olanzapine and Insulin-Resistance

This systematic review aimed to determine whether olanzapine is more likely than other second-generation antipsychotics (SGAs) to induce insulin resistance in patients with schizophrenia in China.. We reviewed all randomized controlled trials on insulin resistance and metabolic abnormalities caused by SGAs in the PubMed, China National Knowledge Infrastructure (CNKI), VIP, and Wanfang databases. Retrieved articles were published on or before December 2018. Meta-analysis was performed to determine the effect size of the treatment on the insulin resistance index (IRI), fasting blood glucose (FBG), and fasting insulin (FINS).. Forty studies (3725 participants in total) were included. All studies contained data suitable for comparing aripiprazole vs. olanzapine, ziprasidone vs. olanzapine, and risperidone vs. olanzapine. Patients treated with olanzapine had higher IRI, FBG, and FINS levels than did patients treated with aripiprazole, ziprasidone, or risperidone, with significant differences (aripiprazole vs. olanzapine: FBG: standardized mean difference [SMD] = 0.72, 95% confidence interval [95%CI] - 0.82, - 0.61; FINS: SMD = - 0.8, 95%CI - 1.00, - 0.61; IRI: SMD = - 0.80, 95%CI - 0.99, - 0.61; ziprasidone vs. olanzapine: FBG: SMD = - 1.19, 95%CI - 1.30, - 1.08; FINS: SMD = - 0.66, 95%CI - 0.85, - 0.47; IRI: SMD = - 0.71, 95%CI - 0.88, - 0.55; risperidone vs. olanzapine: FBG: SMD = - 0.17, 95%CI - 0.34, - 0.00).. Existing data suggest that olanzapine is associated with a significantly greater risk of IRI, FBG, and FINS, while other agents are associated with relatively lower risks. Thus, olanzapine is more likely to induce insulin resistance than are other SGAs in schizophrenic patients in China.

Topics: Antipsychotic Agents; China; Humans; Insulin Resistance; Metabolic Syndrome; Olanzapine; Schizophrenia

Topics: Antipsychotic Agents; Aripiprazole; Benzodiazepines; Clozapine; Diabetes Mellitus; Dibenzothiazepines; Dyslipidemias; Glucose Metabolism Disorders; Humans; Insulin Resistance; Mental Disorders; Obesity; Olanzapine; Phenothiazines; Piperazines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Thiazoles

Recently, increasing attention has been drawn to the potential diabetogenic effect of novel antipsychotics. Until now, large prospective studies examining the relationship between atypical antipsychotics and impaired glucose metabolism have been lacking. However, the case reports and retrospective studies that we review here suggest an increased risk of developing diabetes mellitus (DM) in patients treated with atypical antipsychotics compared to schizophrenic patients treated with conventional antipsychotics or those without treatment. Although most atypical antipsychotic agents might have a diabetogenic potential, the risk of developing DM might be higher in patients treated with either clozapine or olanzapine than with risperidone, whereas data on quetiapine and ziprasidone is presently limited and needs further attention. Possible mechanisms include the induction of peripheral insulin resistance and the direct influence on pancreatic beta-cell function by 5-HT1A/2A/2C receptor antagonism, by inhibitory effects via alpha 2-adrenergic receptors or by toxic effects. On the other hand, atypical antipsychotics might not be an independent risk factor for the development of DM, but hasten the onset of DM in patients bearing other risk factors. It is suggested that schizophrenic patients should be monitored for the occurrence of glucose metabolism abnormalities before starting atypical antipsychotics, and at a 3-month interval at least during therapy.

Topics: Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus; Dibenzothiazepines; Glucose; Humans; Insulin Resistance; Islets of Langerhans; Obesity; Olanzapine; Pancreas; Piperazines; Quetiapine Fumarate; Risperidone; Schizophrenia; Thiazoles

Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) but are unfortunately associated with serious metabolic adverse effects including weight gain and type 2 diabetes. The pathophysiology of AP-induced metabolic dysfunction is largely undetermined. Brain insulin resistance has been posited to be at the cross-roads of many cognitive and metabolic disorders, and disruption of central insulin action has emerged as a possible explanatory mechanism underlying AP induced metabolic dysfunction. Previous studies suggest that change in neuroimaging-based parameters with intranasal insulin administration can be leveraged to investigate brain insulin resistance. In this proof-of-concept study, we will utilize neural signatures of insulin action in the brain to examine if APs disrupt brain insulin signaling. It is hypothesized that: 1) intranasal insulin (INI), but not intranasal placebo (INP), will change cerebral blood flow and resting state connectivity, as well as increase glutamate levels in the striatum and dorsolateral prefrontal cortex; 2) oral olanzapine (OLA), but not oral placebo (PL), will inhibit the effect of INI on these parameters. Thirty-two healthy volunteers will undergo a single blind, cross-over design, wherein all participants receive the following four treatment combinations, 2-6 weeks apart, in a random sequence: INP + PL, INP + OLA, INI + PL, and INI + OLA. Participants will undergo an MRI-based assay of brain insulin resistance 15 minutes after administering 160 IU INI or INP. The scanning protocol includes resting and task-based functional MRI, arterial spin labelling, and proton magnetic resonance spectroscopy. Demonstrating that OLA can acutely induce brain insulin resistance is clinically relevant to metabolic health in SCZ. Evidence of brain insulin resistance induced by acute AP dosing can inform the early use of adjunctive insulin sensitizers for the treatment of metabolic comorbidities associated with AP treatment in severe mental illness. Trial registration ClinicalTrials.gov Registration: NCT03741478.

Topics: Antipsychotic Agents; Brain; Cross-Over Studies; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin, Regular, Human; Magnetic Resonance Imaging; Olanzapine; Single-Blind Method

Second generation antipsychotics are prescribed for an increasing number of psychiatric conditions, despite variable associations with weight gain, dyslipidemia, and impaired glucose tolerance. The mechanism(s) of the apparent causal relationships between these medications and metabolic effects have been inadequately defined and are potentially confounded by genetic risk of mental illness, attendant lifestyle, and concomitant medications. Therefore, we conducted a study in which 24 healthy volunteers were randomized to olanzapine (highly weight-gain liability), iloperidone (less weight-gain liability), or placebo treatment for 28 days under double-blind conditions. We hypothesized that antipsychotics induce weight gain primarily through increased caloric intake, which causes secondary dyslipidemia and insulin resistance. Subjects were phenotyped pre- and post-treatment for body weight, adiposity by dual energy X-ray absorptiometry, energy expenditure by indirect calorimetry, food intake, oral glucose tolerance, plasma lipids, glucose, insulin, and other hormones. We found significantly increased food intake and body weight but no change in energy expenditure in olanzapine-treated subjects, with associated trends towards lipid abnormalities and insulin resistance the extent of which were presumably limited by the duration of treatment. Iloperidone treatment led to modest non-significant and placebo no weightgain, lipid increases and alterations in insulin metabolism. We conclude that second generation antipsychotic drugs, as represented by olanzapine, produce their weight and metabolic effects, predominantly, by increasing food intake which leads to weight gain that in turn induces metabolic consequences, but also through other direct effects on lipid and glucose metabolism independant of food intake and weight gain.

Topics: Adolescent; Adult; Antipsychotic Agents; Blood Glucose; Body Weight; Double-Blind Method; Dyslipidemias; Eating; Energy Metabolism; Female; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin; Insulin Resistance; Isoxazoles; Lipids; Male; Obesity; Olanzapine; Piperidines; Weight Gain; Young Adult

Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths.. To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity.. This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017.. Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49).. Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers.. The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments.. Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.. ClinicalTrials.gov identifier: NCT00205699.

Topics: Abdominal Fat; Absorptiometry, Photon; Adolescent; Antipsychotic Agents; Aripiprazole; Child; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Insulin Resistance; Intention to Treat Analysis; Male; Mental Disorders; Olanzapine; Problem Behavior; Risperidone; Treatment Outcome

We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested.. This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76).. BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01).. The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.

Topics: Adult; Alleles; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Brain-Derived Neurotrophic Factor; Cholesterol, HDL; Cholesterol, LDL; Dyslipidemias; Female; Genotype; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Olanzapine; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Prospective Studies; Psychotic Disorders; Risk Factors; Risperidone; Schizophrenia; Triglycerides

Olanzapine (OLZ), a commonly prescribed second generation antipsychotic drug, is associated with obesity and metabolic syndrome and may contribute to increased cardiovascular morbidity and mortality. Opioidergic neurotransmission may be implicated in the development of these metabolic disturbances. The objective of this study was to assess the effects of opioid blockade on OLZ-treated patients' metabolic status. Patients with schizophrenia or schizoaffective disorder (n=30) on a stable dose of OLZ were randomized in a double-blind fashion to receive an opioid receptor antagonist, naltrexone (NTX), (n=14) or placebo (n=16). The primary outcome measure was the change in body mass index (BMI) at 12 weeks. Secondary measures included body fat and fat-free mass, along with homeostasis model assessment-estimated insulin resistance (HOMA-IR), plasma lipids and liver function tests (LFTs). There was no significant change in BMI between the treatment arms. However, in comparison to the OLZ + placebo combination, the OLZ + NTX group displayed a significant decrease in the fat and increase in fat-free mass along with a trend towards improvement in HOMA-IR values. There were no significant differences in plasma lipids and LFTs. These findings suggest that addition of NTX to OLZ may attenuate OLZ-induced body fat mass gain. A larger study of longer duration will be needed to confirm these results.

Topics: Adipose Tissue; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Double-Blind Method; Female; Humans; Insulin Resistance; Lipids; Liver Function Tests; Male; Middle Aged; Naltrexone; Olanzapine; Pilot Projects; Psychotic Disorders; Schizophrenia; Young Adult

The aim of this study was to assess whether saffron aqueous extract (SAE) or its active constituent, crocin, prevents olanzapine-induced metabolic syndrome (MetS) and insulin resistance in patients with schizophrenia.. 66 patients diagnosed with schizophrenia who were on olanzapine treatment (5-20 mg daily) were randomly allocated to receive a capsule of SAE (n=22; 30 mg daily), crocin (n=22; 30 mg daily) or placebo (n=22) in a 12-week triple-blind trial. Patients were screened not to have MetS at baseline and further assessment was done at weeks 6 and 12. Measurement of fasting blood glucose (FBS) and serum lipids were repeated at weeks 2, 6 and 12. Fasting blood levels of insulin and HbA1c were also measured at baseline and week 12. HOMA-IR and HOMA-β were determined to evaluate insulin resistance.. 61 patients completed the trial and no serious adverse effects were reported. Time-treatment interaction showed a significant difference in FBS in both SAE and crocin groups compared to placebo (p=0.004). In addition, SAE could effectively prevent reaching the criteria of metabolic syndrome (0 patients) compared to crocin (9.1%) and placebo (27.3%) as early as week 6.. SAE could prevent metabolic syndrome compared to crocin and placebo. Furthermore, both SAE and crocin prevented increases in blood glucose during the study.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Carotenoids; Crocus; Double-Blind Method; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Olanzapine; Plant Extracts; Schizophrenia; Waist Circumference

To compare matched paliperidone-ER- and olanzapine-treated schizophrenic patients on measures of glucose and lipid metabolism.. Eighty hospitalized patients with schizophrenia (DSM-IV) were randomly assigned to treatment with paliperidone ER or olanzapine for a period of 12 weeks. At baseline and every 4 weeks, we assessed weight, subcutaneous fat, waist and hip circumferences, fasting glucose, insulin, glycohemoglobin A1, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and prolactin. We also assessed at every time point body mass index (BMI), homeostasis insulin resistance (HOMA-IR), and homeostasis β-cell function (HOMA-B).. Thirty-three patients randomly assigned to paliperidone ER and 23 patients randomly assigned to olanzapine groups completed the entire 12-week treatment. Within-group analyses showed that fasting measures in both groups increased for weight, BMI, waist circumferences, hip circumference, subcutaneous fat, cholesterol, triglycerides, and prolactin. In contrast, fasting glucose, LDL, and HOMA-B increased during treatment only in the olanzapine group. We also detected significantly different serum prolactin levels at all time point between the paliperidone ER- and olanzapine-treated groups, as well as a statistical trend for HOMA-B to increase more in the olanzapine compared to paliperidone-ER group over the 12 weeks of the trial. We did not detect, however, differential drug effects over the 12 weeks of the trial on fasting measures of BMI, glucose, glycohemoglobin A1, insulin, HDL, LDL, cholesterol, triglyceride, or HOMA-IR.. This study reinforces the necessity of regularly monitoring metabolic parameters in patients with schizophrenia taking atypical antipsychotics, including paliperidone ER.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Delayed-Action Preparations; Female; Follow-Up Studies; Humans; Insulin Resistance; Insulin-Secreting Cells; Isoxazoles; Lipid Metabolism; Male; Olanzapine; Paliperidone Palmitate; Prospective Studies; Pyrimidines; Schizophrenia; Time Factors; Young Adult

Atypical antipsychotic (AAP) medications that have revolutionized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal challenge and a euglycemic-hyperinsulinemic clamp to evaluate insulin sensitivity and glucose disposal. We found that olanzapine, an AAP highly associated with weight gain, causes significant elevations in postprandial insulin, glucagon-like peptide 1 (GLP-1), and glucagon coincident with insulin resistance compared with placebo. Aripiprazole, an AAP considered metabolically sparing, induces insulin resistance but has no effect on postprandial hormones. Importantly, the metabolic changes occur in the absence of weight gain, increases in food intake and hunger, or psychiatric disease, suggesting that AAPs exert direct effects on tissues independent of mechanisms regulating eating behavior.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Eating; Female; Humans; Insulin Resistance; Male; Mental Disorders; Olanzapine; Piperazines; Postprandial Period; Quinolones; Weight Gain; Young Adult

Atypical antipsychotics may "directly" influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor α). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.

