clozapine and Diabetes-Mellitus--Type-2

Schizophrenia, a serious psychiatric disorder, is among the top 10 global causes of disability and affects nearly 1% of the world population. Antipsychotics constitute the best treatment for patients with schizophrenia, however, this treatment class carries a high risk of metabolic syndrome, including lipid abnormalities. Indeed, the risk of metabolic syndrome would be increased in the population with schizophrenia compared to the general population. The objective is to summarize the prevalence, the mechanisms, and the potential treatments of antipsychotic-induced metabolic syndrome. This is a narrative review of the literature. We searched the electronic database Medline, accessed through PubMed, to find studies that investigated the prevalence and treatments of metabolic syndrome in the adult population using antipsychotics. The prevalence of metabolic syndrome in patients treated with antipsychotics ranges from 37% to 63%. Antipsychotic iatrogenic effects include weight gain/increased waist circumference, dyslipidemia, insulin resistance/type 2 diabetes, and hypertension. Clozapine and olanzapine are reported to precipitate the onset of metabolic syndrome features. In patients with metabolic syndrome, an antipsychotic with less metabolic side effects such as lurasidone, lumateperone, ziprasidone, and aripiprazole should be prioritized. Unlike medications, aerobic exercise and dietetic counseling were found to be efficient as the nonpharmacologic treatment of antipsychotic-induced metabolic syndrome. Few pharmacological treatments were proven effective against weight gain in this patient population. The risk of metabolic syndrome induced by antipsychotics should be early recognized and closely monitored. Primary and secondary prevention of metabolic syndrome or onset of its feature might help reduce the risk of death for patients using antipsychotics.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypertension; Metabolic Syndrome; Olanzapine; Schizophrenia; Weight Gain

The second generation antipsychotic drug clozapine represents the most effective pharmacotherapy for treatment-resistant psychosis. It is also associated with low rates of extrapyramidal symptoms and hyperprolactinemia compared to other antipsychotic drugs. However, clozapine tends to be underutilized in clinical practice due to a number of disabling and serious side-effects. These are characterized by a constellation of metabolic side-effects which include dysregulation of glucose, insulin, plasma lipids and body fat. Many patients treated with clozapine go on to develop metabolic syndrome at a higher rate than the general population, which predisposes them for Type 2 diabetes mellitus and cardiovascular disease. Treatments for the metabolic side-effects of clozapine vary in their efficacy. There is also a lack of knowledge about the underlying physiology of how clozapine exerts its metabolic effects in humans. In the current review, we focus on key studies which describe how clozapine affects each of the main symptoms of the metabolic syndrome, and cover some of the treatment options. The clinical data are then discussed in the context of preclinical studies that have been conducted to identify the key biological substrates involved, in order to provide a better integrated overview. Suggestions are provided about key areas for future research to better understand how clozapine causes metabolic dysregulation.

Topics: Animals; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Drug-Related Side Effects and Adverse Reactions; Humans; Hyperprolactinemia; Metabolic Syndrome; Psychotic Disorders; Risk Factors

Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950s, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first-generation, conventional APs to so-called "atypical" (or 2nd/3rd generation) APs parallels acknowledgment of serious metabolic side-effects associated in particular with these newer agents. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, contributing to the three- to fivefold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independently of AP treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly and directly influence pathways of glucose metabolism independently of weight gain and even in absence of psychiatric illness. Mechanisms of these direct effects remain poorly elucidated but may involve central and peripheral antagonism of neurotransmitters implicated not only in the therapeutic effects of APs but also in glucose homeostasis, possibly via effects on the autonomic nervous system. The clinical relevance of studying "direct" effects of these drugs on glucose metabolism is underscored by the widespread use of these medications, both on and off label, for a growing number of mental illnesses, extending safety concerns well beyond schizophrenia.

Topics: Animals; Antipsychotic Agents; Autonomic Nervous System; Clozapine; Diabetes Mellitus, Type 2; Glucose; Glucose Clamp Technique; Humans; Insulin Resistance; Receptors, Dopamine D2; Receptors, Serotonin, 5-HT2; Schizophrenia; Weight Gain

Clozapine is the most effective antipsychotic, but its use is tempered by adverse metabolic effects such as weight gain, glucose intolerance and type II diabetes. Current interventions do not facilitate compelling or sustained improvement in metabolic status. Recent studies suggest that glucagon-like peptide-1 (GLP-1) may play a key role in clozapine's metabolic effects, possibly suggesting that clozapine-associated obesity and diabetes are mediated independently through reduced GLP-1. As a result, GLP-1 agonists could show promise in reversing antipsychotic-induced metabolic derangements, providing mechanistic justification that they may represent a novel approach to treat, and ultimately prevent, both diabetes and obesity in patients on clozapine. GLP-1 agonists are already used for diabetes, and they provide a unique combination of glycaemic improvement and metabolically relevant weight loss in diabetic and non-diabetic patients, in the context of a currently favourable safety profile. Using GLP-1 agonists for clozapine-associated obesity and diabetes could be a potentially effective intervention that may reduce cardiometabolic morbidity and mortality in this vulnerable patient population.

Topics: Animals; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Humans; Obesity

The use of antipsychotic therapy has been proven to have an association with the incidence of diabetes mellitus. The use of atypical antipsychotics is shown to have a higher association, in contrast with typical antipsychotics. Olanzapine and Clozapine appear to have the highest rates of diabetes mellitus incidence, due to their tendency to affect glucose metabolism compared with other antipsychotic drugs. In this research the main goal is to understand which antipsychotic drugs are the most diabetogenic and to show the mechanisms involved in the glucose metabolism dysregulations with special focus on Olanzapine considering it is a very commonly prescribed and used drug especially among patients with schizophrenia.. Our study is a literature based research. For our research we reviewed 41 Pubmed published articles from 2005 to 2015.. According to most of the literature, from all the antipsychotics, Clozapine followed by Olanzapine appear to be the atypical neuroleptics that most relate to metabolic syndrome and Diabetes. The basis for this metabolic dysregulations appears to be multifactorial in origin and a result of the drugs, environment and genes interaction.

Topics: Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Female; Humans; Male; Olanzapine; Risk Assessment; Schizophrenia

Clozapine is, and will remain in the coming years, an irreplaceable drug in psychiatry which has elective indication in treatment-resistant schizophrenia, suicide risk in schizophrenia spectrum disorders, aggressiveness or violence in psychiatric patients, psychosis in Parkinson's disease, prevention and treatment of tardive dyskinesia. Unfortunately, the drug is largely underused for many and serious side effects. Only a good knowledge of these side effects and of the main strategies to prevent their occurrence or minimize their impact can allow overcoming the underutilization of this valuable therapy. The article describes the clinical and epidemiological features of the non-motor side effects of clozapine including blood dyscrasias, constipation, diabetes, enuresis, fever, hepatitis, hypersalivation, ileus, myocarditis, nephritis, priapism, seizures, serositis, weight gain and metabolic syndrome. The paper suggests several strategies, supported by scientific evidence, in the management of these side effects. The neuropsychiatric side effects of clozapine are not discussed in this review.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Electroencephalography; Humans; Leptin; Metabolic Syndrome; Paraproteinemias; Receptor, Serotonin, 5-HT2C; Seizures; Weight Gain

Despite treatment advances over the past decades, schizophrenia remains one of the most severe psychiatric disorders that is associated with a chronic relapsing course and marked functional impairment in a substantial proportion of patients. In this article, a historical overview of the pharmacologic advances in the treatment of schizophrenia over the past 50 years is presented. This is followed by a review of the current developments in optimizing the treatment and outcomes in patients with schizophrenia. Methodological challenges, potential solutions, and areas of particular need for further research are highlighted. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good "effectiveness" measure mapping onto functional outcomes is still lacking. Moreover, the field must advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate regarding whether and which first- or second-generation antipsychotics should be used. However, especially when considering individual adverse effect profiles, the differentiation into first- and second-generation antipsychotics as unified classes cannot be upheld, and a more differentiated view and treatment selection are required. The desired, individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Acute and long-term goals and effects of medication treatment should be balanced. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To discover novel treatments with enhanced/broader efficacy and improved tolerability, and to enable personalized treatment, the mechanisms underlying illness development and progression, symptomatic improvement, and side effect development need to be elucidated.

