; Male; Middle Aged; Multivariate Analysis; Risk; Schizophrenia

The aim of this study was to investigate clozapine use and its associated adverse effects in patients in Japan.. We analyzed data recorded from July 2009 to January 2016 (N = 3780 patients) in the Clozaril Patient Monitoring Service, which was established in Japan in 2009 and includes all Japanese patients who have been prescribed clozapine.. The treatment discontinuation rate was 23.9% (869/3780 cases). The average ± SD treatment duration was 234.9 ± 306.9 days (median, 115 days), and the average ± SD dosage was 186.41 ± 151.6 mg/d. The estimated treatment continuation rates resulting from all-cause discontinuation were 78.2 after 1 year and 72.9% after 2 years of treatment. The incidence of neutropenia/leucopenia was 5.4% (206/3780 cases). The average ± SD dose before discontinuation was 233.36 ± 168.15 mg (median, 200 mg; range, 4-600 mg). The incidence of glucose intolerance was 15.4% (583/3780 cases). Of 3780 patients, 98 (2.67%) developed glucose intolerance before and after taking clozapine administration, whereas 485 patients (12.8%) developed glucose intolerance after taking clozapine. The average ± SD time from treatment initiation to new onset of glucose intolerance was 382.2 ± 420.2 days (median, 216 days; range, 4-2053 days).. The data obtained in this study, particularly regarding the incidence of clozapine-induced adverse events, will enable the optimal and safe use of clozapine in Japanese patients with treatment-resistant schizophrenia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Child; Clozapine; Female; Glucose Intolerance; Humans; Japan; Leukopenia; Male; Middle Aged; Neutropenia; Young Adult

Metabolic syndrome is a major concern in psychotic patients receiving atypical antipsychotics. Recent evidence suggests that sterol regulatory element-binding proteins (SREBPs) and insulin-induced genes (INSIGs) are implicated in the antipsychotic-induced metabolic side-effects. Vitamin D (VD) deficiency, a highly prevalent phenomenon among patients with psychosis, might also predispose individuals to metabolic syndrome Considering that VD has modulating effects on the INSIG/SREBP pathway, it is possible that VD may have a role in the antipsychotic-induced metabolic disturbances involving its effects on the INSIG/SREBP system. Thus, the present study aimed to evaluate the effects of VD deficiency and VD supplementation on antipsychotic-induced metabolic changes in rats. After 4-week administration, clozapine (10mg/kg/d) and risperidone (1mg/kg/d) both caused glucose intolerance and insulin resistance in VD deficient rats, but not in rats with sufficient VD status. Antipsychotic treatments, especially clozapine, elevated serum lipid levels, which were most apparent in VD deficient rats, but alleviated in VD-supplemented rats. Additionally, antipsychotic treatments down-regulated INSIGs and up-regulated SREBPs expression in VD deficient rats, and these effects were attenuated when VD status was more sufficient. Collectively, this study disclose the novel findings that antipsychotic-induced metabolic disturbances is exacerbated by VD deficiency and can be alleviated by VD supplementation, providing new evidence for the promising role of VD in prevention and treatment of metabolic disorders caused by antipsychotic medications. Furthermore, our data also suggest the involvement of INSIG/SREBP pathway in the antipsychotic-induced hyperlipidemia and beneficial effects of VD on lipid profile.

Topics: Animals; Antipsychotic Agents; Body Weight; Clozapine; Disease Models, Animal; Eating; Glucose Intolerance; Glucose Tolerance Test; Insulin Resistance; Intra-Abdominal Fat; Male; Random Allocation; Rats, Sprague-Dawley; Risperidone; Vitamin D Deficiency

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

To investigate the prevalence of and risk factors for overweight and diabetes mellitus in long-stay psychiatric inpatients.. Statistical analysis of data collected from medical, laboratory, and pharmacy files.. 80% of the 256 patients were suffering from schizophrenia or other psychotic disorders. The prevalence of diabetes mellitus was 15%. The prevalence of a disturbed glucose tolerance was 14%. Severe overweight (BMI > 30) was positively associated with the use of clozapine (odds ratio (OR) = 2.7; 95% confidence interval (CI): 1.31-5.75), but negatively with the diagnosis schizophrenia (OR = 0.4; 95% CI: 0.22-0.88). Diabetes mellitus was associated with severe overweight (OR = 3.5; 95% CI: 1.57-7.69). Caucasian patients were at a lower risk for diabetes mellitus (OR = 0.2; 95% CI: 0.08-0.54).. In residential psychiatric patients, diabetes mellitus is especially associated with overweight and non-Caucasian origin. In this survey, the use of clozapine was associated with overweight, but not directly with diabetes mellitus. Diabetes mellitus is highly prevalent, which calls for screening for diabetes mellitus at regular intervals.

Topics: Adult; Clozapine; Diabetes Mellitus; Ethnicity; Female; Glucose Intolerance; Humans; Inpatients; Male; Middle Aged; Obesity; Odds Ratio; Prevalence; Psychotic Disorders; Risk Factors; Schizophrenia

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

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

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