Topics: Adipokines; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cross-Over Studies; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hydrocortisone; Insulin; Insulin Resistance; Lipid Metabolism; Male; Olanzapine; Prolactin

Second-generation antipsychotics (SGA), especially clozapine and olanzapine, are associated with an increased metabolic risk. Recent research showed that plasma adiponectin levels, an adipocyte-derived hormone that increases insulin sensitivity, vary in the same way in schizophrenic patients as in the general population according to gender, adiposity and metabolic syndrome (MetS). The aim of the present study was to investigate whether different SGAs differentially affect plasma adiponectin levels independent of body mass index (BMI) and MetS status. 113 patients with schizophrenia (65.5% males, 32.3years old) who were free of antipsychotic medication were enrolled in this open-label prospective single-center study and received either risperidone (n=54) or olanzapine (n=59). They were followed prospectively for 12weeks. Average daily dose was 4.4mg/day for risperidone and 17.4mg/day for olanzapine. Plasma adiponectin levels as well as fasting metabolic parameters were measured at baseline, 6weeks and 12weeks. The two groups had similar baseline demographic and metabolic characteristics. A significant increase in body weight was observed over time. This increase was significantly larger in the olanzapine group than in the risperidone group (+7.0kg versus +3.1kg, p<0.0002). Changes in fasting glucose and insulin levels and in HOMA-IR, an index of insulin resistance, were not significantly different in both treatment groups. MetS prevalence increased significantly more in the olanzapine group as compared to the risperidone groups where the prevalence did not change over time. We observed a significant (p=0.0015) treatment by time interaction showing an adiponectin increase in the risperidone-treated patients (from 10,154 to 11,124ng/ml) whereas adiponectin levels decreased in olanzapine treated patients (from 11,280 to 8988ng/ml). This effect was independent of BMI and the presence/absence of MetS. The differential effect of antipsychotic treatment (risperidone versus olanzapine) on plasma adiponectin levels over time, independent of changes in waist circumference and antipsychotic dosing, suggests a specific effect on adipose tissues, similar to what has been observed in animal models. The observed olanzapine-associated reduction in plasma adiponectin levels may at least partially contribute to the increased metabolic risk of olanzapine compared to risperidone.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Waist Circumference

Patients with an acute psychotic episode underwent HOMA testing for insulin sensitivity (IS) prior to and after 3 weeks of treatment with olanzapine (n = 7) or risperidone (n = 7).. The HOMA-IS index was reduced in the olanzapine group, but significantly increased in patients treated with risperidone. There was a significant "time × medication" interaction (p = 0.03). The BMI significantly increased as a result of both treatments. IS can be acutely ameliorated by antipsychotic treatment with risperidone despite weight increase.. Compared to risperidone, the IS is impaired after a 3-week treatment with olanzapine. Already short-term antipsychotic treatment may have eff ects on insulin sensitivity.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Female; Homeostasis; Humans; Insulin Resistance; Male; Metabolic Diseases; Middle Aged; Olanzapine; Pilot Projects; Prospective Studies; Risperidone; Schizophrenia; Young Adult

Increased risks of weight gain and diabetes mellitus have been reported for schizophrenic patients under long-term treatment with several atypical antipsychotic drugs including olanzapine. Among other antipsychotic drugs, treatment with the selective dopamine D2 and D3 receptor antagonist amisulpride has been implicated with a lower risk for metabolic complications.. In this study we compared the acute, non-adiposity related effects of a single dose of olanzapine, amisulpride and placebo on insulin sensitivity and secretion in 10 healthy subjects in a randomised, double blind cross-over design. Subjects underwent euglycemic-hyperinsulinemic and hyperglycemic clamp tests using an automated clamp device. C-peptide and pro-insulin levels were determined using highly specific immuno-assays.. Insulin sensitivity was not significantly different between both verum medications and placebo. However, C-peptide secretion during hyperglycemic clamp was significantly higher after administration of amisulpride than after olanzapine or placebo. This was true both for the early phase and for the second phase of insulin secretion (C-peptide at 0, 5,10 and 30 min: amisulpride 1.49±0.49; 4.22±1.45; 3.19±1.22; 5.33±1.85; olanzapine 1.35±0.47; 3.84±1.37; 2.72±0.91; 4.28±1.96; placebo 1.72±0.82; 3.59±1.19; 2.71±1.02; 4.54±1.42 ng/mL, mean±SD; ANOVA p=0.043). Pro-insulin levels did not differ significantly between groups.. A low dose of the D2/D3 antagonist amisulpride, but not olanzapine appears to acutely increase pancreatic insulin secretion in healthy controls. Stimulation of β-cells could be a protective factor against the development of diabetes mellitus.

Topics: Adult; Amisulpride; Antipsychotic Agents; Benzodiazepines; C-Peptide; Cross-Over Studies; Double-Blind Method; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Insulin Secretion; Male; Olanzapine; Proinsulin; Sulpiride

To assess changes in insulin sensitivity in non-diabetic adults with schizophrenia or schizoaffective disorder treated with olanzapine or risperidone.. One hundred and thirty patients were randomly assigned to 12 weeks double-blind treatment with olanzapine or risperidone. Insulin sensitivity was measured using a two-step euglycaemic, hyperinsulinaemic clamp procedure. Whole-body adiposity was measured using dual-energy X-ray absorptiometry. The primary endpoint was the within-group change from baseline in insulin sensitivity normalized to fat-free mass (M(ffm) /I) during the clamp procedure's low-insulin phase, using an analysis of covariance model including the covariate weight change.. Forty-one olanzapine-treated and 33 risperidone-treated patients completed baseline and endpoint clamp measurements. Mean M(ffm) /I during the low-insulin phase declined 9.0% (p = 0.226) in olanzapine-treated patients and 13.2% (p = 0.047) in risperidone-treated patients (between-group difference p = 0.354). During the high-insulin phase, M(ffm) /I declined 10.4% (p = 0.036) in olanzapine-treated patients and 2.1% (p = 0.698) in risperidone-treated patients (between-group difference p = 0.664). Changes in M(ffm) /I correlated inversely with changes in body weight and adiposity, which were generally higher in olanzapine-treated patients. Significant within-group increases in fasting glucose, but not haemoglobin A1c (HbA1c), were observed during olanzapine treatment. The fasting glucose change was not correlated with M(ffm) /I changes.. Small, but statistically significant, decrements in insulin sensitivity were observed in olanzapine- and risperidone-treated patients at 1 of 2 insulin doses tested. Significant increases in fasting glucose and insulin and total fat mass were observed only in olanzapine-treated patients. Changes in insulin sensitivity correlated significantly with changes in weight or adiposity, but not with changes in glucose.

Topics: Absorptiometry, Photon; Adolescent; Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Double-Blind Method; Female; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia; Treatment Outcome; Young Adult

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ-induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double-blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12-day washout. Twenty-four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18-49 years) and 22.6 +/- 2.2 kg/m(2), respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor-I (PAI-I), leptin, and tumor necrosis factor-alpha (TNF-alpha) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short-term perturbations in IS.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Metabolism; Benzodiazepines; Biomarkers; Double-Blind Method; Energy Intake; Exercise; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Olanzapine; Plasminogen Activator Inhibitor 1; Reference Values; Triglycerides; Tumor Necrosis Factor-alpha; Weight Gain; Young Adult

Treatment with olanzapine is associated with obesity, diabetes mellitus, and dyslipidemia. Reports have indicated that orally disintegrating tablets (ODT) cause less weight gain than oral standard tablets (OST). The aim of this study was to compare the effect of short-term treatment with these 2 distinct olanzapine formulations on glucose and lipid metabolism in healthy men.. Twelve healthy men (mean ± SEM age: 25.1 ± 5.5 years) received olanzapine ODT (10 mg od, 8 days), olanzapine OST (10 mg od, 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, glucose, insulin, free fatty acids (FFA), and triglyceride concentrations were measured at 10-minute intervals from 30 minutes prior to 2 hours after ingestion of standard meals. Leptin and adiponectin concentrations were measured at 20- and 30-minute intervals, respectively, between 0000h-1200h. Physical activity was assessed with an accelerometer. Fuel oxidation was measured in fasting condition by indirect calorimetry. The study was conducted from April 2006 through September 2006.. Treatment with olanzapine ODT and OST equally elevated the homeostasis model assessment of insulin resistance (HOMA-IR) (P = .005). At breakfast, both formulations equally increased fasting and postprandial triglyceride concentrations (P = .013 and P = .005, respectively) while decreasing fasting and postprandial FFA concentrations (P = .004 and P = .009, respectively). Body weight, body composition, physical activity, or fuel oxidation did not differ between treatment modalities.. Eight days of treatment with both olanzapine formulations similarly increased HOMA-IR and triglyceride concentrations and decreased FFA concentrations in response to standard meals without affecting anthropometrics or physical activity. These data suggest that olanzapine hampers insulin action via mechanistic routes other than body adiposity or physical inactivity.. controlled-trials.com. Identifier: ISRCTN17632637.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cross-Over Studies; Dosage Forms; Energy Metabolism; Fatty Acids, Nonesterified; Homeostasis; Humans; Insulin; Insulin Resistance; Leptin; Male; Motor Activity; Olanzapine; Reference Values; Triglycerides; Young Adult

This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment.. A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol).. 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated.. Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Female; Follow-Up Studies; Haloperidol; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Olanzapine; Prospective Studies; Risk Factors; Risperidone; Schizophrenia; Spain; Triglycerides; Weight Gain; Young Adult

Excessive body weight gain (BWG), hyperglycemia and dyslipidemia are important side effects of olanzapine. We assessed the effects of rosiglitazone on BWG, the insulin resistance index (HOMA-IR), lipids, glycated hemoglobin and fibrinogen in olanzapine-treated schizophrenia patients.. Thirty patients taking olanzapine (10-20 mg daily for 8 months) were randomly allocated to rosiglitazone (n=15; 4 to 8 mg daily) or placebo (n=15) in a 12-week double-blind protocol. Anthropometric and biochemical variables were evaluated at baseline, weeks 6 and 12.. The rosiglitazone and placebo groups gained 3.2+/-4.5 and 2.2+/-2.3 kg, respectively (p=0.65). Insulin and the HOMA-IR significantly decreased after rosiglitazone (p<0.05). Rosiglitazone did not improve the lipid profile, fibrinogen and Hb1c levels.. The positive impact of rosiglitazone was limited to improved glycemic control. It cannot be recommended for metabolic control during olanzapine treatment.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Double-Blind Method; Female; Fibrinogen; Hemoglobins; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Male; Metabolic Diseases; Middle Aged; Olanzapine; Pilot Projects; Rosiglitazone; Schizophrenia; Statistics as Topic; Thiazolidinediones

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

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

Topics: Adolescent; Adult; alpha-Tocopherol; Antioxidants; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Double-Blind Method; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Middle Aged; Olanzapine; Oxidative Stress; Schizophrenia; Young Adult