Topics: Antipsychotic Agents; Chlorpromazine; Clozapine; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Monitoring; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Evidence-Based Medicine; Humans; Long-Term Care; Metabolic Clearance Rate; Parkinsonian Disorders; Precision Medicine; Psychiatric Status Rating Scales; Research; Schizophrenia; Schizophrenic Psychology; Secondary Prevention; Treatment Outcome

Atypical antipsychotic drugs have less extra pyramidal side effects and are more effective to control the clinical manifestations of schizophrenia. However, their use may be associated to a higher incidence of weight gain, dyslipidemia, metabolic syndrome, glucose intolerance and type 2 diabetes mellitus. We performed a systematic literature search to evaluate the risk of type 2 diabetes mellitus incidence associated to the use of atypical antipsychotic drugs, compared to conventional treatment. If users of all types of atypical antipsychotic drugs are compared with users of conventional treatment, no significant differences in the incidence of type 2 diabetes mellitus were observed. If individual drugs are evaluated, clozapine and risperidone are associated with a higher risk of diabetes than haloperidol. Quetiapine is associated with a lower risk of diabetes than conventional treatment. The quality of the evidence found was low; therefore, new studies should been performed.

Topics: Antipsychotic Agents; Chronic Disease; Clozapine; Diabetes Mellitus, Type 2; Humans; Mental Disorders; Risk Factors; Risperidone

Most of the data evaluating the potential relationship between diabetes, schizophrenia, and anti-psychotics currently derive from retrospective analysis. Relevant confounders of such data include screening and selection bias. Prospective data collected from randomized controlled trials may reduce such biases. As no single trial has glucose comparisons as a primary endpoint, we undertook a systematic review of available data.. Embase, HealthStar, MEDLINE, Pre-MEDLINE, and PsycINFO databases were searched online for relevant articles. Abstracts from major congresses held between January 2000 and April 2006 were included. Search terms included all currently available antipsychotics: olanzapine, risperidone, clozapine, quetiapine, ziprasidone, aripiprazole, haloperidol, chlorpromazine, and zotepine.. Prospective clinical trials involving schizophrenia patients with no stated previous glucose abnormalities randomly assigned to cohorts receiving active or placebo comparator antipsychotic medications were included with no restrictions on study length. 16 studies were from peer-reviewed publications, 4 were from posters at major congresses, and 2 were available only on Internet-based sites.. Glucose parameters reported included fasting and random glucose and glycosylated hemoglobin. Data reported included mean changes and categorical reports of abnormal levels.. Data were available in 6329 patients from 22 trials. The most common comparator agents were aripiprazole and olanzapine in 4 studies including 1432 patients. 14 studies reported fasting and 9 studies reported nonfasting data. 15 studies were a minimum of 5 months, with 8 studies of at least 1 year's duration. No consistent significant glucose differences were found between any comparator antipsychotics or placebo in any trial.. In contrast to some of the retrospective data, an analysis of prospective data from randomized clinical trials showed no consistent significant differences in the incidence of treatment-emergent glucose abnormalities in patients treated with antipsychotics. The reduction in both screening and selection biases may be relevant. Although one third of the studies had at least 1 year's duration, the data are not sufficient to reach conclusions regarding patients receiving longer-term treatment with atypical antipsychotics.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Olanzapine; Piperazines; Quinolones; Schizophrenia

Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings.. A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached.. Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations.. The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Cataract; Clozapine; Diabetes Mellitus, Type 2; Health Status; Humans; Hyperlipidemias; Hyperprolactinemia; Long QT Syndrome; Monitoring, Physiologic; Myocarditis; Obesity; Practice Guidelines as Topic; Schizophrenia; Sexual Dysfunctions, Psychological; Weight Gain

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Humans; Middle Aged; Olanzapine; Risk Factors; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

Five new antipsychotic drugs introduced in the United States in the last decade offer physicians the ability to treat patients with schizophrenia and bipolar mania without the adverse effects of the first-generation antipsychotics. In this article, the authors discuss the advantages and side effects of these agents and present a guide to help physicians choose the optimal drug in the most favorable formulation for each patient.

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Administration Schedule; Humans; Hyperprolactinemia; Mental Disorders; Olanzapine; Patient Compliance; Piperazines; Practice Guidelines as Topic; Prescription Fees; Quetiapine Fumarate; Quinolones; Risk Assessment; Risperidone; Thiazoles; Torsades de Pointes; Treatment Outcome; Weight Gain

Dyslipidemia is an increasing problem in most industrialized societies and is a risk factor for coronary heart disease (CHD). Imbalances in individual lipid components, including total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and serum triglycerides, have each been shown to contribute to this increased risk. Certain psychiatric patient populations, such as those afflicted with schizophrenia, are of particular concern. Psychiatric patients with schizophrenia are naturally at increased risk for dyslipidemia and obesity, in part due to poor diet and sedentary lifestyle, but these conditions can be exacerbated by some antipsychotic medications. Clozapine and olanzapine, for example, appear to be associated with hyperlipidemia, which may be associated with changes in body weight. Other, newer antipsychotic agents may exhibit less liability for weight gain and the development of dyslipidemia. This review is intended to briefly highlight the association between dyslipidemia and cardiovascular disease, the changes in serum lipids associated with some antipsychotic agents, and how these changes in serum lipids affect the monitoring of schizophrenia patients.

Topics: Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Cholesterol; Cholesterol, VLDL; Clozapine; Coronary Disease; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Obesity; Olanzapine; Risk Factors; Schizophrenia; Triglycerides; Weight Gain

After the introduction of the so-called "atypical antipsychotics" in the clinical experience hyperglycemia as well as increased triglyceride and cholesterol serum levels were reported in patients treated with some of these agents. In this article, the recently published population-based studies are reviewed.. According to the available data, the risk to develop type 2 diabetes mellitus or hyperlipidemia in patients treated with clozapine and olanzapine is increased. The underlying pathomechanism still remains widely unclear. Since overweight is a known risk factor for type 2 diabetes mellitus, the weight-inducing effect of atypical antipsychotics may play an important role.. Since metabolic disorders often lead to severe diseases, these side effects of antipsychotics should be paid more attention.

Topics: Antipsychotic Agents; Benzodiazepines; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypercholesterolemia; Hypertriglyceridemia; Olanzapine; Pirenzepine; Risk

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Clinical Trials as Topic; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Glucose; Haloperidol; Humans; Intellectual Disability; Male; Mental Disorders; Metabolic Syndrome; Middle Aged; Olanzapine; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Time Factors; Weight Gain

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

Clozapine remains the most effective agent for treatment-resistant patients with schizophrenia. Recently, treatment with clozapine has been linked to a number of metabolic disturbances, including weight gain, diabetes mellitus, and serum lipid abnormalities. Despite the potential risks of medical morbidities, clozapine continues to have a major role in the care of treatment-resistant patients with schizophrenia. This article discusses the diagnosis and significance of the above metabolic abnormalities and potential mechanisms for these abnormalities as well as recommendations for monitoring and treatment.

Topics: Cholesterol; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypertriglyceridemia; Schizophrenia; Weight Gain

Clozapine and olanzapine are some of the most effective antipsychotics, but both are associated with weight gain and relevant metabolic disturbances, including pre-diabetes and diabetes. Non-pharmacological/behavioural interventions have had limited effects counteracting these adverse effects. Semaglutide, a glucagon-like peptide 1 receptor agonist, is approved for the treatment of type 2 diabetes and obesity. We will investigate the long-term effects of add-on treatment with semaglutide once a week versus placebo once a week on the metabolic status in pre-diabetic (glycated haemoglobin A1c (HbA1c) 35-47 mmol/mol (5.4%-6.4%) and diabetic (HbA1c 48-57 mmol/mol (6.5%-7.4%)) patients diagnosed with a schizophrenia spectrum disorder who initiated clozapine or olanzapine treatment within the last 60 months.. This is a 26-week, double-blinded, randomised, placebo-controlled trial. Altogether, 104 patients diagnosed with a schizophrenia spectrum disorder, aged 18-65 years, with pre-diabetes or diabetes will be randomised to injections of 1.0 mg semaglutide once a week or placebo for 26 weeks. The primary endpoint is change from baseline in HbA1c. Secondary endpoints include changes in body weight, hip and waist circumference and plasma levels of insulin, glucagon, glucose, and C-peptide, insulin sensitivity, beta cell function, hepatic function, fibrosis-4 score, lipid profile, incretin hormones, bone markers, body composition, bone density, proteomic analyses and oxidative stress markers. Together with alcohol, tobacco and drug use, potential effects on the reward value of a sweet-fat stimulus, psychopathology, level of activity and quality of life will also be assessed.. This study is approved by the Danish Medicines Agency and the regional scientific ethics committee of the Capital Region of Denmark (committee C, #H-20019008) and will be carried out in accordance with International Council for Harmonisation Good Clinical Practice guidelines and the Helsinki Declaration. The results will be disseminated through peer-review publications and conference presentations.. NCT04892199.