Comparisons of diabetic potential, glucose related metabolic levels, and insulin resistance between olanzapine and risperidone have produced variable results in cross-sectional and epidemiologic studies. Randomized prospective studies of metabolic effects during treatment with these drugs may provide results that are more informative.. Hospitalized patients with chronic schizophrenia (DSM-IV), most of whom had been treated with multiple antipsychotics in the past, were randomly assigned to treatment with a single antipsychotic, olanzapine or risperidone, for a period of 5 months. At baseline and every treatment month thereafter, fasting glucose, insulin, insulin-related metabolic measures, and prolactin were assessed, and an oral glucose tolerance test (OGTT) was performed during baseline and months 1, 2, and 5 of treatment. Weight was assessed monthly, and waist and hip measures were taken at baseline and month 5. Data were analyzed on 23 patients randomly assigned to risperidone and 23 patients randomly assigned to olanzapine. The study was conducted from February 2003 to August 2007.. Most patients were overweight or obese at baseline (mean body mass index [BMI] = 29.4), but there were no differential drug effects on weight change and no differences between drug groups at the 5-month time point. There were no overall drug treatment differences in fasting glucose or glycohemoglobin or 2-hour glucose levels in OGTT and no differences between the two drug groups at the 5-month time point. There were no consistent drug treatment differences in the number of patients who developed borderline or diabetic glucose levels. Olanzapine-treated patients showed a significantly greater increase than risperidone-treated patients in a fasting measure of insulin resistance (P = .041), and olanzapine patients showed greater decreases in insulin sensitivity during OGTT (P = .023) compared to risperidone-treated patients. Olanzapine-treated patients had a significantly greater increase in 1-hour glucose and insulin levels during OGTT in subsequent months compared to baseline and greater increase in glucose and insulin area under the curve over time than the risperdone-treated patients. Prolactin levels decreased in olanzapine patients and increased in risperidone patients (P values approximately .02). There were no significant drug treatment differences in C-peptide levels or 2 indices proposed as measures of insulin secretion or beta-cell function (homeostasis model assessment of beta-cell function [HOMA-B], BIGTT-acute insulin response surrogate measure [BIGTT-AIR]). Changes in insulin resistance over time were not strongly related to changes in BMI or waist circumference during study drug treatment.. The increase in insulin levels during olanzapine treatment may compensate for the increase in insulin resistance and serve to reduce fasting and postprandial glucose levels. This may contribute to the lack of differences between olanzapine and risperidone in indices of diabetic or prediabetic glucose levels or glycohemoglobin. How many years this compensatory mechanism will persist needs further investigation. Periodic OGTT tests measuring glucose and insulin levels would be helpful in assessing the status of beta-cell insulin reserve in patients treated with olanzapine and other second-generation antipsychotics and assessing an individual patient's risk for conversion to type 2 diabetes.. clinicaltrials.gov Identifier NCT00287820.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Chronic Disease; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Longitudinal Studies; Male; Middle Aged; Olanzapine; Prolactin; Risk Factors; Risperidone; Schizophrenia

Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown.. We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (SI) and (4) pancreatic function ("disposition index", DI) by intravenous glucose tolerance test.. At baseline, groups (risperidone: n=28; olanzapine: n=31) were overweight or obese by body mass index (risperidone: 28.4+/-5.4, olanzapine: 30.6+/-7.0kg/m2). Both drugs induced weight gain (p<0.004). Total adiposity was increased by olanzapine at 6 weeks (p=0.0006) and by both treatments at 24 weeks (p<0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p<0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S(I), we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p<0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p=0.033), indicating inadequate pancreatic compensation for insulin resistance.. This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.

Topics: Absorptiometry, Photon; Adult; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Brief Psychiatric Rating Scale; Double-Blind Method; Ethnicity; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Psychotic Disorders; Risperidone; Schizophrenia; Time Factors; Tomography, X-Ray Computed

Topics: Adult; Antipsychotic Agents; Appetite; Benzodiazepines; Blood Glucose; Chronic Disease; Delayed-Action Preparations; Female; Fluphenazine; Humans; Insulin; Insulin Resistance; Male; Olanzapine; Reference Values; Risperidone; Schizophrenia; Weight Gain

In this study, the Authors assessed some insulin counter-regulatory factors, fibrinogen and C-reactive protein after olanzapine administration, and the effect of metformin on these variables, 37 patients with chronic schizophrenia were given olanzapine (10 mg/day for 14 weeks). Nineteen patients received metformin (850-2550 mg/day) and 18 received placebo in a randomized, double-blind protocol. The following variables were quantified before and after olanzapine: cortisol, leptin, tumor necrosis factor-alpha, glucagon, growth hormone, fibrinogen and C-reactive protein. Results were correlated with the changes in body weight and the insulin resistance index. We have reported elsewhere that metformin did not prevent olanzapine-induced weight gain, and the insulin resistance index significantly decreased after metformin and placebo; Baptista T, et al. Can J Psychiatry 2006; 51: 192-196. Cortisol, tumor necrosis factor-alpha and fibrinogen levels significantly decreased in both groups. Glucagon significantly increased after metformin (P=0.03). Leptin tended to increase after placebo (P=0.1) and displayed a small nonsignificant reduction after metformin. The C-reactive protein did not change significantly in any group. Contrarily to most published studies, olanzapine was associated with decreased insulin resistance. Decrements in cortisol, fibrinogen and tumor necrosis factor-alpha levels point to an improvement in the metabolic profile. The trend for leptin to increase after placebo, but not after metformin in spite of similar weight gain suggests a beneficial effect of this antidiabetic agent.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; C-Reactive Protein; Double-Blind Method; Female; Fibrinogen; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemic Agents; Insulin; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Metformin; Middle Aged; Olanzapine; Schizophrenia; Sex Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Excessive body weight gain (BWG) is a clinically relevant side effect of olanzapine administration. The primary objective of this study was to assess whether metformin prevents or reverses BWG in patients with schizophrenia or bipolar disorder under olanzapine administration. Secondarily we evaluated diverse metabolic variables.. Eighty patients taking olanzapine (5-20 mg daily for more than 4 consecutive months) were randomly allocated to metformin (n=40; 850 to 2550 mg daily) or placebo (n=40) group in a 12-week double-blind protocol. Waist circumference (WC) body weight (BW), body mass index (BMI) fasting glucose, glycated hemoglobin (Hb1c), insulin, an insulin resistance index (HOMA-IR) lipids, leptin, c-reactive protein, fibrinogen, cortisol and the growth hormone (GH) were evaluated at baseline and at week 12 of treatment.. The metformin group lost 1.4+/-3.2 kg (p=0.01) and tended to decrease its leptin levels, whereas the placebo group maintained a stable weight: -0.18+/-2.8 kg (p=0.7). The HOMA-IR significantly increased after placebo (p=0.006) and did not change after metformin (p=0.8). No ostensible differences were observed in the other variables, even though metformin did not improve the lipid profile and the Hb1c levels.. Metformin may safely assist olanzapine-treated patients in body weight and carbohydrate metabolism control.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Blood Glucose; Body Mass Index; Body Weight; Brief Psychiatric Rating Scale; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Energy Metabolism; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Resistance; Leptin; Lipids; Male; Metformin; Middle Aged; Olanzapine; Schizophrenia; Statistics as Topic

Melkersson proposed leptin dysregulation as a factor in the olanzapine-induced metabolic dysfunction. Their suggestion was based on the absence of the expected positive correlation between serum leptin levels and the BMI, and the loss of the sex-dependent difference in leptin levels, which are higher in women. Although subsequent studies did not confirm that proposal, few of them assessed basal leptin levels and corrected for body fat percentage. Along with these variables, we added a precise definition of participants out of the expected positive correlation in a large sample of schizophrenia patients. Sixty patients (26 women and 34 men) with severe schizophrenia undergoing chronic hospitalization and conventional antipsychotic treatment were switched to olanzapine (10-20 mg/day). We assessed at baseline, and at weeks 8 and 16 of treatment, the percentage of participants with abnormal correlation (out of the 95% confidence interval in the regression line) between leptin levels and the BMI, and the correlation between leptin and insulin, glucose, the insulin resistance index, c-reactive protein (CRP) and treatment response. Leptin levels were higher in women than in men (P<0.01). The positive correlation between leptin levels, BMI and percentage of fat were preserved. After olanzapine, 3.8% of women and 2.9-5.8% of men were out the 95% confidence interval, and the proportion was similar at baseline. Glucose, insulin, the insulin resistance index and the CRP levels significantly increased after olanzapine. The impact of olanzapine on leptin regulation appears discrete and limited to a small number of participants. Additional studies must clarify the features that render them to metabolic dysregulation.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Reactive Protein; Female; Humans; Insulin; Insulin Resistance; Leptin; Linear Models; Male; Middle Aged; Multivariate Analysis; Olanzapine; Schizophrenia; Sex Factors; Weight Gain

Although treatment with antipsychotics, particularly olanzapine and clozapine, has been implicated in weight gain and higher incidence of diabetes, the mechanism of these adverse reactions remains unclear. The purposes of this study were to explore the early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin, three recently identified hormones that play crucial roles in the regulation of energy balance and glucose metabolism. Thirteen patients with schizophrenia who had not received any medication in the 4 weeks prior to this study were included. The patients received olanzapine at an average dose of 14.5mg/day. Serum levels of ghrelin, adiponectin, leptin and insulin, as well as weight and fasting glucose, were investigated at the baseline and at 4 weeks. Serum ghrelin levels had decreased (p 0.03) and leptin had increased (p 0.02), while adiponectin and insulin levels had not significantly changed at Week 4 (p 0.29 and p 0.25, respectively). Weight had increased (p 0.01), while fasting glucose had not significantly changed (p 0.46). These findings suggest that ghrelin levels decrease and leptin levels increase after initiation of olanzapine therapy. Weight gain is also considered to be an early change, while change in insulin sensitivity is not an early change of treatment with olanzapine. Further large-scale and longitudinal studies are warranted to elucidate metabolic changes involving ghrelin, adiponectin, leptin and insulin and their impact on weight and glucose metabolism during treatment with olanzapine and other antipsychotics.

Topics: Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Body Weight; Female; Ghrelin; Humans; Insulin; Insulin Resistance; Leptin; Male; Olanzapine; Peptide Hormones; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Glucose and lipid metabolism dysfunction is a significant side effect associated with antipsychotics. Although there are many studies about the linkages between drugs and metabolic dysfunction, most of these studies have compared the effects of two antipsychotics on only one metabolic measure: either glucose or lipid metabolism.. The present study aimed to investigate the effects of clozapine, olanzapine, risperidone, and sulpiride on glucose and lipid metabolism in first-episode schizophrenia.. One hundred twelve schizophrenics were assigned randomly to receive clozapine, olanzapine, risperidone, or sulpiride for 8 weeks. Planned assessments included body mass index (BMI), waist-to-hip ratio, fasting glucose, insulin, C-peptide, insulin resistance index (IRI), cholesterol, and triglyceride. All measures were collected at baseline and at the end of the 8-week treatment.. After treatment, insulin, C-peptide, and IRI were significantly increased in the four groups, but not fasting glucose levels. Cholesterol and triglyceride levels were significantly increased in the clozapine and olanzapine groups. Patients treated with clozapine and olanzapine had higher fasting insulin, C-peptide, and IRI levels than those treated with risperidone and sulpiride. Among the four antipsychotics, the increases of mean BMI from high to low were as follows: clozapine, olanzapine, sulpiride, and risperidone.. This study confirmed that the four antipsychotic drugs were associated with an increase of insulin, C-peptide, and IRI. It was found that clozapine and olanzapine were associated with an increase in cholesterol and triglyceride levels. The effects of clozapine and olanzapine on the glucose and lipid metabolism outweighed those of risperidone and sulpiride.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; C-Peptide; Cholesterol; Clozapine; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Lipid Metabolism; Male; Metabolic Syndrome; Olanzapine; Prospective Studies; Risperidone; Schizophrenia; Sulpiride; Triglycerides; Waist-Hip Ratio

To assess whether metformin prevents body weight gain (BWG) and metabolic dysfunction in patients with schizophrenia who are treated with olanzapine.. Forty patients taking olanzapine (10 mg daily) were randomly allocated to a metformin (n = 20; 850 to 1700 mg daily) or placebo (n = 20) group in a 14-week double-blind study. Waist circumference (WC), BWG, body mass index (BMI) fasting glucose, insulin, and lipids were evaluated at baseline and at Weeks 7 and 14 of treatment.. At Week 14, BWG (kg) was similar in the metformin group (5.5 kg) and the placebo group (6.3 kg), P = 0.4. There were no differences between the changes in BMI, WC, glucose, insulin, insulin resistance index (HOMA-IR), and plasma lipid levels observed in the treatment group and the placebo group; however, glucose levels decreased significantly after metformin administration (P = 0.02). The HOMA-IR decreased significantly in both groups, but 3 subjects from the placebo group developed fasting glucose levels greater than 5 mmol/L. After taking metformin, triglyceride levels increased, but the cholesterol profile improved significantly.. Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypercholesterolemia; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Obesity; Olanzapine; Schizophrenia; Weight Gain

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

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

The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Fasting; Fatty Acids, Nonesterified; Female; Food; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Middle Aged; Olanzapine; Pirenzepine; Placebos; Reference Values; Risperidone

The aim of this study was to compare glucose metabolism in patients with schizophrenia receiving olanzapine with that in control subjects.. We conducted a prospective, controlled, open study comparing body weight, fat mass, and indices of insulin resistance/ sensitivity in 10 olanzapine-treated patients with ICD-10 schizophrenia (olanzapine dose range, 7.5-20 mg/day) with those of a group of 10 mentally and physically healthy volunteers. Weight, fat mass, and indices of insulin resistance/sensitivity were assessed over individual 8-week observation periods from November 1997 to October 1999.. Fasting serum glucose and fasting serum insulin increased significantly in the olanzapine-treated patients (p =.008 for glucose and p =.006 for insulin). The homeostasis model assessment (HOMA) index for beta cell function did not change significantly in the olanzapine-treated patients, whereas the HOMA index for insulin resistance did increase (p =.006). In the control group, these parameters were stable. A significant increase in body weight (p =.001) and body fat (p =.004) was seen in patients treated with olanzapine, while the control group showed no significant changes.. This study indicates that the disturbances in glucose homeostasis during antipsychotic treatment with olanzapine are mainly due to insulin resistance. However, beta cell function remains unaltered in olanzapine-treated patients. We conclude that treatment with some second-generation antipsychotic drugs may lead to insulin resistance.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Composition; Body Weight; Dose-Response Relationship, Drug; Female; Homeostasis; Humans; Insulin Resistance; Islets of Langerhans; Male; Olanzapine; Pirenzepine; Prospective Studies; Schizophrenia