Topics: Clozapine; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Olanzapine; Prediabetic State; Proteomics; Quality of Life; Randomized Controlled Trials as Topic; Schizophrenia

Treatment with antipsychotics is associated with an increased risk of type 2 diabetes mellitus (T2D), and increased levels of inflammatory biomarkers are present in patients with T2D. We previously demonstrated that the glucagon-like peptide-1 receptor agonist liraglutide significantly reduced glucometabolic disturbances and body weight in prediabetic, overweight/obese schizophrenia-spectrum disorder patients treated with clozapine or olanzapine. This study aims to assess the involvement of cytokines in the therapeutic effects of liraglutide.. Serum concentrations of 10 cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α, interleukin 1β [IL-1β], IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13) from fasting prediabetic and normal glucose-tolerant (NGT) patients with schizophrenia-spectrum disorders were measured using multiplexed immunoassays. Prediabetic patients were randomized to 16 weeks of treatment with liraglutide or placebo, and cytokines were measured again at the end of the treatment.. IFN-γ (1.98 vs 1.17 pg/ml, P = .001), IL-4 (0.02 vs 0.01 pg/ml, P < .001), and IL-6 (0.73 vs 0.46 pg/ml, P < .001) were significantly higher in prediabetic (n = 77) vs NGT patients (n = 31). No significant changes in cytokine levels following treatment with liraglutide (n = 37) vs placebo (n = 40) were found.. Prediabetic vs NGT patients with schizophrenia treated with clozapine or olanzapine had increased serum levels of several proinflammatory cytokines, further substantiating the link between inflammation and T2D. Treatment with liraglutide did not affect the investigated cytokines. Further testing of these findings in larger numbers of individuals is needed.

Topics: Biomarkers; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Interleukin-4; Interleukin-6; Liraglutide; Olanzapine; Prediabetic State; Schizophrenia

Clozapine is associated with obesity and type 2 diabetes. Glucagon-like-peptide-1 (GLP-1) receptor agonists such as exenatide can counter clozapine-associated GLP-1 dysregulation. Our 24-week randomized, controlled, open-label, pilot trial of once-weekly extended-release subcutaneous exenatide or usual care (CODEX) (n = 28), found exenatide was associated with significantly greater weight loss. We examined whether this effect was maintained at 12-months post-intervention. We followed up CODEX trial participants at 12-months post trial endpoint, collecting information on weight, BMI, waist circumference, blood pressure, fasting glucose, HbA1c, and use of metformin. The primary outcome of interest was change in weight from trial baseline to 12-months post endpoint and trial endpoint to 12-months post endpoint compared between former exenatide and usual care participants. Only HbA1c differed between baseline and 12-months post endpoint between the exenatide and control groups. From endpoint to 12-month follow up there were significantly greater increases among the former exenatide versus former usual care participants for weight, BMI, HbA1c and proportion with >5% weight gain. Stratifying results by whether participants used metformin post trial did not alter proportion with >5% weight gain. Although there were no significant differences in weight and BMI between baseline and 12-month post endpoint, there were significant increases in weight and BMI in the 12 months post endpoint for the former exenatide group. This was irrespective of metformin use and is in keeping with studies of other GLP-1RA agents. Further studies on GLP-1RAs use beyond 24 weeks for people with clozapine associated weight gain are needed.

Topics: Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Obesity

Topics: Adolescent; Adult; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Humans; Male; Middle Aged; Obesity; Pilot Projects; Schizophrenia; Weight Loss; Young Adult

Clozapine, while effective in treatment refractory schizophrenia, is associated with significant weight gain, heart disease and increased risk of type 2 diabetes mellitus (T2DM). Although there is evidence for weight loss with metformin for people with obesity who are already taking clozapine, there have been no published trials that have investigated the effect of metformin in attenuating weight gain at the time of clozapine initiation.. A 24-week double-blind placebo-controlled trial of concomitant prescription of metformin at clozapine commencement. Eighty-six people being commenced on clozapine will be randomised to placebo or metformin (variable dose, up to 2 g/day). The primary outcome is comparative end point body weight, between the placebo and metformin groups. Secondary outcomes are comparative rates of conversion to T2DM, alteration of metabolic syndrome parameters, proportion gaining >5% body weight and changes in diet and appetite. We will additionally examine biomarkers associated with change in weight among trial participants.. Ethics approval was granted by the Metro South Human Research Ethics Committee HREC/17/QPAH/538-SSA/17/QPAH/565. We plan to submit a manuscript of the results to a peer-reviewed journal, and present results at conferences, consumer forums and hospital grand rounds.. ACTRN12617001547336; Pre-results.

Topics: Antipsychotic Agents; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Male; Metabolic Syndrome; Metformin; Obesity; Research Design; Schizophrenia; Secondary Prevention; Treatment Outcome; Weight Gain; Weight Loss

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

The goal of this 5-year naturalistic study of patients treated with clozapine was to examine the incidence of treatment-emergent diabetes mellitus in relation to other factors, including weight gain, lipid abnormalities, age, clozapine dose, and treatment with valproate.. Data on age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation were collected from medical records of 82 outpatients with schizophrenia or schizoaffective disorder. Clozapine dose, data on use of valproate, and laboratory test results were recorded at 6-month intervals.. The mean age at the time of clozapine initiation of the 82 patients was 36.4 years; 26.8% of the patients were women, and 91.5% were Caucasian. The mean baseline weight was 175.5 lb, and the mean body mass index was 26.9 kg/m(2). Thirty patients (36.6%) were diagnosed with diabetes during the 5-year follow-up. Weight gain, use of valproate, and total daily dose of clozapine were not significant risk factors for developing diabetes mellitus. Patients experienced significant weight gain that continued until approximately month 46 from initiation of clozapine. There was a nonsignificant increase in total serum cholesterol and a significant increase in serum triglycerides level.. The results support the hypotheses that patients treated with clozapine experience significant weight gain and lipid abnormalities and appear to be at increased risk for developing diabetes.

Topics: Adult; Age Factors; Antipsychotic Agents; Body Mass Index; Body Weight; Cholesterol; Clozapine; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Family; Female; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Hypertriglyceridemia; Incidence; Male; Obesity; Psychotic Disorders; Risk Factors; Schizophrenia; Triglycerides; Valproic Acid

Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities.. Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression.. Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine.. With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

Topics: Antipsychotic Agents; Aripiprazole; Clozapine; Diabetes Mellitus, Type 2; Humans; Metabolic Syndrome; Orexins; Prospective Studies; Schizophrenia

Metabolic syndrome and related cardiovascular risk factors are well-known comorbidities among patients with schizophrenia. Biomarkers of these antipsychotic-associated metabolic adverse effects and antipsychotic-induced weight gain are needed. Glucagon-like peptide-1 (GLP-1) is involved in insulin secretion, regulation of satiety, inhibition of food intake, and inhibition of gastric emptying. GLP-1 also induces reduction in body weight. Visfatin/ NAMPT/ PBEF is an adipocytokine secreted by several cells and tissues. Increased plasma visfatin levels have been associated with overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, low grade inflammation, and proinflammatory markers. Associations between antipsychotic-induced weight gain and serum visfatin and GLP-1 levels have been little studied in patients with schizophrenia. The aim of the present study was to test the possible role of serum GLP-1 and visfatin level alterations as markers of weight gain in association with metabolic and inflammatory markers in 190 patients (109 male, 81 female) with schizophrenia on clozapine treatment. High serum levels of GLP-1 correlated significantly with higher levels of visfatin, leptin, insulin, HOMA-IR, higher BMI, and weight change among men. Associations between serum visfatin levels and BMI or weight change were not found in the present patients. Serum GLP-1 level seems to be a marker of metabolic risk factors among men with schizophrenia on clozapine treatment. Female patients may be more sensitive to suppressive effects of clozapine on GLP-1 secretion. Patients on clozapine would benefit from GLP-1 agonists as preventive treatment.

Topics: Clozapine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Humans; Male; Obesity; Weight Gain

Clozapine is one of the drugs that cause the highest level of weight gain. Additionally, obese patients are at higher risk of developing various physical co-morbidities, such as type 2 diabetes and cardiovascular diseases. Forty-nine percent of patients on clozapine suffer from constipation. Apple vinegar (AV) had been assigned health benefits, such as weight loss, laxative properties, blood glucose lowering effects, and reducing the risk of heart disease. Our hypothesis was that AV would lower the mean glycated haemoglobin level and reduce the level of constipation.. Pilot intervention study with a 12-week follow-up. All patients receiving clozapine treatment for schizophrenia at one outpatient clinic were eligible for inclusion. Intervention: Ten millilitres of AV diluted in 200 ml drinking water with breakfast and dinner.. Forty patients were suitable for inclusion and nine completed the intervention. Women had much higher-than-recommended body mass index. Scores for constipation were high. The reduction in constipation was of clinical interest (2.6 (. AV lower the constipation problems faced by patients with schizophrenia treated with clozapine. Further research, repeating this pilot study with a meaningfully larger sample size and randomized with placebo, is needed.