Olanzapine (OLZ) is an atypical antipsychotic agent for psychotic disorders. Evidence has shown that OLZ is related to metabolic side effects, including obesity, hypertension, and insulin resistance. Thymoquinone (TQ) is the principal bioactive component of Nigella sativa. Several studies have been conducted to investigate the effectiveness of TQ in alleviating metabolic abnormalities. In the current research work, the protective effects of TQ on metabolic disorders induced by OLZ and possible underlying mechanisms were investigated.. Wistar rats were exposed to TQ alone (10 mg/kg), OLZ (5 mg/kg), or OLZ plus TQ (2.5, 5, or 10 mg/kg) given daily by intraperitoneal injection. After the treatment, variations in body weight, food intake, systolic blood pressure, serum leptin, biochemical factors, liver malondialdehyde (MDA), and glutathione (GSH) content were evaluated. Protein expression of AMPK in the liver was also measured by a western blotting test. OLZ increased body weight, food intake, MDA levels, and blood pressure. OLZ also elevated glucose, triglyceride, low-density lipoprotein cholesterol, and leptin serum levels. It decreased GSH. In the western blot, decreased AMPK protein level was obtained. These changes were attenuated by TQ co-administration.. The present study demonstrates the effectiveness of TQ on OLZ-induced metabolic abnormalities related to its antioxidant activity and regulation of glucose homeostasis and lipid metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Benzoquinones; Glucose; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Wistar

A rapid increase has been observed in insulin resistance (IR) incidence induced by a long-term olanzapine treatment with no better ways to avoid it. Our study aimed to demonstrate the mechanism underlying the olanzapine-induced insulin resistance and find appropriate drug interventions. In this study, firstly, we constructed rat insulin resistance model using a two-month gavage of olanzapine and used the main active ingredient mixture of Gegen Qinlian Decoction for the treatment. The activity of brown adipose tissue (BAT) was measured using the PET/CT scan, whereas Western blot and quantitative real-time PCR were used to detect the expression of GLUT4 and UCP1. The results showed that the long-term administration of olanzapine impaired glucose tolerance and produced insulin resistance in rats, while Gegen Qinlian Decoction could improve this side effect. The results of the PET/CT scan showed that the BAT activity in the insulin-resistant rats was significantly lower than that of the Gegen Qinlian Decoction treated rats. Also, the expression of GLUT4 and UCP1 in the insulin resistance group showed a significant decrease, which could be up-regulated by Gegen Qinliane Decoction treatment. The results of both in vivo and in vitro experiments were consistent. we demonstrated that the olanzapine could induce IR in vitro and in vivo by decreasing the expression of UCP1; thus, suppressing the thermogenesis of BAT and impairing glucose uptake. More importantly, we demonstrated a possible novel strategy to improve the olanzapine-induced IR by Gegen Qinlian Decoction.

Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Insulin; Insulin Resistance; Olanzapine; Positron Emission Tomography Computed Tomography; Rats

The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.

Topics: Adiponectin; Adipose Tissue; Animals; Antipsychotic Agents; Female; Fenofibrate; Fibroblast Growth Factors; Hypolipidemic Agents; Insulin Resistance; Olanzapine; Oxidative Stress; Rats; Rats, Sprague-Dawley; Weight Gain

Topics: Anthocyanins; Diabetes Mellitus, Type 2; Elaeocarpaceae; Fatty Liver; Glucosides; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipids; Liver; Muscle Fibers, Skeletal; Muscle, Skeletal; Obesity; Olanzapine; Plant Extracts; Polyphenols

The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats.. Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis.. Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine.. Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents; Blood Glucose; Cytokines; Disease Models, Animal; Epididymis; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Macrophages; Male; Metformin; Olanzapine; Phenotype; Rats, Sprague-Dawley; Signal Transduction; Weight Gain

Antipsychotic use is associated with an increased risk of type 2 diabetes. Recent work suggests antipsychotics can induce insulin resistance immediately and independently of weight gain, and that this may occur via the central nervous system (CNS). We have previously shown that the highly effective and widely prescribed antipsychotic, olanzapine inhibits CNS insulin-mediated suppression of hepatic glucose production, but the mechanisms remain unknown. The ATP-sensitive potassium (K

Topics: Adenosine Triphosphate; Diabetes Mellitus, Type 2; Glucose; Humans; Insulin; Insulin Resistance; Olanzapine

The ancient Chinese herbal formula Longdan Xiegan Tang (LXT, also called Gentiana Longdancao Decoction to Drain the Liver) treats insulin resistance- and inflammation-associated liver injuries in clinical practice.. To investigate the molecular mechanisms underlying LXT-elicited improvement of the liver injuries.. Male rats were co-treated with olanzapine (5 mg/kg) and LXT extract (50 and 500 mg/kg) for eight weeks. Blood parameters were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry.. The present results demonstrate that LXT attenuates liver injury and hepatic insulin resistance by regulating the ACE2/Ang (1-7)/Mas axis-mediated anti-inflammatory pathway in rats. Our findings provide a better understanding of LXT for treatment of insulin resistance- and inflammation-associated liver injuries.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Cytokines; Drugs, Chinese Herbal; Fasting; I-kappa B Kinase; Insulin Resistance; Liver; Male; NF-kappa B; Olanzapine; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled

c-jun N-terminal kinase (JNK) plays pivotal roles in many physiological processes, including inflammation and glucose metabolism. However, the effects of JNK on olanzapine-induced insulin resistance and the underlying mechanisms have not been fully elucidated. The aim of our study was to explore the role of JNK in olanzapine-induced insulin resistance and the underlying mechanisms.. We studied glucose metabolism in olanzapine-treated female C57B/J mice and mice with adeno-associated virus (AAV)-mediated downregulation of JNK1 in epididymal white adipose tissue (eWAT). 3T3-L1 adipocytes were used to investigate the mechanism of JNK1 regulating insulin signaling after olanzapine treatment.. JNK was activated in eWAT after olanzapine treatment. JNK1 downregulation in eWAT ameliorated the insulin resistance and adipose tissue inflammation in olanzapine-treated mice. Furthermore, overexpression of JNK1 in adipocytes exacerbated the glucose disorder while JNK1 knockdown alleviated the impaired insulin signaling on olanzapine challenge, which was likely mediated by the reduced inflammation and insulin receptor substrate 1 (IRS1) phosphorylation. Moreover, the effect of JNK1 was attenuated by downregulation of IRS1 in adipocytes. Finally, the JNK1-IRS1 interaction and IRS1. Our results demonstrated that JNK1 activation by olanzapine induced insulin resistance by promoting IRS1

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Antipsychotic Agents; Down-Regulation; Female; Gene Knockdown Techniques; Glucose; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 8; Olanzapine; Phosphorylation

Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of the development of metabolic syndrome that increases morbidity and mortality and impairs compliance with treatment. Mechanism of the high association of metabolic syndrome with the use of atypical antipsychotics is not clear. Literature and our data suggest that chronic inflammation- or stress-induced dysregulation of the peripheral down-stream kynurenine (Kyn) metabolism, shared by both Sz and metabolic syndrome, contributes to the development of metabolic syndrome in Sz patients treated with atypical antipsychotics. Correction of dysregulation of the peripheral down-stream metabolism of Kyn would prevent/treat metabolic syndrome. This is a pre-clinical trial of the effect of benserazide (BRZ), an inhibitor of the key enzymes of Kyn metabolism, on olanzapine-induced mouse model of metabolic syndrome. Olanzapine is one of the most effective atypical antipsychotics but has high potential to induce metabolic syndrome. Olanzapine (4 mg/kg, p.o) and/or BRZ (100 mg/day, p.o.) were administered to 6-week-old C57Bl/6 female mice, 5 days/week, for 10 weeks. The study was approved by the Tufts Medical Center Institutional Animal Care and Use Committee. BRZ attenuated olanzapine-induced excessive weight gain, impairment of glucose tolerance, and elevation of plasma cholesterol and triglycerides. Present results suggest that peripheral down-stream Kyn metabolism is a new target for prevention/treatment of olanzapine-induced metabolic syndrome. BRZ has a high translational potential as medication already approved for human use.

Topics: Animals; Antipsychotic Agents; Benserazide; Dyslipidemias; Female; Insulin Resistance; Kynurenine; Metabolic Syndrome; Mice, Inbred C57BL; Obesity; Olanzapine; Weight Gain

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

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

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

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

To elucidate the protective effect of berberine on olanzapine induced-metabolic syndrome.. This prospective experimental study involved thirty Sprague-Dawley male rats which were divided into three groups. Group A (n=10): Rats treated with distilled water, Group B (n=10): Rats treated with olanzapine, Group C (n=10): Rats treated with olanzapine plus berberine. The duration of the study was 8 weeks, baseline and follow up data were evaluated. Fasting blood glucose(FBG) total cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL), Low density lipoprotein (LDL), atherogenic index of plasma (AI), fasting serum insulin level, insulin resistance, β- cell function and insulin sensitivity were evaluated.SPSS 20.. Olanzepine led to significant deterioration in gluco-metabolic profile compared with control P<0.01. Olanzapine plus berberine improved body weight, FBG, FSI, HOMA-IR and QUICKI compared with olanzapine P=0.0001.. Berberine attenuates olanzapine induced-metabolic via amelioration of gluco-lipid disturbances.

Topics: Animals; Berberine; Biomarkers; Insulin Resistance; Male; Metabolic Syndrome; Olanzapine; Prospective Studies; Rats; Rats, Sprague-Dawley; Weight Gain

Chronic treatment with antipsychotics, especially most of atypical ones, leads to development of metabolic abnormalities. Olanzapine is an atypical antipsychotic widely used in the treatment of schizophrenia and bipolar disorder. The mechanisms underlying olanzapine-induced metabolic adverse effects in the liver, however, remain unclear. This study was designed to investigate olanzapine-induced insulin-desensitivity in the liver.. Male rats were treated with olanzapine (5 mg/kg, by a gavage method, once daily for consecutive 8 weeks. Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot.. Olanzapine treatment significantly increased fasting plasma insulin concentration, the index of the homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triglyceride and fatty droplet accumulation in rats. Hepatic gene/protein expression profile revealed that olanzapine activated mRNA and protein expression of sterol regulatory element-binding protein-1c, and mRNA levels of its downstream lipogenic enzymes, acetyl-CoA carboxylase-1, fatty acid synthase and stearoyl-CoA desaturase-1. More importantly, phosphorylated protein level of both Ser. Our results suggest that the IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Our findings may provide better understanding of the antipsychotic-induced metabolic adverse effects.

Topics: Animals; Antipsychotic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Liver; Male; Olanzapine; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction

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

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

Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.

Topics: 3T3-L1 Cells; Adipocytes; Adult; Animals; Antipsychotic Agents; Blood Glucose; Cytokines; Disease Models, Animal; Duration of Therapy; Female; Glucose Transporter Type 4; Humans; Inflammation Mediators; Insulin Resistance; Male; Metabolic Syndrome; Mice; Models, Biological; NF-kappa B; Olanzapine; Rats; Schizophrenia; Young Adult

Second generation antipsychotic (AP)s remain the gold-standard treatment for schizophrenia and are widely used on- and off-label for other psychiatric illnesses. However, these agents cause serious metabolic side-effects. The hypothalamus is the primary brain region responsible for whole body energy regulation, and disruptions in energy sensing (e.g. insulin signaling) and inflammation in this brain region have been implicated in the development of insulin resistance and obesity. To elucidate mechanisms by which APs may be causing metabolic dysregulation, we explored whether these agents can directly impact energy sensing and inflammation in hypothalamic neurons.. The rat hypothalamic neuronal cell line, rHypoE-19, was treated with olanzapine (0.25-100 uM), clozapine (2.5-100 uM) or aripiprazole (5-20 uM). Western blots measured the energy sensing protein AMPK, components of the insulin signaling pathway (AKT, GSK3β), and components of the MAPK pathway (ERK1/2, JNK, p38). Quantitative real-time PCR was performed to determine changes in the mRNA expression of interleukin (IL)-6, IL-10 and brain derived neurotrophic factor (BDNF).. Olanzapine (100 uM) and clozapine (100, 20 uM) significantly increased pERK1/2 and pJNK protein expression, while aripiprazole (20 uM) only increased pJNK. Clozapine (100 uM) and aripiprazole (5 and 20 uM) significantly increased AMPK phosphorylation (an orexigenic energy sensor), and inhibited insulin-induced phosphorylation of AKT. Olanzapine (100 uM) treatment caused a significant increase in IL-6 while aripiprazole (20 uM) significantly decreased IL-10. Olanzapine (100 uM) and aripiprazole (20 uM) increased BDNF expression.. We demonstrate that antipsychotics can directly regulate insulin, energy sensing, and inflammatory pathways in hypothalamic neurons. Increased MAPK activation by all antipsychotics, alongside olanzapine-associated increases in IL-6, and aripiprazole-associated decreases in IL-10, suggests induction of pro-inflammatory pathways. Clozapine and aripiprazole inhibition of insulin-stimulated pAKT and increases in AMPK phosphorylation (an orexigenic energy sensor) suggests impaired insulin action and energy sensing. Conversely, olanzapine and aripiprazole increased BDNF, which would be expected to be metabolically beneficial. Overall, our findings suggest differential effects of antipsychotics on hypothalamic neuroinflammation and energy sensing.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Cell Line; Clozapine; Energy Metabolism; Hypothalamus; Inflammation; Insulin; Insulin Resistance; MAP Kinase Signaling System; Neurons; Olanzapine; Phosphorylation; Rats; Schizophrenia; Signal Transduction

Antipsychotic drugs can negatively affect the metabolic status of patients, with olanzapine as one of the most potent drugs. While patients are often medicated for long time periods, experiments in rats typically run for 1 to 12 weeks, showing olanzapine-related weight gain and increased plasma lipid levels, with transcriptional upregulation of lipogenic genes in liver and adipose tissue. It remains unknown whether metabolic status will deteriorate with time.. To examine long-term metabolic effects, we administered intramuscular long-acting injections of olanzapine (100 mg/kg BW) or control substance to female rats for up to 13 months.. Exposure to olanzapine long-acting injections led to rapid weight gain, which was sustained throughout the experiment. At 1, 6, and 13 months, plasma lipid levels were measured in separate cohorts of rats, displaying no increase. Hepatic transcription of lipid-related genes was transiently upregulated at 1 month. Glucose and insulin tolerance tests indicated insulin resistance in olanzapine-treated rats after 12 months.. Our data show that the continuous increase in body weight in response to long-term olanzapine exposure was accompanied by surprisingly few concomitant changes in plasma lipids and lipogenic gene expression, suggesting that adaptive mechanisms are involved to reduce long-term metabolic adverse effects of this antipsychotic agent in rats.

Topics: Adipose Tissue; Animals; Animals, Outbred Strains; Antipsychotic Agents; Blood Glucose; Female; Glucose Tolerance Test; Injections, Intramuscular; Insulin; Insulin Resistance; Lipids; Liver; Olanzapine; Random Allocation; Rats, Sprague-Dawley; Time Factors; Weight Gain

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

Clinical use of the antipsychotic drug olanzapine (OLA) is associated with metabolic side effects to variable degrees. N-desmethyl-olanzapine (DMO) is one major metabolite of OLA, but its potential involvement in the metabolic responses remains unclear. Here we examined whether DMO can directly impact the metabolic, endocrinal and inflammatory parameters under conditions of metabolic disturbance. DMO administration (2 mg/kg, i.g.) to high-fat diet induced obesity mice for 4 weeks induced a remarkable loss of body weight and fat mass. DMO improved insulin resistance and energy expenditure in mice, but had no significant effects on dyslipidemia or hepatic steatosis. Moreover, DMO induced morphological changes in the white adipose tissue, accompanied by reduced interleukin-1β (IL-1β) production and increased UCP1 expression. These findings demonstrate that DMO is devoid of the metabolic side effects commonly observed for OLA during obesity, which suggests that the N-desmethyl metabolism may function to regulate the metabolic responses to OLA.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Dyslipidemias; Energy Metabolism; Fatty Liver; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Olanzapine; Pirenzepine

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

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

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

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

Topics: Humans; Insulin Resistance; Obesity; Olanzapine

The precise effect of antipsychotic drugs on either central or peripheral inflammation remains unclear. An important issue in this debate is to what extent the known peripheral metabolic effects of antipsychotics, including increased adiposity, may contribute to increased inflammation. Adipose tissue is known to contribute to the development of systemic inflammation, which can eventually lead to insulin resistance and metabolic dysregulation. As a first step to address this question, we evaluated whether chronic exposure to clinically comparable doses of haloperidol or olanzapine resulted in the immune activation of rat adipose tissue. Samples of visceral adipose tissue were sampled from male Sprague-Dawley rats exposed to, haloperidol, olanzapine or vehicle (all n = 8), for 8 weeks. From these we measured a cytokine profile, protein expression of F4/80 (a phenotypic macrophage marker) and translocator protein (TSPO), a target for radiotracers putatively indicating microgliosis in clinical neuroimaging studies. Chronic olanzapine exposure resulted in significantly higher adipose IL-6 levels compared with vehicle-controls (ANOVA p = 0.008, Bonferroni post-hoc test p = 0.006); in parallel, animals exposed to olanzapine had significantly higher F4/80 expression when compared with vehicle-controls (Mann Whitney Test, p = 0.014), whereas there was no difference between haloperidol and vehicle groups (Mann Whitney test, p = 0.1). There were no significant effects of either drug on adipose TSPO protein levels. Nevertheless, we found a positive correlation between F4/80 and TSPO adipose protein levels in the olanzapine-exposed rats (Spearman's rho = 0.76, p = 0.037). Our data suggest that chronic exposure to olanzapine, but not haloperidol, increases production of the pro-inflammatory cytokine IL-6 in adipose tissue and increased macrophages expression (F4/80), in the absence of measurable changes in TSPO with respect to vehicle. This may have potentially important consequences in terms of metabolic dysregulation associated with long-term antipsychotic treatment.

Topics: Adipose Tissue; Adiposity; Animals; Antigens, Differentiation; Antipsychotic Agents; Biomarkers; Carrier Proteins; Cytokines; Gene Expression; Haloperidol; Inflammation; Insulin Resistance; Interleukin-6; Intra-Abdominal Fat; Macrophages; Male; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley; Receptors, GABA-A

The use of antipsychotics is associated with severe disruptions in whole body glucose and lipid metabolism which may in part occur through the central nervous system and impaired insulin action at the brain. Here we investigated whether olanzapine treatment might also affect the ability of central insulin treatment to regulate food intake and fuel preference in the light and dark cycle. Male Sprague-Dawley rats were treated with olanzapine (or vehicle solution; 3 mg/kg, subcutaneous) and a simultaneous acute intracerebral ventricular (ICV) infusion of insulin (or vehicle; 3 μL at 10mU; ICV) at the beginning of the 12-h light and dark cycles. Olanzapine treatment reduced RER in the dark and light phases (most consistently in the 4-hours post-treatment), while ICV insulin reduced average RER predominantly in the dark phase, but also at the end of the light cycle. The RER lowering effect of ICV-insulin during the light cycle was absent in the group co-administered olanzapine. The reduction in RER during the dark phase was mirrored by decreased food intake with ICV insulin, but not olanzapine treated rats. The reduction in food intake by ICV-insulin was abolished in rats co-administered olanzapine suggesting rapid induction of central insulin resistance. A combination of ICV-insulin and olanzapine similarly reduced RER in the dark phase, independent of changes in food intake. Olanzapine treatment, alone or in combination with ICV-insulin, significantly reduced VCO

Topics: Animals; Antipsychotic Agents; Eating; Exhalation; Glucose; Hypothalamus; Insulin; Insulin Resistance; Lipid Metabolism; Male; Olanzapine; Rats; Rats, Sprague-Dawley

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.

Topics: Adipose Tissue; Adolescent; Adult; Animals; Antipsychotic Agents; Body Mass Index; Eating; Female; HeLa Cells; Humans; Hypothalamus; Insulin Resistance; Intramolecular Oxidoreductases; Lipids; Lipolysis; Liver; Macrophage Migration-Inhibitory Factors; Male; Mice; Middle Aged; Muscle, Skeletal; Olanzapine

Olanzapine, an atypical antipsychotic, is associated with glucoregulatory abnormalities, but the nature of this link is not fully elucidated. This is the first olanzapine oral glucose tolerance test (oGTT) study to consider treatment dose and duration, and to compare complementary indices respectively assessing insulin sensitivity (Matsuda index) and resistance (homeostasis model assessment).. Body mass index (BMI), body composition, plasma lipids, and oGTT were measured in olanzapine-treated nondiabetic patients with DSM-IV-TR diagnosis of schizophrenia or schizoaffective disorder (n = 35).. While only one previously undiagnosed participant met diabetes criteria based on fasting plasma glucose alone (≥126 mg/dL), seven were diagnosed with oGTT (2-hr plasma glucose ≥200 mg/dL). Multiple regression analyses revealed that the Matsuda index correlated with BMI (p < 0.0001) and plasma triglycerides (p = 0.01), but not with age, olanzapine dose, olanzapine treatment duration, or plasma cholesterol. Homeostasis model assessment and fasting plasma glucose correlated with triglycerides only (p < 0.0001 for both).. Our data suggest that BMI and triglycerides may be implicated in olanzapine-related glucoregulatory abnormalities. The lack of correlation between glucoregulatory abnormalities and olanzapine dose or treatment duration suggests preexisting metabolic disturbances and/or disturbances arising early in the course of treatment. Clinicians prescribing antipsychotics should consider oGTT, especially in patients with obesity and/or hypertriglyceridemia.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Dose-Response Relationship, Drug; Female; Glucose Tolerance Test; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Psychotic Disorders; Regression Analysis; Schizophrenia; Triglycerides

Olanzapine, an antipsychotic agent mainly used for treating schizophrenia, is frequently associated with body weight gain and diabetes mellitus. Nonetheless, studies have shown that not every individual is equally susceptible to olanzapine's weight-gaining effect. Therefore, Roman high and low avoidance rat strains were examined on their responsiveness to olanzapine treatment. The Roman high avoidance rat shares many behavioral and physiological characteristics with human schizophrenia, such as increased central dopaminergic sensitivity, whereas the Roman low avoidance rat has been shown to be prone to diet-induced obesity and insulin resistance. The data revealed that only the Roman high avoidance rats are susceptible to olanzapine-induced weight gain and attenuated glucose tolerance. Here it is suggested that the specific olanzapine-induced weight gain in Roman high avoidance rats could be related to augmented dopaminergic sensitivity at baseline through increased expression of prefrontal cortex dopamine receptor D1 mRNA and nucleus accumbens dopamine receptor D2 mRNA expression. Regression analyses revealed that olanzapine-induced weight gain in the Roman high avoidance rat is above all related to increased prolactin levels, whereas changes in glucose homeostasis is best explained by differences in central dopaminergic receptor expressions between strains and treatment. Our data indicates that individual differences in dopaminergic receptor expression in the cortico-mesolimbic system are related to susceptibility to olanzapine-induced weight gain.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dopamine; Gene Expression; Glucose; Homeostasis; Insulin Resistance; Nucleus Accumbens; Obesity; Olanzapine; Prefrontal Cortex; Rats; Schizophrenia

Insulin receptors are widely expressed in the brain and may represent a crossroad between metabolic and cognitive disorders. Although antipsychotics, such as olanzapine, are the cornerstone treatment for schizophrenia, they are associated with high rates of type 2 diabetes and lack efficacy for illness-related cognitive deficits. Historically, this risk of diabetes was attributed to the weight gain propensity of antipsychotics, but recent work suggests antipsychotics can have weight-independent diabetogenic effects involving unknown brain-mediated mechanisms. Here, we examined whether antipsychotics disrupt central insulin action, hypothesizing that olanzapine would impair the well-established ability of central insulin to supress hepatic glucose production.. Pancreatic euglycemic clamps were used to measure glucose kinetics alongside a central infusion of insulin or vehicle into the third ventricle. Male rats were pretreated with olanzapine or vehicle per our established model of acute olanzapine-induced peripheral insulin resistance. Groups included (central-peripheral) vehicle-vehicle (. There were no differences in peripheral glucose or insulin levels. Unexpectedly, we showed that central insulin increased glucose uptake, and this effect was not perturbed by olanzapine. We replicated suppression of glucose production by insulin (clamp relative to basal: 77.9% ± 13.1%, all. This study used only male rats and an acute dose of olanzapine.. To our knowledge, this is the first study suggesting olanzapine may impair central insulin sensing, elucidating a potential mechanism of antipsychotic-induced diabetes and opening avenues of investigation related to domains of schizophrenia psychopathology.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Brain; Catheters, Indwelling; Glucose; Infusions, Intraventricular; Insulin; Insulin Resistance; Male; Olanzapine; Rats, Sprague-Dawley; Subcutaneous Absorption