Topics: Acetic Acid; Antipsychotic Agents; Clozapine; Constipation; Diabetes Mellitus, Type 2; Female; Humans; Malus; Pilot Projects; Schizophrenia

In Australia, general practitioners usually are the first point of contact for patients with non-urgent medical conditions. Appropriate and efficient utilisation of pathology tests by general practitioners forms a key part of diagnosis and monitoring. However overutilisationand underutilisation of pathology tests have been reported across several tests and conditions, despite evidence-based guidelines outlining best practice in pathology testing. There are a limited number of studies evaluating the impact of these guidelines on pathology testing in general practice. The aim of our quantitative observational study is to define how pathology tests are used in general practice and investigate how test ordering practices align with evidence-based pathology guidelines.. Access to non-identifiable patient data will be obtained through electronic health records from general practices across three primary health networks in Victoria, Australia. Numbers and characteristics of patients, general practices, encounters, pathology tests and problems managed over time will be described. Overall rates of encounters and tests, alongside more detailed investigation between subcategories (encounter year, patient's age, gender, and location and general practice size), will also be undertaken. To evaluate how general practitioner test ordering coincides with evidence-based guidelines, five key candidate indicators will be investigated: full blood counts for patients on clozapine medication; international normalised ratio measurements for patients on warfarin medication; glycated haemoglobin testing for monitoring patients with diabetes; vitamin D testing; and thyroid function testing.. Ethics clearance to collect data from general practice facilities has been obtained by the data provider from the RACGP National Research and Evaluation Ethics Committee (NREEC 17-008). Approval for the research group to use these data has been obtained from Macquarie University (5201700872). This study is funded by the Australian Government Department of Health Quality Use of Pathology Program (Agreement ID: 4-2QFVW4M). Findings will be reported to the Department of Health and disseminated in peer-reviewed academic journals and presentations (national and international conferences, industry forums).

Topics: Adult; Blood Chemical Analysis; Clozapine; Diabetes Mellitus, Type 2; Electronic Health Records; Evaluation Studies as Topic; General Practice; Glycated Hemoglobin; Guideline Adherence; Health Services Misuse; Humans; International Normalized Ratio; Pathology, Clinical; Thyroid Function Tests; Utilization Review; Victoria; Vitamin D; Warfarin

A 63-year-old woman with diabetes type II and a history of breast cancer was treated with clozapine for her refractory schizophrenia. She developed a dilated cardiomyopathy with an ejection fraction of 25%, a life-threatening event. The cause of heart failure could be multifactorial, with clozapine, family history, chemotherapy, diabetes type II and/or lithium as possible contributing risk factors. Clozapine was discontinued and the patient was referred to a hospice. Two weeks later, her heart failure slowly improved. Subsequently, she became extremely psychotic with a severe decline in quality of life. Therefore, it was decided to restart clozapine under cardiac monitoring. The patient's psychotic symptoms improved and her heart failure status remained stable for more than a year. Thereafter, a small deterioration was seen in cardiac function. In this case, re-exposure to clozapine was successful for at least 2 years.

Topics: Antipsychotic Agents; Cardiomyopathy, Dilated; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Heart Failure; Humans; Middle Aged; Quality of Life; Recurrence; Schizophrenia; Treatment Outcome

Type 2 diabetes (T2D) and raised blood lipids are associated with the use of antipsychotics, not least clozapine.. To describe the prevalence of high blood glucose levels, T2D, and dyslipidemia, in association with the use of clozapine or other antipsychotics in patients with schizophrenia in Iceland.. This study identified 188 patients treated with clozapine and 395 patients never treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital. The comparison group consisted of Icelandic population controls. Data were obtained on blood glucose, HbA1c, and blood lipid levels from these health records.. The prevalence of T2D was 14.3% in the clozapine group, where the mean age was 51.2 years, and 13.7% in the never-on-clozapine group, where the mean age was 58.6 years. Males on clozapine were 2.3-times more likely and females 4.4-times more likely to have developed T2D than controls from an age-adjusted Icelandic cohort, while males on other antipsychotics were 1.5-times more likely and females 2.3-times as likely to have T2D than controls. Only one case of ketoacidosis was identified. Triglyceride levels were significantly higher in both treatment groups compared to controls in the age-adjusted Icelandic cohort.. Clinicians must take active steps to reduce the risk of T2D and raised triglycerides in patients with schizophrenia. Antipsychotics were associated with a greater risk of T2D developing in females compared to males.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Case-Control Studies; Clozapine; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Dyslipidemias; Female; Humans; Iceland; Lipids; Male; Middle Aged; Prevalence; Risk; Schizophrenia; Sex Factors

It has been suggested that clozapine has one of the largest diabetic effects of all atypical antipsychotics. To confirm these findings, we examined retrospectively the risk of new-onset diabetes in long-term clozapine treatment compared to treatment with other antipsychotics in a matched control population with schizophrenia or schizoaffective disorder. Ninety-four adult patients with schizophrenia or schizoaffective disorder who had been treated with clozapine for 5 years or longer were matched on age, diagnosis, and sex to 94 patients without any use of clozapine. The groups were followed up for as long as 20 years. The cumulative incidence of new detection of diabetes in the clozapine group was 22.3% (mean follow-up, 12.3 years; absolute risk difference, 6.3%; 95% confidence interval, -4.9% to 17.5%). An additional rigorous analysis of the 83 matched pairs with normal glucose measurement before end point showed a significant risk difference between the 2 groups (21.7% compared with 8.4%) but may have been biased against clozapine. We conclude that definitive evidence showing a clinically significant larger risk for new-onset diabetes after long-term treatment with clozapine in comparison to other antipsychotics is lacking.

Topics: Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Schizophrenia; Time Factors; Treatment Outcome

Topics: Adult; Clozapine; Diabetes Mellitus, Type 2; Exenatide; Humans; Male; Peptides; Schizophrenia; Venoms; Weight Loss

The atypical antipsychotic agent clozapine, although an effective treatment for schizophrenia, is linked with metabolic adverse effects. We report a case of diabetic ketoacidosis and very severe hypertriglyceridaemia associated with clozapine use, in a patient with type 2 diabetes mellitus, who was successfully treated with continuous insulin infusion and fluids. As clozapine proved to be the most efficacious in controlling the patient's psychotic symptoms, the patient has been continued on clozapine despite its known metabolic side effects. Importantly the patient has achieved satisfactory long-term lipid and glycaemic control. The current recommendations related to the metabolic care for patients treated with atypical antipsychotic agents as well as the mechanisms behind abnormal glucose and lipid regulation with clozapine therapy are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Fluid Therapy; Humans; Hypertriglyceridemia; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Male; Psychotic Disorders; Treatment Outcome

People with severe mental illness have a 20-year life-expectancy shortfall. The majority of antipsychotic medications are associated with obesity and heightened diabetes risk. People with severe mental illness less frequently achieve benchmarked diabetes care, often attributed to poor adherence, lower clinical attendance and documented medical biases in treatment. This case is presented to highlight the profound effect medication change can have on diabetes control.. A 56-year-old man with a 42-year history of schizophrenia had required clozapine treatment for the preceding 14 years. Type 2 diabetes and obesity occurred within 4 years of clozapine instigation. Glycaemic control had been continuously poor, despite frequent contact with diabetes services and multiple medications, including insulin at a dose exceeding 200 IU daily. Request for consideration of antipsychotic review and close interaction with the psychiatry team was initiated at the diabetes outpatient clinic. A gradual medication switch from clozapine to aripiprazole was associated with a reduction in HbA(1c) from 80 to 50 mmol/mol (9.5 to 6.7%) over 4 months, associated with a weight loss of 10 kg. Over the ensuing 2 years, the improvement in HbA(1c) has endured, with total weight loss of 13 kg and halving of insulin requirements.. This case illustrates the benefits of engagement between endocrinologists and psychiatrists to achieve the shared goal of improved physical health in severe mental illness. Greater interdisciplinary collaboration will help bridge the life-expectancy gap in severe mental illness and may assist in preventing disabling diabetes complications in this vulnerable patient group.