Atypical antipsychotics such as olanzapine cause metabolic side effects leading to obesity and insulin resistance. The underlying mechanisms remain elusive. In this study we investigated the effects of chronic treatment of olanzapine on the fatty acid composition of plasma in mice.. Twenty 8-week female Balb/c mice were randomly assigned to two groups: the OLA group and the control group. After treatment with olanzapine (10 mg/kg/day) or vehicle intraperitoneally for 8 weeks, fasting glucose, insulin levels and oral glucose tolerance test were determined. Effects on plasma fatty acid profile and plasma indices of D5 desaturase, D6 desaturase and SCD1 activity were also investigated.. Chronic administration of olanzapine significantly elevated fasting glucose and insulin levels, impaired glucose tolerance, but did not increase body weight. Total saturated fatty acids and n-6 polyunsaturated fatty acids were significantly increased and total monounsaturated fatty acids were significantly decreased, while total n-3 polyunsaturated fatty acids showed no prominent changes. Chronic olanzapine treatment significantly up-regulated D6 desaturase activity while down-regulating D5 desaturase activity. Palmitic acid (C16:0), dihomo-γ-linolenic acid (C20:3n-6) and D6 desaturase were associated with an increase probability of insulin resistance, whereas nervonic acid (C24:1) and SCD1 were significantly associated with a lower insulin resistance probability.. All results indicated that such drug-induced effects on fatty acid profile in plasma were relevant for the metabolic adverse effects associated with olanzapine and possibly other antipsychotics. Further studies are needed to investigate geneticand other mechanisms to explain how plasma fatty acids regulate glucose metabolism and affect the risk of insulin resistance.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antipsychotic Agents; Area Under Curve; Benzodiazepines; Blood Glucose; Chronic Disease; Fatty Acid Desaturases; Fatty Acids; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Mice; Mice, Inbred BALB C; Olanzapine; Palmitic Acid; Random Allocation

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Diabetes Mellitus; Diagnostic and Statistical Manual of Mental Disorders; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Psychiatric Status Rating Scales; Psychotic Disorders; Schizophrenia; Statistics as Topic; Triglycerides

Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats. Then, under anaesthesia, the carotid artery and jugular vein was prepared and cannulated to obtain samples for blood glucose and hormone determination as well as for insulin/glucose infusion, respectively. Basal insulin sensitivity and MIS was determined by homeostasis model assessment (HOMA) calculation and by rapid insulin sensitivity test, respectively. In fasted animals, olanzapine increased blood glucose and plasma insulin and reduced basal insulin sensitivity, but it failed to modify other hormone levels. Postprandial leptin and glucose-dependent insulinotropic polypeptide (GIP) levels increased, and ghrelin level decreased significantly (p < 0.05) both in vehicle- and olanzapine-treated groups, but plasma insulin increased only in vehicle-treated animals. Furthermore, decrement in ghrelin level was attenuated in olanzapine-treated animals compared to controls. There was no significant change in the first meal size and duration or in the total amount of food consumed. Olanzapine had no effect on the MIS. We demonstrated that olanzapine can induce insulin resistance without weight gain in healthy rats. Furthermore, the MIS was preserved after acute olanzapine treatment. The blunted postprandial ghrelin and insulin response could contribute to the effect of olanzapine on feeding behaviour. Pharmacological induction of MIS may improve the olanzapine-induced insulin resistance.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Energy Intake; Fasting; Feeding Behavior; Female; Ghrelin; Glucose Tolerance Test; Insulin; Insulin Resistance; Leptin; Olanzapine; Postprandial Period; Rats, Sprague-Dawley

Antipsychotics (APs) are linked to diabetes, even without weight gain. Whether anti-diabetic drugs are efficacious in reversing the direct effects of APs on glucose pathways is largely undetermined. We tested two metformin (Met) doses to prevent impairments seen following a dose of olanzapine (Ola) (3 mg/kg); glucokinetics were measured using the hyperinsulinemic-euglycemic clamp (HIEC). Met (150 mg/kg; n=13, or 400 mg/kg; n=11) or vehicle (Veh) (n=11) was administered through gavage preceding an overnight fast, followed by a second dose prior to the HIEC. Eleven additional animals were gavaged with Veh and received a Veh injection during the HIEC (Veh/Veh); all others received Ola. Basal glucose was similar across treatment groups. The Met 400 group had significantly greater glucose appearance (Ra) in the basal period (i.e., before Ola, or hyperinsulinemia) vs other groups. During hyperinsulinemia, glucose infusion rate (GINF) to maintain euglycemia (reflective of whole-body insulin sensitivity) was higher in Veh/Veh vs other groups. Met 150/Ola animals demonstrated increased GINF relative to Veh/Ola during early time points of the HIEC. Glucose utilization during hyperinsulinemia, relative to basal conditions, was significantly higher in Veh/Veh vs other groups. The change in hepatic glucose production (HGP) from basal to hyperinsulinemia demonstrated significantly greater decreases in Veh/Veh and Met 150/Ola groups vs Veh/Ola. Given the increase in basal Ra with Met 400, we measured serum lactate (substrate for HGP), finding increased levels in Met 400 vs Veh and Met 150. In conclusion, Met attenuates hepatic insulin resistance observed with acute Ola administration, but fails to improve peripheral insulin resistance. Use of supra-therapeutic doses of Met may mask metabolic benefits by increasing lactate.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Glucose Clamp Technique; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Metformin; Olanzapine; Rats; Rats, Sprague-Dawley

Meal-induced insulin sensitization (MIS), an endogenous adaptive mechanism is activated post-prandially. Reduced MIS leads to diabetes, but its activation improves insulin sensitivity. MIS is preserved to single olanzapine administration, therefore we aimed to investigate the chronic effect of olanzapine on fasted-state insulin sensitivity and on MIS in female Sprague-Dawley rats. Daily food and water intake, stool and urine production and body weight were determined. The MIS was characterized by a rapid insulin sensitivity test. Fasting hepatic and peripheral insulin sensitivity were determined by a hyperinsulinaemic euglycaemic glucose clamping supplemented with radiotracer technique. Fasted and post-prandial blood samples were obtained for plasma insulin, leptin, ghrelin, amylin, GLP-1, GIP, PYY and PP determination. Adiposity was characterized by weighing intra-abdominal and inguinal fat pads. Olanzapine caused hepatic insulin resistance and a reduced metabolic clearance rate of insulin, but the MIS retained its function. Body weight and adiposity were enhanced, but olanzapine failed to increase food intake. Fasting insulin and leptin were elevated and the post-prandial reduction in ghrelin level was inhibited by olanzapine.The MIS remained functionally intact after long-term olanzapine treatment. Altered insulin, leptin and ghrelin levels indicate olanzapine-induced metabolic derangements. Pharmacological activation of MIS could potentially be exploited to treat or prevent olanzapine-induced insulin resistance.

Topics: Animals; Benzodiazepines; Blood Glucose; Body Weight; Eating; Female; Gastrointestinal Hormones; Ghrelin; Insulin; Insulin Resistance; Leptin; Obesity; Olanzapine; Rats; Rats, Sprague-Dawley

Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRβ and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Cell Line, Tumor; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Matrix Metalloproteinase 9; Mice; Neuraminidase; Olanzapine; Phosphorylation; Protein Processing, Post-Translational; Protein Transport; Rats; Receptor, IGF Type 1; Receptor, Insulin; Signal Transduction

Olanzapine is a second generation antipsychotic. A common side effect in humans is weight gain, but the mechanisms are mostly unknown.. To study the effects of subchronic olanzapine treatment on body weight, fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, insulin sensitivity index (ISI), and expression of glucose transporter 2 (GLUT2) in rat pancreatic β cells.. Female Sprague-Dawley rats were randomly divided into two groups: the olanzapine-treated group and the control group (each n = 8). Rats in the olanzapine-treated group intragastrically received olanzapine 5 mg/kg/day for 28 days; the rats in the control group received the same volume of vehicle. FPG and body weight were measured on the 1st, 7th, 14th and 28th day. FINS and C-peptide were measured using immunoradiometric assays at baseline and on the 28th day. GLUT2 mRNA and protein expressions in pancreatic β cells were analyzed by RT-PCR and western blot.. Olanzapine-treated rats had higher body weight (227.4 ± 8.9 vs. 211.0 ± 9.9 g), FPG (5.86 ± 0.42 vs. 4.24 ± 0.29 mmol/L), FINS (17.34 ± 3.64 vs. 10.20 ± 1.50 µIU/mL), and C-peptide (0.154 ± 0.027 vs. 0.096 ± 0.009 ng/mL) than those in controls (all P < 0.05) at the 28th day. Pancreatic β cells of the olanzapine-treated group showed lower ISI (-4.60 ± 0.23 vs. -3.76 ± 0.20) and GLUT2 levels (mRNA: 1.12 ± 0.02 vs. 2.00 ± 0.03; protein: 0.884 ± 0.134 vs. 1.118 ± 0.221) than those in controls (all P < 0.05).. Subchronic olanzapine treatment inhibited expression of GLUT2 in rat pancreatic β cells. Therefore, it may disturb glucose metabolism via the insulin resistance of β cells, but confirmation in humans is needed.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Fasting; Female; Glucose Transporter Type 2; Insulin; Insulin Resistance; Insulin-Secreting Cells; Olanzapine; Rats; Rats, Sprague-Dawley

Over the past two decades, there has been a notable rise in the use of antipsychotic drugs, as they are used to treat an increasing number of neuropsychiatric disorders. This rise has been led predominantly by greater use of the second generation antipsychotic (SGA) drugs, which have a low incidence of neurological side-effects. However, many SGAs cause metabolic dysregulation, including glucose intolerance and insulin resistance, thus increasing the risk of cardiometabolic disorders. The metabolic effects of the novel SGA lurasidone, which was approved by the Food and Drug Administration in 2010, remain largely unknown. As rodent models accurately predict the metabolic effects of SGAs in humans, the aim of the present study was to use sophisticated animal models of glucose tolerance and insulin resistance to measure the metabolic effects of lurasidone. In parallel, we compared the SGA olanzapine, which has established metabolic effects. Adult female rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (10.0 mg/kg, s.c.) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (1.5 and 15 mg/kg, s.c.) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC). Compared to vehicle treated animals, lurasidone caused mild glucose intolerance in the GTT with a single dose, but there was no effect on insulin resistance in the GTT, measured by HOMA-IR. The HIEC also confirmed no effect of lurasidone on insulin resistance. In contrast, olanzapine demonstrated dose-dependent and potent glucose intolerance, and insulin resistance in both tests. Thus, in preclinical models, lurasidone demonstrates mild metabolic liability compared to existing SGAs such as olanzapine. However, confirmation of these effects in humans with equivalent tests should be confirmed.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Female; Glucose Tolerance Test; Insulin Resistance; Isoindoles; Lurasidone Hydrochloride; Olanzapine; Rats; Rats, Sprague-Dawley; Thiazoles

The second generation antipsychotic (SGA) drugs are widely used in psychiatry due to their clinical efficacy and low incidence of neurological side-effects. However, many drugs in this class cause deleterious metabolic side-effects. Animal models accurately predict metabolic side-effects for SGAs with known clinical metabolic liability. We therefore used preclinical models to evaluate the metabolic side-effects of glucose intolerance and insulin resistance with the novel SGAs asenapine and iloperidone for the first time. Olanzapine was used as a comparator.. Adults female rats were treated with asenapine (0.01, 0.05, 0.1, 0.5, 1.0 mg/kg), iloperidone (0.03, 0.5, 1.0, 5.0, 10.0 mg/kg) or olanzapine (0.1, 0.5, 1.5, 5.0, 10.0 mg/kg) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with asenapine (0.1 and 1.0 mg/kg), iloperidone (1.0 and 10 mg/kg) or olanzapine (1.5 and 15 mg/kg) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC).. Asenapine showed no metabolic effects at any dose in either test. Iloperidone caused large and significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with both doses in the HIEC. Olanzapine caused significant glucose intolerance with the three highest doses in the GTT, and insulin resistance with the higher dose in the HIEC.. In preclinical models, asenapine shows negligible metabolic liability. By contrast, iloperidone exhibits substantial metabolic liability, comparable to olanzapine. These results emphasize the need for appropriate metabolic testing in patients treated with novel SGAs where current clinical data do not exist.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Dibenzocycloheptenes; Fasting; Female; Glucose Clamp Technique; Glucose Tolerance Test; Heterocyclic Compounds, 4 or More Rings; Hyperinsulinism; Insulin Resistance; Isoxazoles; Metabolism; Olanzapine; Piperidines; Rats; Rats, Sprague-Dawley

Patients taking atypical antipsychotics are frequented by serious metabolic (eg, hyperglycemia, obesity, and diabetes) and cardiac effects. Surprisingly, chronic treatment also appears to lower free fatty acids (FFAs). This finding is paradoxical because insulin resistance is typically associated with elevated not lower FFAs. How atypical antipsychotics bring about these converse changes in plasma glucose and FFAs is unknown. Chronic treatment with olanzapine, a prototypical, side effect prone atypical antipsychotic, lowered FFA in Sprague-Dawley rats. Olanzapine also lowered plasma FFA acutely, concomitantly impairing in vivo lipolysis and robustly elevating whole-body lipid oxidation. Increased lipid oxidation was evident from accelerated losses of triglycerides after food deprivation or lipid challenge, elevated FFA uptake into most peripheral tissues (∼2-fold) except heart, rises in long-chain 3-hydroxylated acyl-carnitines observed in diabetes, and rapid suppression of the respiratory exchange ratio (RER) during the dark cycle. Normal rises in RER following refeeding, a sign of metabolic flexibility, were severely blunted by olanzapine. Increased lipid oxidation in muscle could be explained by ∼50% lower concentrations of the negative cytoplasmic regulator of carnitine palmitoyltransferase I, malonyl-CoA. This was associated with loss of anapleurotic metabolites and citric acid cycle precursors of malonyl-CoA synthesis rather than adenosine monophosphate-activated kinase activation or direct ACC1/2 inhibition. The ability of antipsychotics to lower dark cycle RER in mice corresponded to their propensities to cause metabolic side effects. Our studies indicate that lipocentric mechanisms or altered intermediary metabolism could underlie the FFA lowering and hyperglycemia (Randle cycle) as well as some of the other side effects of atypical antipsychotics, thereby suggesting strategies for alleviating them.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Carnitine; Clozapine; Energy Metabolism; Fatty Acids, Nonesterified; Female; Haloperidol; Insulin Resistance; Lipolysis; Male; Malonyl Coenzyme A; Mice; Olanzapine; Piperazines; Rats; Rats, Sprague-Dawley; Risperidone; Thiazoles; Vitamin B Complex

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

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

Retinol-binding protein 4 (RBP4) has been shown to be associated with insulin resistance (IR), metabolic indices and metabolic syndrome (MetS) in various patient populations and in obesity. We investigated the association between metabolic parameters, IR and RBP4 during olanzapine therapy.. A prospective study.. Thirty-seven participants with psychiatric disorder who were atypical antipsychotic naive and newly initiated on olanzapine were assessed.. Fasting RBP4, anthropometric and metabolic variables were measured before and after 3 months of olanzapine therapy.. Participants who developed MetS showed higher RBP4 levels compared with those without MetS, although not significant (P = 0·053). The variation in RBP4 level was correlated with changes in systolic blood pressure (r = 0·423, P = 0·009), diastolic blood pressure (r = 0·390, P = 0·017), total cholesterol (r = 0·446, P = 0·006) and low-density lipoprotein (LDL) (r = 0·407, P = 0·012). Multiple linear regression analysis illustrated that end-point log insulin level was the most significant independent predictor of final log RBP4 levels (standardized ß = 0·353, P = 0·024).. Our results suggest that RBP4 levels might be associated with at least some olanzapine-induced metabolic abnormalities and cardiovascular disease risk factors.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Linear Models; Male; Metabolic Syndrome; Middle Aged; Olanzapine; Prospective Studies; Retinol-Binding Proteins, Plasma

To investigate the influence of a single episode of psychiatric inpatient treatment on metabolic parameters.. A total of 294 consecutive patients of an Upper Austrian psychiatric department were assessed at admission and discharge regarding bodyweight, body mass index (BMI), high density cholesterol (HDL), low density cholesterol (LDL), triglycerides (TG) and fasting glucose (FG), and the TG/HDL ratio.. Patients showed an increase of BMI of 0.35 kg/m² (+ 1.3%) during a mean duration of inpatient stay of 25.8 days. LDL rose by 10.7 mg/dl (+ 8.1%), triglycerides by 23.0 mg/dl (+ 17%), HDL decreased by 4.4 mg/dl (-7.4%). Fasting glucose decreased by 3.6 mg/dl (-3.8%), yet the TG/HDL ratio, as a marker for insulin resistance, increased significantly from 2.86 to 3.58 (+ 25.2%) on average. Patients with psychotic disorders gained about three times more weight than patients with other diagnoses. Negative alterations of serum lipids were to be found in all diagnostic groups but were especially pronounced in patients with psychotic disorders who were treated with second-generation antipsychotics clozapine, olanzapine and quetiapine.. Psychiatric inpatient treatment leads to clinically relevant deterioration of metabolic parameters within a short time, most pronouncedly in patients with psychotic disorders.

Topics: Antipsychotic Agents; Austria; Benzodiazepines; Biomarkers; Body Mass Index; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Clozapine; Dibenzothiazepines; Female; Glucose; Hospitalization; Humans; Insulin Resistance; Length of Stay; Lipid Metabolism; Male; Mental Disorders; Middle Aged; Multivariate Analysis; Olanzapine; Polypharmacy; Prospective Studies; Psychiatric Department, Hospital; Psychotic Disorders; Quetiapine Fumarate; Regression Analysis; Triglycerides; Weight Gain

The underlying mechanism for second-generation antipsychotic (SGA)-related glucose-lipid metabolic dysfunction is not fully understood. Recent studies have suggested a possible impact of SGAs on endocrine regulation, especially on adipocytokines. We examined the effect of each SGA on various adipocytokines in normal fasting glucose (NFG) subjects.. The study population comprised 113 Japanese inpatients with schizophrenia who were treated with olanzapine, risperidone, or quetiapine, and 123 healthy control (CONT) volunteers. All of the subjects were diagnosed with NFG. Plasma concentration of adiponectin, leptin, tumor necrosis factor α, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were compared between the SGA and CONT groups.. Second-generation antipsychotic subjects had significantly higher leptin levels in comparison to the CONT subjects. The plasma concentration of adiponectin, total cholesterol, and high-density lipoprotein cholesterol in the SGA subjects were significantly lower than those in the CONT subjects. There were no significant differences in tumor necrosis factor α, triglyceride, and low-density lipoprotein cholesterol levels between the 2 groups. In a stepwise multiple regression analysis, olanzapine was found to be a factor that contributed to decreased adiponectin levels, and the CONT subjects were detected to be a factor associated with lower leptin levels.. The present study indicates the possibility that the administration of SGAs may affect adipocytokines in the NFG stage, excluding the impaired fasting glucose group, which is in the transition stage into diabetes mellitus.

Topics: Adiponectin; Adolescent; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cross-Sectional Studies; Diagnostic and Statistical Manual of Mental Disorders; Dibenzothiazepines; Down-Regulation; Female; Humans; Insulin Resistance; Leptin; Male; Middle Aged; Olanzapine; Quetiapine Fumarate; Risperidone; Schizophrenia; Up-Regulation; Young Adult

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

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

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

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

Olanzapine (OLZ) is known to cause weight gain and metabolic disturbances, which may have serious implications with respect to medical comorbidities such as metabolic syndrome and insulin resistance.. The aim of this study was to evaluate the effects of two angiotensin II type 1 receptor blockers (ARBs) which are widely used as antihypertensive agents, valsartan (VAL) and telmisartan (TEL), on insulin resistance in patients with schizophrenia treated with OLZ.. Thirty inpatients with schizophrenia with OLZ monotherapy over 8 weeks participated in this study. To assess insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR), fasting plasma glucose (PG) levels and immunoreactive insulin (IRI) levels were measured [HOMA-IR = fasting PG level (mmol/L) x fasting IRI level (μU/ml)/22.5]. VAL add-on treatment was performed in insulin-resistant patients (HOMA-IR > 1.6) for 12 weeks. After a 12-week VAL washout period, TEL add-on treatment was carried out for 12 weeks. The effects of ARBs on insulin resistance and other metabolic variables were assessed.. In all 30 patients, both body mass index and abdominal circumference were strongly correlated with HOMA-IR. Twelve patients showed high HOMA-IR and were deemed to be insulin resistant. Add-on therapy of VAL and TEL resulted in a significant decrease in fasting IRI levels and HOMA-IR. No differences in any effects were observed between VAL and TEL. No adverse effects of either ARBs were observed in this study.. ARBs for patients treated with OLZ improved insulin sensitivity and attenuated insulin resistance.

Topics: Angiotensin II Type 1 Receptor Blockers; Antipsychotic Agents; Benzimidazoles; Benzoates; Benzodiazepines; Female; Humans; Hyperinsulinism; Insulin Resistance; Male; Middle Aged; Olanzapine; Receptor, Angiotensin, Type 1; Schizophrenia; Telmisartan; Tetrazoles; Valine; Valsartan

The atypical antipsychotic drug olanzapine induces weight gain and defects in glucose metabolism in patients. Using a rat model we investigated the effects of acute and long term olanzapine treatment on weight gain, food preference and glucose metabolism. Olanzapine treated rats fed a chow diet grew more slowly than vehicle controls but olanzapine treated animals fed a high fat/sugar diet grew faster than control animals on the same diet. These changes in weight were paralleled by changes in fat mass. Olanzapine also induced a strong preference for a high fat/high sugar diet. Acute exposure to olanzapine rapidly induced severe impairments of glucose tolerance and increased insulin secretion but did not impair insulin tolerance. These results indicate the defect in glucose metabolism induced by acute olanzapine treatment was most likely due to increased hepatic glucose output associated with a reduction in active GLP-1 levels and correspondingly high glucagon levels.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Body Composition; Body Weight; Diet, High-Fat; Food Preferences; Glucagon; Glucagon-Like Peptide 1; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Liver; Male; Obesity; Olanzapine; Rats; Schizophrenia; Weight Gain

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

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

The effect of risperidone and olanzapine on beta-cell function and mass was investigated in 90% pancreatectomized and ovariectomized female rats, of which some were treated with estrogen replacement and some were not. Ovariectomized diabetic rats were divided into two groups: one group received daily estrogen replacement (30 mug 17beta-estradiol/kg body weight) and the other group received a vehicle. Each group was further divided into three subgroups and orally given either a placebo, risperidone (0.5 mg/kg body weight), or olanzapine (2 mg/kg body weight) each day in conjunction with a high-fat diet for eight weeks. Ovariectomy reduced serum prolactin levels, while risperidone and estrogen replacement increased them. Olanzapine, not risperidone, increased body weight gain and epididymal fats, and impaired glucose tolerance in ovariectomized diabetic rats, while estrogen replacement improved them. This was related to changes in insulin secretion capacity. Ovariectomized rats had decreased beta-cell mass, due to decreasing beta-cell proliferation, compared with Sham rats, and olanzapine, but not risperidone, caused further reduction. Olanzapine reduced IRS2 protein levels in the islets of ovariectomized rats. Decreased IRS2 attenuated the phosphorylation of Akt and, subsequently, PDX-1 protein levels were lowered in olanzapine-treated rats. Estrogen replacement activated insulin/IGF-1 signaling regardless of treatment. In conclusion, olanzapine, but not risperidone, exacerbated glucose homeostasis partly by attenuating beta-cell function and mass in ovariectomized diabetic rats, while estrogen replacement reversed its negative impact. Further human studies are needed to support the claim that olanzapine should be avoided in the treatment of schizophrenic postmenopausal patients with diabetes.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Blotting, Western; Cell Separation; Cell Survival; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Estradiol; Estrogen Replacement Therapy; Female; Glucose; Glucose Tolerance Test; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Secreting Cells; Olanzapine; Ovariectomy; Pancreatectomy; Prolactin; Rats; Rats, Sprague-Dawley; Risperidone; Weight Gain

In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.. C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg(-1) body weight), alone or with APAP (30 mg kg(-1) body weight) or THII (4.5 mg kg(-1) body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined.. OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O(2) uptake and H(2)O(2) production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.. We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.

Topics: Acetaminophen; Adipose Tissue; Adipose Tissue, White; Animals; Antioxidants; Antipsychotic Agents; Benzodiazepines; Body Weight; Dietary Fats; Female; Indoles; Insulin Resistance; Lipid Peroxidation; Mice; Mice, Inbred C57BL; NADPH Oxidases; Obesity; Olanzapine; Oxidative Stress

We investigated whether estrogen replacement modulated energy and glucose metabolic changes induced by olanzapine (OZP) and risperidone (RPD) in 90% pancreatectomized diabetic rats, some of whom had also been ovariectomized (OVX) and some of whom had not (sham).. OVX diabetic rats were subcutaneously injected with estrogen replacement (17beta-estradiol, 30 microg/kg/day) or a vehicle. Each group was divided into 3 subgroups, and each subgroup was orally either given a placebo, RPD (0.5 mg/kg body weight/day) or OZP (2 mg/kg body weight/day) for 8 weeks. Sham rats were also divided into 3 subgroups and given drugs in the same manner as the OVX rats were. All rats were fed high-fat diets.. OZP increased body weight and epididymal fat pads more than the control (vehicle) in sham and OVX rats. Increased body weight in OZP-treated sham and OVX rats was due to the increment in food intake, which was associated with potentiating the phosphorylation of hypothalamic adenosine-monophosphate-activated protein kinase. At euglycemic hyperinsulinemic clamping, OZP decreased glucose infusion rates and increased hepatic glucose output in OVX diabetic rats. In sham rats, OZP increased hepatic glucose output but not as much as in OVX rats. Hepatic insulin signaling and glucose sensing were attenuated in OZP-treated OVX rats, and the attenuation increased hepatic phosphoenolpyruvate carboxykinase expression to induce gluconeogenesis. These negative and harmful effects noted among OZP-treated OVX rats were reversed by estrogen replacement treatment. However, RPD did not alter body weight and peripheral insulin sensitivity in sham and OVX rats.. OZP treatment should be avoided when treating diabetic and schizophrenic women, especially those in their postmenopausal period.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Diabetes Mellitus, Type 2; Eating; Estradiol; Estrogen Replacement Therapy; Female; Glucose; Insulin Resistance; Liver; Olanzapine; Ovariectomy; Pancreatectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Risperidone; Weight Gain

The second generation antipsychotic drugs (SGAs) are effective in treating patients with schizophrenia and have been considered as the first line therapy. Recently, increasing attention has been drawn to the potential diabetogenic effect of these novel antipsychotics. The goal of this study was to evaluate the time-dependent effects of olanzapine treatment on pancreatic beta cell function in SGA-naïve schizophrenic patients. Forty-two schizophrenic subjects received olanzapine therapy for 8 weeks and thirty-three of them completed the trial. Of whom 33 completers (21 male, mean+/-SD age: 37.6+/-8.0 years) were inpatients and unexposed to SGA. The metabolic parameters were quantitatively assessed at weeks 0, 2, 4, and 8 by the intravenous glucose tolerance test. After 56-day olanzapine treatment, subjects had significant increases in body weight and as well as in the levels of triglyceride, total cholesterol, and low-density lipoprotein. Insulin secretion significantly decreased at week 2, returned to baseline at week 4, and significantly increased at week 8. Of the total samples, 18.2% and 33.3% of them met the criteria for significant weight gain and metabolic syndrome after 8-week olanzapine treatment, respectively. This study indicates that olanzapine-treated schizophrenic patients displayed biphasic changes in insulin secretion to a hyperglycemic challenge. The results of this study support that olanzapine might directly influence pancreatic beta cell function.