Topics: Antipsychotic Agents; Aripiprazole; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Piperazines; Quinolones; Schizophrenia; Treatment Outcome; Weight Loss

Clozapine, an evidence-based treatment of refractory schizophrenia, is associated with increased weight gain and metabolic dysregulation compared with most antipsychotics in short-term clinical trials. However, there are limited data describing comparative long-term metabolic risks. In this report, we examined whether short-term differences persist with long-term exposure to clozapine.. The data of all patients in a university-based clinic with a psychotic illness or a mood disorder with psychotic features, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis, and treated with an antipsychotic in calendar year 2012 were examined. A total of 307 patients met the criteria; 96 patients were treated with clozapine and the remaining 211 patients were treated with 1 or more non-clozapine antipsychotics. Body mass index, type 2 diabetes, hypertension, dyslipidemia, and obesity were compared.. The mean duration of the clozapine treatment was 7.6 years (range, 2 months to 21 y). On all metabolic measures, there were no statistically significant differences between the clozapine and non-clozapine groups (mean body mass index, 31 vs 32; type 2 diabetes, 17% vs 18%; dyslipidemia, 35% vs 38%; hypertension, 32% vs 39%; and obesity, 48% vs 54%). Removing the olanzapine-treated patients (n = 51) from the non-clozapine group did not change the findings.. In this university-based clinic sample with a large number of clozapine-treated patients, we found no evidence of increased risk in any individual measure for those receiving clozapine. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables likely also impact metabolic risk during the life span. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time due to the accumulated impact of other variables that also impact metabolic risk across the life span.

Topics: Adult; Aged; Antipsychotic Agents; Clozapine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Electronic Health Records; Female; Humans; Male; Metabolic Diseases; Middle Aged; Obesity; Psychotic Disorders; Schizophrenia; Weight Gain; Young Adult

The association between the use of antipsychotics and diabetes mellitus (DM) is still unclear, as depicted by several conflicting reports. Our study aims to assess the risk of DM in new users of antipsychotics.. Our nested case-control study used the Quebec Health Insurance Board databases. People in the source cohort were DM-free and had initiated an antipsychotic treatment. Subjects were cohort members who initiated an antidiabetic or had a diagnosis of DM during their follow-up period. Three variables were used to assess antipsychotic exposure: the antipsychotic used (any typical, clozapine, olanzapine, quetiapine, risperidone, or more than 1 drug); the number of 30-day periods of use; and antipsychotic use at index date (current or past). A paired multivariate logistic regression model was used to calculate adjusted odds ratios.. Among the 88 467 people included in the cohort, 6109 subjects with DM were identified and were matched to 61 090 control subjects. New users of quetiapine were less likely to develop DM than new users of typical antipsychotics (OR, 0.89; 95% CI 0.81 to 0.99). The risk of DM was not statistically different across the atypical antipsychotics. A longer exposure to any antipsychotic (for each 30-day period, OR 1.009; 95% CI 1.006 to 1.011) and current use of antipsychotics (OR 1.26; 95% CI 1.17 to 1.36) were associated with DM.. These results suggest that metabolic parameters of people exposed to antipsychotics should be monitored, irrespective of the drug taken, among the drugs available at the time of analysis.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Case-Control Studies; Clozapine; Cohort Studies; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Humans; Logistic Models; Male; Middle Aged; Olanzapine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risperidone; Time Factors; Young Adult

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Liraglutide; Middle Aged; Obesity; Receptors, Glucagon; Schizophrenia; Weight Loss

Second-generation antipsychotics (SGAs) increase the risk of type 2 diabetes. The mechanism is thought to center on drug-induced weight gain, which starts the dysmetabolic cascade of insulin resistance, increased insulin production and pancreatic beta-cell failure. An independent effect of SGAs on insulin secretion has been suggested in animal models, but has not been demonstrated in clinical samples.. To determine the post-challenge insulin secretion in patients treated with SGAs.. We identified 520 non-diabetic individuals treated with clozapine (N=73), olanzapine (N=190), quetiapine (N=91) or risperidone (N=166) in a consecutive, single-site cohort of 783 adult psychiatric inpatients who underwent a comprehensive metabolic assessment. Insulin secretion was measured as the area under the curve (AUC(insulin)) generated by levels recorded at baseline, 30, 60 and 120 min after the intake of 75 g of glucose. The independent predictors of insulin secretion were determined with regression analysis in the entire sample and separately in patients with normal glucose tolerance (NGT) and prediabetes.. The post-challenge AUC(insulin) was independently predicted by AUC(glucose), waist circumference, triglyceride levels and younger age (p<0.0001); non-smoking status (p=0.0012); and treatment with clozapine (p=0.021). The model explained 33.5% of the variance in insulin secretion (p<0.0001). The clozapine effect was present in the NGT group, but not in prediabetics.. Clozapine, but not olanzapine, quetiapine and risperidone, is an independent predictor of post-challenge insulin secretion in non-diabetics, particularly in those with normal glucose tolerance. The findings suggest that the diabetogenic risk of clozapine may persist even after weight reduction.

Topics: Adult; Antipsychotic Agents; Area Under Curve; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Olanzapine; Predictive Value of Tests; Quetiapine Fumarate; Regression Analysis; Risperidone

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Withholding Treatment

Patients with schizophrenia requiring long-term institutionalization represent those with the worst outcome, leading to personal costs for patients and relatives and constituting a large economical burden for society.. To identify characteristics and predictors of outcome of institutionalized patients with schizophrenia.. One-year follow-up cohort study, utilizing the Danish national registers, of all institutionalized and non-institutionalized patients with schizophrenia in Denmark with an ICD-10 lifetime diagnosis of schizophrenia (F20.0-F20.9) since 1969 and alive at the index date of January 1st 2006 (total number 22,395).. Compared with non-institutionalized patients, institutionalized patients (n=2188; 9.8%) had earlier onset of schizophrenia and lower scholastic achievements, were more often diagnosed with a hebephrenic subtype (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.95-2.80; p<0.001), received higher dosages of antipsychotics, more antipsychotic polypharmacy and more concomitant medications, and had more substance misuse and early retirement pension. In a logistic regression model adjusted for sex and age, institutionalized patients with schizophrenia had an increased risk of type II diabetes (AOR, 1.22; CI, 1.01-1.42; p<0.001), but the mean age of onset of type II diabetes did not differ. The mean patient age was higher in the institutionalized group (62.7 vs. 58.7 years; p=0.027), which was mainly driven by absence of death from suicide in the institutionalized group. Multivariate predictors of institutionalization included hebephrenic subtype, a diagnosis of epilepsy, early retirement pension, male sex, a greater proportion of prior hospitalization, and substance misuse.. Institutionalized patients with schizophrenia had a more complex and worse outcome of the disorder, except for less suicide, illustrated by lower scholastic achievement, receiving higher dosages of antipsychotic medications, more concomitant medications and more prior bed-days.

Topics: Aged; Antipsychotic Agents; Clozapine; Cohort Studies; Denmark; Diabetes Mellitus, Type 2; Educational Status; Female; Humans; Institutionalization; International Classification of Diseases; Logistic Models; Male; Middle Aged; Predictive Value of Tests; Retrospective Studies; Risk Factors; Schizophrenia

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Humans; Psychotic Disorders; Smoking Cessation

Impaired functioning of pancreatic beta cells is a key hallmark of type 2 diabetes. beta cell function is modulated by the actions of different classes of heterotrimeric G proteins. The functional consequences of activating specific beta cell G protein signaling pathways in vivo are not well understood at present, primarily due to the fact that beta cell G protein-coupled receptors (GPCRs) are also expressed by many other tissues. To circumvent these difficulties, we developed a chemical-genetic approach that allows for the conditional and selective activation of specific beta cell G proteins in intact animals. Specifically, we created two lines of transgenic mice each of which expressed a specific designer GPCR in beta cells only. Importantly, the two designer receptors differed in their G protein-coupling properties (G(q/11) versus G(s)). They were unable to bind endogenous ligand(s), but could be efficiently activated by an otherwise pharmacologically inert compound (clozapine-N-oxide), leading to the conditional activation of either beta cell G(q/11) or G(s) G proteins. Here we report the findings that conditional and selective activation of beta cell G(q/11) signaling in vivo leads to striking increases in both first- and second-phase insulin release, greatly improved glucose tolerance in obese, insulin-resistant mice, and elevated beta cell mass, associated with pathway-specific alterations in islet gene expression levels. Selective stimulation of beta cell G(s) triggered qualitatively similar in vivo metabolic effects. Thus, this developed chemical-genetic strategy represents a powerful approach to study G protein regulation of beta cell function in vivo.

Topics: Animals; Chlorocebus aethiops; Clozapine; COS Cells; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation; Glucose Tolerance Test; GTP-Binding Proteins; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Transgenic; Radioligand Assay; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

Type 2 diabetes is a major health problem in individuals with schizophrenia. The genetic basis of diabetes risk in individuals with schizophrenia has not been previously defined. We measured polymorphisms in a human endogenous retrovirus, Herv K-18, which is located in the CD48 signaling lymphocyte activating (SLAM) gene on chromosome 1. The study population consisted of 229 individuals with schizophrenia, 29 of whom had a history of type 2 diabetes, as well as 136 control individuals without a history of a psychiatric disorder or type 2 diabetes. We found that a haplotype defined by 2 polymorphisms in the envelope region of Herv K-18 is highly associated with type 2 diabetes in a population of 229 individuals with schizophrenia, with an odds ratio of 9.0 (95% confidence limits 2.3-34.7, p<.001) adjusted for race, gender and type of antipsychotic medication. Lower levels of association were found in other polymorphisms located in the 3'untranslated region of Herv K-18 and in adjacent loci in CD48. Polymorphisms in endogenous retroviruses which are located near immunomodulatory genes may constitute risk factors for diabetes in individuals with schizophrenia.

Topics: 3' Untranslated Regions; Antigens, CD; Antipsychotic Agents; Benzodiazepines; CD48 Antigen; Chromosomes, Human, Pair 1; Clozapine; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Endogenous Retroviruses; Female; Haplotypes; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Olanzapine; Polymorphism, Genetic; Risk Factors; Risperidone; Schizophrenia; Signaling Lymphocytic Activation Molecule Associated Protein

In recent years, several studies showed increased rates of hyperglycaemia, diabetes, dyslipidemia, metabolic syndrome as well as cardiovascular disease in schizophrenic patients. The underlying mechanism, however, is poorly understood. Adiponectin is a recently identified adipocyte-derived protein, with low adiponectin levels being associated with metabolic abnormalities such as obesity, insulin resistance and type 2 diabetes.. Fasting adiponectin levels were assessed in a cross-sectional sample of 386 patients with schizophrenia or schizoaffective disorder. All patients were on monotherapy of second-generation antipsychotics (SGA) and underwent an extensive metabolic screening including an oral glucose tolerance test (OGTT).. Adiponectin plasma levels were inversely correlated with BMI, and differed significantly between patients with normal weight, overweight or obesity (p<0.05). Patients who met criteria for the metabolic syndrome, according to adapted National Cholesterol Educational Program - Adult Treatment Panel criteria (NCEP-ATP III) (29.3%), had significantly lower adiponectin levels than patients not meeting metabolic syndrome criteria (p<0.0001). Patients without glucose abnormalities (78%) had significantly higher adiponectin levels than patients with diabetes (5.7%) (p<0.05). After controlling for components of metabolic syndrome and sex, antipsychotic medication independently influenced adiponectin levels (p<0.0001), with the lowest mean levels in patients on clozapine and olanzapine.. Adiponectin levels in schizophrenic patients mirror what is observed in the general population, with the lowest levels in the most metabolically comprised subjects. However, antipsychotic medication may also influence adiponectin regulation independently, a finding that should be confirmed in longitudinal studies.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Metabolic Syndrome; Olanzapine; Psychotic Disorders; Risk Factors; Schizophrenia

To investigate 3-month changes in glucose metabolism in a naturalistic sample of patients with schizophrenia newly started on or switched to specific atypical antipsychotic medication therapy.. One hundred eighty-three patients were evaluated before initiation and 3 months after with a 75-g glucose load oral glucose tolerance test (OGTT). Data were collected between November 2003 and January 2007.. Eight patients (4.4%) developed new-onset diabetes within 3 months. Initiation of clozapine resulted in a significantly higher risk for new-onset glucose abnormalities than initiation of aripiprazole (odds ratio = 67.29, 95% CI = 5.23 to 866.49). Significant drug x time interactions were found for all OGTT glucose assessments (fasting: F = 6.79, df = 5,177; p < .0001; 30 minutes: F = 3.89, df = 5,177; p = .0023; 60 minutes: F = 5.03, df = 5,177; p = .0002; 120 minutes: F = 3.78, df = 5,177; p = .0028), with the evolution of plasma glucose levels being significantly worse in patients initiated on clozapine therapy (fasting, 30 minutes, and 60 minutes), olanzapine therapy (fasting, 60 minutes, and 120 minutes), and quetiapine therapy (fasting and 60 minutes) than in patients initiated on aripiprazole therapy (p < .05). Clozapine was also significantly more deleterious than risperidone and amisulpride for fasting plasma glucose level changes (p < .05). Type of initiation (start or switch) did not affect any of the metabolic parameters.. The incidence of new-onset glucose abnormalities, including diabetes, in the first 3 months after newly starting or switching atypical antipsychotic medication is high and may be markedly influenced by type of prescribed antipsychotic. The importance of accurately screening for new-onset glucose abnormalities after initiation of an atypical antipsychotic is emphasized.

Topics: Adult; Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Blood Glucose; Body Mass Index; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Fasting; Feeding Behavior; Female; Glucose; Glucose Tolerance Test; Humans; Incidence; Insulin; Male; Middle Aged; Olanzapine; Piperazines; Prevalence; Psychotic Disorders; Quetiapine Fumarate; Quinolones; Risk Factors; Schizophrenia; Time Factors

Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT.. Rat hepatocytes were studied in short-term primary culture.. Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by alpha-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. alpha-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by alpha-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of alpha-methyl-5-HT on phosphorylase inactivation.. This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

Topics: Amides; Animals; Antipsychotic Agents; Benzodiazepines; Blotting, Western; Cells, Cultured; Clozapine; Diabetes Mellitus, Type 2; Enzyme Activation; Glycogen; Hepatocytes; Immunoblotting; Indoles; Male; Olanzapine; Phosphorylases; Rats; Rats, Wistar; Serotonin; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

Topics: Antipsychotic Agents; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Blood Glucose; Body Mass Index; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Diet, Diabetic; Drug Therapy, Combination; Female; Fluphenazine; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Mass Screening; Quetiapine Fumarate; Risk Factors; Schizophrenia

Schizophrenia is associated with abnormalities in glucose metabolism that may lead to insulin resistance and a 3 fold higher incidence of type II diabetes mellitus. The goal of the present studies was to assess the role of insulin-dependent Akt signaling in schizophrenia and in animal and cellular models of insulin resistance. Our studies revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the dorsolateral prefrontal cortex (BA46) of medicated schizophrenics relative to control patients using post-mortem brain material. We found approximately 50% decreases in the content and autophosphorylation levels of IRbeta and approximately 76-78% decreases in Akt content and activity (pSer(473)-Akt). The inhibition of IRbeta signaling was accompanied by an elevated content of glycogen synthase kinase (GSK)-3 alpha and GSK-3beta without significant changes in phospho-Ser(21/9) GSK-3 alpha/beta levels. A cellular model of insulin resistance was induced by IRbeta knockdown (siRNA). As in schizophrenia, the IRbeta knockdown cells demonstrated a reduction in the Akt content and activity. Total GSK-3 alpha/beta content remained unaltered, but phospho-Ser(21/9) GSK-3 alpha/beta levels were reduced indicating a net increase in the overall enzyme activity similar to that in schizophrenia. Insulin resistance phenotype was induced in mice by treatment with antipsychotic drug, clozapine. Behavioral testing showed decreases in startle response magnitude in animals treated with clozapine for 68 days. The treatment resulted in a functional inhibition of IRbeta but the Akt activation status remained unaltered. Changes in GSK-3 alpha/beta were consistent with a net decrease in the enzyme activity, as opposed to that in schizophrenia. The results suggest that alterations in insulin-dependent Akt signaling in schizophrenia are similar to those observed in our cellular but not animal models of insulin resistance. In animal model, clozapine ameliorates IRbeta deficits at the GSK-3 alpha/beta level, which may justify its role in treatment of schizophrenia. Our studies suggest that aberrant IR function may be important in the pathophysiology of schizophrenia.

Topics: Animals; Antibodies, Anti-Idiotypic; Antipsychotic Agents; Brain; Carrier Proteins; Clozapine; Diabetes Mellitus, Type 2; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Incidence; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Prefrontal Cortex; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Reflex, Startle; Schizophrenia; Signal Transduction

There is an extensive literature documenting that people with schizophrenia have marked impairments in social role functioning and social skill. One of the most widely employed strategies for assessing social skill has been role-play tests: simulated social interactions that are videotaped for subsequent behavioral coding. There has been considerable discussion of the validity of the approach in the literature, but there has not been adequate consideration of other psychometric characteristics of role-play tests. This paper examines the psychometric characteristics of a representative role-play measure: the Maryland Assessment of Social Competence (MASC). Data from 5 large schizophrenia studies that included the MASC were examined: a study of victimization in women who abuse drugs, a study of health care among people with diabetes, a study of vocational outcomes, a study of social skill among drug abusers, and a clinical trial comparing two antipsychotic medications. Data were examined in terms of five questions: (1) Can role-play scenes be rated reliably? (2) How are role-play ratings distributed across populations? (3) How many and which behaviors should be rated? (4) How many role-play scenes are required? (5) Is role-play behavior temporally stable? Overall, the data suggest that the MASC, and by implication other similar role-play procedures, does have good psychometric properties. However, several things often taken for granted in the literature warrant careful consideration in the design of research using role-play. Implications of the results for design of research are discussed.

Topics: Adult; Antipsychotic Agents; Clozapine; Comorbidity; Crime Victims; Diabetes Mellitus, Type 2; Female; Health Behavior; Humans; Problem Solving; Psychometrics; Risperidone; Role Playing; Schizophrenia; Social Behavior; Social Perception; Substance-Related Disorders

While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes.. To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test.. A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis.. Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis.. Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness.. The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapineolanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Clozapine; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Metabolic Syndrome; Obesity; Olanzapine; Risperidone; Schizophrenia

The atypical antipsychotic clozapine has been reported to be associated with metabolic adverse effects, including type-2 diabetes mellitus. We present two cases of diabetes mellitus associated with clozapine treatment. One case resolved entirely upon withdrawal of the drug, whereas the other did not. We discuss the molecular basis of the diabetogenic action of clozapine and recommendations for monitoring.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Monitoring, Physiologic; Psychotic Disorders; Schizophrenia, Paranoid

To examine the risk of developing type 2 diabetes mellitus among people with schizophrenia exposed to atypical antipsychotics (clozapine, olanzapine, quetiapine, risperidone) compared to those exposed to conventional antipsychotics.. A matched case-control design was used to examine California Medicaid beneficiaries. Cases developed diabetes subsequent to being diagnosed with schizophrenia (ICD-9295), were 18 years or older, and were exposed to at least one antipsychotic medication at some point during the 12 weeks preceding diabetes diagnosis. Diabetes was defined by diagnostic claim (ICD-9250) or prescription for antidiabetic agents. A total of 3663 cases were matched to 14 523 non-diabetic controls (people with schizophrenia matched on gender and age +/-5 years). All had to be continuously eligible for benefits during the 12-week period preceding diabetes onset in the case. Conditional logistic regression modeled the risk of exposure, controlling for age, ethnicity, and exposure to selected concomitant medications. Analyses were repeated with 24- and 52-week exposure windows.. Using a 12-week exposure window, olanzapine (OR = 1.36, 95%CI 1.20-1.53), clozapine (OR = 1.34, 95%CI 1.16-1.55), and combination atypical therapy (OR = 1.58, 95%CI 1.33-1.88), but not risperidone or quetiapine, were associated with increased odds of developing diabetes compared to conventional antipsychotics. Changing to a 24-week exposure window, the risks were: olanzapine (OR = 1.38, 95%CI 1.22-1.56), clozapine (OR = 1.32, 95%CI 1.14-1.53), or combinations (OR = 1.54, 95%CI 1.29-1.84). With a 52-week exposure window, the risks were: olanzapine (OR = 1.41, 95%CI 1.24-1.60), clozapine (OR = 1.41, 95%CI 1.21-1.65), combinations (OR = 1.58, 95%CI 1.31-1.90). Risk for olanzapine increased with dose. Hispanic, African American, and unknown ethnicity were significant risks for development of type 2 diabetes as was exposure to selected concomitant medications.. Exposure to olanzapine or clozapine is associated with a 34-41% increase in the developing of type 2 diabetes among California Medicaid recipients with schizophrenia. Prospective, randomized trials are needed to confirm these retrospective, observational findings.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Benzodiazepines; California; Case-Control Studies; Clozapine; Databases, Factual; Diabetes Mellitus, Type 2; Dibenzothiazepines; Drug Therapy, Combination; Female; Humans; Incidence; Logistic Models; Male; Medicaid; Middle Aged; Odds Ratio; Olanzapine; Quetiapine Fumarate; Risk Assessment; Risperidone; Schizophrenia; Time Factors

Topics: Adult; Antipsychotic Agents; Case-Control Studies; Clozapine; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Psychotic Disorders; Risk Factors

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

We report a case of diabetic ketoacidosis in a 54-year-old white female with type 2 diabetes and schizophrenia during clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Female; Humans; Middle Aged; Schizophrenia

Three male schizophrenia patients, aged 41, 40 and 61 years respectively, who had undergone treatment without a satisfactory result, were treated with the antipsychotic clozapine. Diabetes mellitus developed within a period of several months to several years. The antipsychotic medication could be continued once the patients had been started on blood-glucose lowering medication. There seems to be an increased incidence of type-2 diabetes mellitus in patients with schizophrenia. It has been suggested that treatment with neuroleptics, especially atypical neuroleptics, provokes the onset of diabetes mellitus. The relatively young age (often < 50 years) at onset is a cause for concern. From a pathophysiological viewpoint, an increased prevalence of diabetic risk factors has been suggested for schizophrenia in addition to the toxic effect of neuroleptics in general. The possible consequences for the general health of this vulnerable group of patients warrant recommendations concerning the regular monitoring of these patients during treatment.

Topics: Adult; Age of Onset; Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Humans; Incidence; Male; Middle Aged; Risk Factors; Schizophrenia

Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with increased insulin and lipid levels.. The aim of the present study was to investigate potential relationships between insulin or other hormones related to glucose-insulin homeostasis or lipids and steady-state serum concentrations of clozapine or olanzapine in patients on therapeutic doses.. Thirty-four patients, diagnosed with schizophrenia or related psychoses according to the DSM-IV criteria and treated with clozapine ( n=18) or olanzapine ( n=16), were studied. Median treatment time with the antipsychotics was 5.3 years (range 0.5-16.3 years). Fasting blood samples for insulin, C-peptide, insulin-like growth factor I, insulin-like growth factor binding protein-1, leptin, glucose and lipids were analyzed and investigated in relation to the patients' drug serum concentrations.. Hyperinsulinemia was found in 30-60% of the patients, hyperglycemia in 10-30%, hyperlipidemia in 40-60% and hyperleptinemia in 10-20%. Moreover, levels of insulin, C-peptide and triglycerides correlated positively to the clozapine serum concentration and to the ratio of olanzapine to N-desmethylolanzapine concentrations. In contrast, levels of C-peptide, leptin and blood glucose were inversely correlated to the serum concentration of the metabolite N-desmethylolanzapine.. Metabolic abnormalities (i.e. hyperinsulinemia, hyperlipidemia and hyperleptinemia) and insulin resistance were associated with both clozapine and olanzapine treatments. Levels of insulin and triglycerides increased by increasing clozapine serum concentration and by increasing ratio of olanzapine to N-desmethylolanzapine; the last due to the metabolite N-desmethylolanzapine probably having an inverse effect to the main compound olanzapine. Thus, the metabolic abnormalities induced by these two drugs are clozapine-concentration dependent in clozapine-treated patients, and ratio of olanzapine to N-desmethylolanzapine-concentration dependent in olanzapine-treated patients.

Topics: Adult; Benzodiazepines; Blood Glucose; Body Mass Index; C-Peptide; Chromatography, High Pressure Liquid; Clozapine; Diabetes Mellitus, Type 2; Diagnostic and Statistical Manual of Mental Disorders; Dose-Response Relationship, Drug; Female; Hormones; Humans; Insulin; Lipids; Male; Middle Aged; Olanzapine; Radioimmunoassay; Schizophrenia; Smoking; Statistics as Topic; Triglycerides

Since a few years, an increasing number of cases of atypical neuroleptic-associated diabetes are reported in the literature. But few are dedicated to diabetologists. We report here two cases of patients with a severe deterioration of preexisting diabetes, with clozapine for the first case report and olanzapine for the second one. We also make a literature review and discuss the possible mechanisms involved in this atypical neuroleptic-associated diabetes. We recommend a thigh follow-up of weight, glycemic and lipidic parameters during psychotic patients treatment with atypical neuroleptics, in order to prevent or rapidly treat the metabolic complications described in the literature.

Topics: Adolescent; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Disease Progression; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Risk

The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels.. The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses.. Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations.. It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Haloperidol; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Quetiapine Fumarate; Retrospective Studies; Risk Factors; Risperidone; Triglycerides; Weight Gain

Case series suggest that some antipsychotics may induce or exacerbate type 2 diabetes. This study measured the association of antipsychotic treatments with diabetes at a population level.. Claims data for psychosis patients (ICD-CM-9 290.xx-299.xx) within health plans encompassing 2.5 million individuals were analyzed. Patients reporting preexisting type 2 diabetes up to 8 months prior to observation were excluded. The frequency of newly reported type 2 diabetes in untreated patients and among patients treated with antipsychotics from 5 categories (risperidone, olanzapine, clozapine, and high-potency and low-potency conventionals) was compared. Logistic regression models compared the odds of diabetes based on exposure to each of the antipsychotic categories.. Based on 12 months of exposure, the odds of type 2 diabetes for risperidone-treated patients (odds ratio = 0.88, 95% CI = 0.372 to 2.070) was not significantly different from that for untreated patients, whereas patients receiving other antipsychotics had a significantly greater risk of diabetes than untreated patients (p < .05): olanzapine, 3.10 (95% CI = 1.620 to 5.934); clozapine, 7.44 (95% CI = 0.603 to 34.751); high-potency conventionals, 2.13 (95% CI = 1.097 to 4.134); and low-potency conventionals, 3.46 (95% CI = 1.522 to 7.785). Older age and greater use of non-antipsychotic psychotropic medications also contributed to risk of type 2 diabetes. Olanzapine also showed significantly higher (p < .01) odds of diabetes associated with increasing dose.. Consistent with previously published literature, these data suggest that olanzapine, clozapine, and some conventional antipsychotics appear to increase the risk of acquiring or exacerbating type 2 diabetes and that the effect may vary by drug. In contrast to these agents, risperidone was not associated with an increased risk of type 2 diabetes.

Topics: Acute Disease; Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Comorbidity; Confidence Intervals; Databases as Topic; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Insurance Claim Review; Logistic Models; Male; Middle Aged; Odds Ratio; Olanzapine; Pirenzepine; Psychotic Disorders; Risk Factors; Risperidone; United States

The development of both type I and type II diabetes after initiation of some atypical neuroleptics has been reported, primarily in studies involving small series of patients. This study used administrative data from a large national sample of patients with a diagnosis of schizophrenia to compare the prevalence of diabetes mellitus in patients receiving prescriptions for atypical and typical neuroleptics.. All outpatients with schizophrenia treated with typical and atypical neuroleptics over 4 months in 1999 in the Veterans Health Administration of the Department of Veterans Affairs (VA) were included in this study. Patients treated with atypical neuroleptics were those who received prescriptions for clozapine, olanzapine, risperidone, or quetiapine. Patients with a diagnosis of diabetes were also identified by using ICD-9 codes in VA administrative databases. The prevalence of diabetes mellitus across age groups and among patients receiving prescriptions for different atypical neuroleptics was examined with multiple logistic regression.. A total of 38,632 patients were included in the study: 15,984 (41.4%) received typical neuroleptics and 22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903 [43.7%], risperidone; 387 patients received prescriptions for more than one atypical neuroleptic). When the effects of age were controlled, patients who received atypical neuroleptics were 9% more likely to have diabetes than those who received typical neuroleptics, and the prevalence of diabetes was significantly increased for patients who received clozapine, olanzapine, and quetiapine, but not risperidone. However, for patients less than 40 years old, all of the atypical neuroleptics were associated with a significantly increased prevalence of diabetes.. In this large group of patients with schizophrenia, receipt of a prescription for atypical neuroleptics was significantly associated with diabetes mellitus.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Quetiapine Fumarate; Regression Analysis; Risk Factors; Risperidone; Schizophrenia

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Humans; Male; Olanzapine; Patient Compliance; Pirenzepine; Quality of Life; Schizophrenia, Paranoid

Numerous case reports have linked clozapine to the development of diabetes mellitus and hyperlipidemia in patients with schizophrenia. However, investigators have been unable to clearly demonstrate this association when compared with a control group receiving conventional antipsychotics.. Medical and pharmacy claims from the Iowa Medicaid program were used to compare incidence rates for diabetes, hyperlipidemia, and hypertension in 552 patients receiving clozapine and 2461 patients receiving conventional antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use of a retrospective cohort design. Logistic regression was used to compare incidence rates adjusting for age, sex, and duration of available follow-up.. No significant differences in overall incidence rates for diabetes, hyperlipidemia, or hypertension were observed in patients receiving clozapine vs conventional antipsychotics. However, among younger patients (aged 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia (2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence interval, 0.4-2.0]).. These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine fumarate). The potential long-term medical and economic implications of the early induction of diabetes and hyperlipidemia in patients with schizophrenia warrant further study.

Topics: Adult; Age Factors; Antipsychotic Agents; Causality; Clozapine; Cohort Studies; Confidence Intervals; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension; Incidence; Iowa; Male; Middle Aged; Product Surveillance, Postmarketing; Retrospective Studies; Risk; Schizophrenia

In a 40-year old patient with schizophrenia treated with sustained-action perfenazine for schizophrenia, diabetes mellitus type 2 and hypertension developed when clozapine was added to the regimen. The blood sugar values and the blood pressure normalized when clozapine was discontinued two weeks later. When he was 44 years old, clozapine was resumed as the psychotic symptoms did not subside. Diabetes mellitus reappeared and did not disappear after discontinuation of the clozapine. Insulin therapy was necessary. An association between the emergence of diabetes mellitus and the use of clozapine is suggested. Previously 15 cases of diabetes mellitus emerging during treatment with clozapine were described in the international literature. Monitoring of blood glucose is advised in patients with a positive family history of diabetes mellitus or with a personal history of impaired glucose tolerance.

Topics: Adult; Antipsychotic Agents; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Humans; Hypertension; Hypoglycemic Agents; Insulin; Male; Schizophrenia

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

Topics: Adult; Antipsychotic Agents; Clozapine; Contraindications; Diabetes Mellitus, Type 2; Humans; Male; Schizophrenia

Recent case reports suggest the association of the emergence of diabetes mellitus with clozapine treatment, although conventional neuroleptics have also been implicated. This study was conducted to determine if there is an increased risk of diabetes mellitus and/or impaired glucose tolerance (IGT) during clozapine treatment compared with treatment with conventional depot neuroleptics.. In a district hospital in northern Sweden, blood glucose tests and, if necessary an oral glucose tolerance test were used to assess the prevalence of diabetes mellitus or IGT in 63 patients treated with clozapine compared with 67 patients treated with conventional depot neuroleptics (haloperidol, zuclopenthixol, fluphenazine, perphenazine, or flupenthixol). Diabetes mellitus and impaired glucose tolerance were classified according to World Health Organization criteria.. There were 3 dropouts in the clozapine group and 4 in the control group. Of subjects treated with clozapine, 12% (7/60) had type 2 diabetes mellitus, and 10% (6/60) had IGT. Of subjects treated with depot injections of neuroleptics, 6% (4/63) had type 2 diabetes mellitus and 3% (2/63) had IGT. None in either group had type 1 diabetes mellitus. Subjects in the clozapine group were significantly (p < .001) younger than subjects in the control group, whereas the 2 groups did not differ with respect to body weight, body mass index, or prevalence of diabetes mellitus in first-degree relatives.. Subjects treated with clozapine were more often classified as having type 2 diabetes mellitus or IGT compared with subjects in the control group. This difference did not, however, achieve statistical significance (p=.06).

Topics: Adult; Aged; Antipsychotic Agents; Blood Glucose; Clozapine; Comorbidity; Delayed-Action Preparations; Diabetes Mellitus; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Male; Mental Disorders; Middle Aged; Prevalence; Schizophrenia; Sweden

The new antipsychotics induce minimal extrapyramidal side effects, probably due to their relatively greater affinity for certain nondopaminergic receptors than their older, conventional counterparts; however, this polyreceptor affinity may be responsible for the development of other adverse effects. One serious adverse effect that may be linked to these effects is non-insulin-dependent diabetes mellitus.. We summarize 6 new cases of clozapine- and olanzapine-associated diabetes that we have documented in our clinic. We compare our cases to previous reports and tabulate the pertinent similarities among cases.. Two of the cases were olanzapine-associated and 4 were clozapine-associated diabetes. Five of our 6 patients had risk factors for diabetes, as have 7 of the 9 previously reported in the literature. Four of our 6 patients, and 2 of the 4 prior cases in which such data were reported, experienced substantial weight gain after starting their antipsychotics.. Novel antipsychotics should be administered with great care to patients with risk factors for diabetes. Although the precise mechanism of the novel antipsychotic-associated diabetes is unclear, we hypothesize that histaminic and possibly serotonergic antagonism induces weight gain, which in turn leads to changes in glucose homeostasis. Additionally, serotonin1A antagonism might decrease pancreatic beta-cell responsiveness, resulting in inappropriately low insulin and hyperglycemia.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Clozapine; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Olanzapine; Pirenzepine; Psychotic Disorders; Risk Factors; Schizophrenia

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

A 58-year-old man with chronic paranoid-hallucinatoric psychosis had transient episodes with marked paranoid delusions, auditory hallucinations without confusion, shakiness of both upper extremities, tachycardia and sweating. EMG performed with surface electrodes revealed many silent periods in postural active muscles with maximum duration of 120 ms; blood glucose was 65-75 mg/dl. At other times, blood glucose was 135-140 mg/dl, EMG revealed few silent periods in postural active muscles with maximal duration of 50 ms and the patient noted some vibration in his outstretched hands only. Drug-induced asterixis (clozapine, benperidol) amplified by relative hypoglycemia was therefore assumed, and symptoms disappeared after oral antidiabetics were reduced.

Topics: Antipsychotic Agents; Clozapine; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electromyography; Fasciculation; Glyburide; Hallucinations; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Motor Neurons; Muscle, Skeletal; Myoclonus; Neurologic Examination; Paranoid Disorders; Tremor