Topics: Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Olanzapine; Prospective Studies; Schizophrenia; Time Factors

Second-generation antipsychotics are widely used in the treatment of all forms of psychoses, but they often produce undesirable side effects, among which are weight gain and other elements of metabolic syndrome. The mechanisms of these adverse effects are not known. The liver and adipose tissue are the principal candidate organs implicated in the development of antipsychotic-induced metabolic adverse effects. The present study investigated in the rat the effects on liver and white adipose tissue of a chronic treatment (46 days) with olanzapine 2 mg/kg or haloperidol 1 mg/kg, as compared with a control solution. In the liver, the expression of key genes involved in glucose transport and lipid metabolism and of regulatory transcription factors, as well as the TNFalpha gene, was not altered in response to either antipsychotic. Similarly, key genes involved in glucose transport and lipid metabolism were not changed in adipose tissue. However, the white adipose tissue was inflammatory in olanzapine-treated rats, with extensive macrophage infiltration and a significant increase in TNFalpha expression. In the plasma, TNFalpha and IL-1beta concentrations were slightly elevated. Chronic olanzapine treatment therefore produces a low-grade inflammatory state, likely initiated in the adipose tissue. Such an inflammatory state is known to be associated with an increased risk of insulin-resistance and cardiovascular diseases. This antipsychotic-induced inflammatory syndrome may participate in the inflammatory syndrome often observed in patients with schizophrenia. The strong and rather selective effect of olanzapine on TNFalpha expression may open new therapeutic opportunities for the prevention of olanzapine-induced metabolic abnormalities.

Topics: Adipose Tissue; Analysis of Variance; Animals; Antipsychotic Agents; Benzodiazepines; Cytokines; Glucose; Haloperidol; Immunoassay; Inflammation; Insulin Resistance; Leptin; Lipid Metabolism; Liver; Male; Olanzapine; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Olanzapine (OLZ) is an atypical antipsychotic whose clinical efficacy is hampered by side effects including weight gain and diabetes. Recent evidence shows that OLZ alters insulin sensitivity independent of changes in body weight and composition. The present study addresses whether OLZ-induced insulin resistance is driven by its central actions.. Sprague-Dawley rats received an intravenous (OLZ-IV group) or intracerebroventricular (OLZ-ICV group) infusion of OLZ or vehicle. Glucose kinetics were assessed before (basal period) and during euglycemic-hyperinsulinemic clamp studies.. OLZ-IV caused a transient increase in glycemia and a higher rate of glucose appearance (R(a)) in the basal period. During the hyperinsulinemic clamp, the glucose infusion rate (GIR) required to maintain euglycemia and the rate of glucose utilization (R(d)) were decreased in OLZ-IV, whereas endogenous glucose production (EGP) rate was increased compared with vehicle-IV. Consistent with an elevation in EGP, the OLZ-IV group had higher hepatic mRNA levels for the enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Phosphorylation of hypothalamic AMP-activated protein kinase (AMPK) was increased in OLZ-IV rats compared with controls. Similarly, an intracerebroventricular infusion of OLZ resulted in a transient increase in glycemia as well as a higher R(a) in the basal period. During the hyperinsulinemic period, OLZ-ICV caused a decreased GIR, an increased EGP, but no change in R(d). Furthermore, OLZ-ICV rats had increased hepatic gluconeogenic enzymes and elevated hypothalamic neuropeptide-Y and agouti-related protein mRNA levels.. Acute central nervous system exposure to OLZ induces hypothalamic AMPK and hepatic insulin resistance, pointing to a hypothalamic site of action for the metabolic dysregulation of atypical antipsychotics.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Carotid Arteries; DNA Primers; Glucose Clamp Technique; Glucose-6-Phosphatase; Hyperinsulinism; Infusions, Intravenous; Injections, Intraventricular; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Jugular Veins; Kinetics; Liver; Male; Neuropeptides; Olanzapine; Orexins; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Tubulin

Atypical antipsychotics are increasingly replacing conventional neuroleptic agents, but induction of impaired glucose tolerance and development of type 2 diabetes are of concern as side effects. Risperidone has been suggested to be superior to olanzapine for glucose tolerance in whites, but there is little information on these drugs in Asian populations, even though Asians have a higher risk of type 2 diabetes compared to whites.. A 75-g oral glucose tolerance test (OGTT) was performed in 100 age-matched, sex-matched, and body mass index (BMI)-matched Japanese inpatients with schizophrenia (DSM-IV criteria) who did not suffer from diabetes and had taken risperidone (N=50) or olanzapine (N=50) for at least 3 months. Subjects were from 1 university hospital and 3 mental hospitals in Japan; data were collected from April 2005 to March 2006. The same test was performed in 50 age-matched, sex-matched, and BMI-matched healthy Japanese subjects. Plasma glucose and serum insulin concentrations were measured just before loading (0 minutes) and 30, 60, and 120 minutes after oral glucose loading, and sorbitol levels in red blood cells were assayed at 0 and 120 minutes.. The fasting glucose level and insulin concentration did not differ among the risperidone, olanzapine, and control groups, but the areas under the concentration time curves for plasma glucose and serum insulin concentrations from 0 to 120 minutes in patients receiving risperidone or olanzapine were significantly higher (p<.05) than those for healthy controls. However, neither the insulinogenic index nor homeostasis model assessment of insulin resistance differed among the 3 groups. Sorbitol in red blood cells was significantly higher (p<.05) in both patient groups compared to the control group.. Olanzapine and risperidone may impair glucose tolerance due in part to increased insulin resistance. However, neither drug influenced insulin secretion in Japanese patients, and, therefore, these findings do not necessarily imply that atypical antipsychotics are directly associated with a risk of impairment of glucose tolerance.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Japan; Male; Matched-Pair Analysis; Middle Aged; Olanzapine; Risperidone; Schizophrenia

The goal of this study was to evaluate which anthropometric measure (human body measurement) best predicts insulin resistance measured by the insulin sensitivity index (SI) and the homeostasis model of assessment of insulin resistance (HOMA-IR) in nondiabetic patients with schizophrenia treated with clozapine or olanzapine.. We conducted a cross-sectional study of nondiabetic subjects with schizophrenia being treated with olanzapine or clozapine using a frequently sampled intravenous glucose tolerance test, nutritional assessment, and anthropometric measures, to assess the relationship between anthropometric measures and insulin resistance.. No difference was found between the groups treated with clozapine and olanzapine in age, gender, race, body mass index (BMI), waist circumference (WC), lipid levels, HOMA-IR, or SI. The disposition index (SI x the acute insulin response to glucose), which measures how the body compensates for insulin resistance to maintain a normal glucose level, was significantly lower in the group treated with clozapine than in the group treated with olanzapine (1067+/-1390 vs. 2521+/-2805; P=0.013), suggesting that the subjects treated with clozapine had a reduced compensatory response to IR compared with the subjects treated with olanzapine. In the clozapine group, both higher WC and BMI were significantly associated with elevated HOMA-IR and lower SI; however, WC was a stronger correlate of IR than BMI, as measured by SI (-0.50 vs. -0.40). In the olanzapine group, neither WC nor BMI was significantly associated with any measure of glucose metabolism.. In this study, WC was the single best anthropometric surrogate for predicting IR in patients treated with clozapine but not olanzapine. The results suggest that WC may be a valuable screening tool for predicting IR in patients with schizophrenia being treated with clozapine who are at relatively higher risk of developing the metabolic syndrome, type 2 diabetes mellitus, and associated cardiovascular disease.

Topics: Adult; Anthropometry; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Clozapine; Cross-Sectional Studies; Female; Glucose; Glucose Tolerance Test; Health Status; Humans; Insulin Resistance; Male; Olanzapine; Predictive Value of Tests; Schizophrenia; Waist Circumference

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

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

Some atypical antipsychotics have been linked to an increased propensity for weight gain and metabolic disturbances, including type II diabetes. The objective of this study was to investigate an animal model to help understand the mechanisms underlying this phenomenon. Female, Sprague-Dawley rats were treated with olanzapine (2.0 or 7.5 mg/kg, via osmotic mini-pump) for 4 weeks, followed by the hyperinsulinemic/euglycemic and hyperglycemic clamp procedures to assess insulin sensitivity and secretion in vivo. Changes in body weight, visceral fat, food intake and locomotor activity were also assessed. Hepatic glucose production (R(A)) was increased in the hyperinsulinemic/euglycemic clamp for both treatment groups compared to control rats, while the high-dose olanzapine group had decreased peripheral glucose utilization (R(D)). No changes in insulin secretion were detected in the hyperglycemic clamp. Olanzapine did not change body weight or food intake, but did result in significant accumulation of visceral fat and decreases in locomotor activity. Like others, we found that a rodent model for antipsychotic-related weight gain per se is not tenable. However, chronic treatment with olanzapine was found to confer both hepatic and peripheral insulin resistance independent of weight gain, indicating a direct effect on glucose dysregulation.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Weight; C-Peptide; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hyperinsulinism; Insulin Resistance; Locomotion; Olanzapine; Rats; Rats, Sprague-Dawley

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

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

Leptin dysregulation has been implicated in the body weight gain and metabolic dysfunction observed with the second generation antipsychotic drugs (SGAD) olanzapine and clozapine.. This study quantified the frequency of subjects with abnormal correlation between leptin and the body mass index controlling for gender (defined as being out of the upper or lower 95% confidence interval in the regression line when combining each group with the drug-free subjects) after prolonged treatment with olanzapine (n=126), clozapine (n=62), first generation antiypsychotics (n=91), other SGAD (n=22), other psychotropic drugs (n=65) and drug-free subjects (n=229).. None of the analysis was significant (p>0.05). In fact, in 17 out of 20 comparisons, the drug-free group had numerically higher frequencies of outliers than the corresponding treatment group. There were 28 outliers (4.7% of the total sample). In agreement with previous studies, cross-sectional analysis did not report gross alterations in serum leptin levels during olanzapine or clozapine administration.. Longitudinal studies should focus on leptin regulation early on treatment, on the frequency of abnormal leptin receptor sensitivity and/or specific polymorphisms in the leptin allele and on several confounding factors in order to design personalized preventive and therapeutic measures.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Body Mass Index; Body Weight; Clozapine; Cross-Sectional Studies; Female; Humans; Insulin Resistance; Leptin; Male; Mental Disorders; Middle Aged; Olanzapine; Outliers, DRG; Receptors, Leptin; Schizophrenia; Sex Factors; Weight Gain

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Antipsychotic Agents; Benzimidazoles; Benzoates; Benzodiazepines; Female; Humans; Insulin Resistance; Olanzapine; Schizophrenia; Telmisartan

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

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

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Dogs; Dose-Response Relationship, Drug; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Olanzapine; Risperidone

Differences in the glucose metabolism were examined and analysed in this study between patients treated with olanzapine and risperidone in comparison with healthy volunteers. The aim of the study was to determine differences of the impaired glucose metabolism in the study groups as well as to point out to the possible mechanisms which bring to these differences. To the group of 15 schizophrenic patients treated with olanzapine, and group of 15 schizophrenic patients treated with risperidone and to 14 healthy volunteers oral glucose tolerancy test is applied in order to determine the level of the impaired glucose tolerance. In the group of the patients treated with olanzapine glucose tolerance was impaired in 33% of the patients, while in the group of the patients treated with risperidone in 20%. Impaired glucose tolerance mostly manifested as hyperinsulinemia. Authors discussed about possible mechanisms responsible for the impaired glucose tolerance in the patients treated with new antipsychotics. Authors conclude that insulin resistance is the main mechanism for development of the diabetes type II in the schizophrenic patients treated with antipsychotics. Insulin resistance is the result of the multiple effects of the antipsychotics, among which most common are: increased body mass and direct involvement of the antipsychotics in the glucose metabolism.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Body Mass Index; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Insulin Resistance; Male; Middle Aged; Olanzapine; Risperidone; Schizophrenia

We studied a sample of schizophrenia out-patients to test the hypotheses that serum homocysteine concentrations would correlate positively with measures of glucose metabolism.. Subjects underwent a nutritional assessment and fasting plasma, serum insulin and homocysteine tests.. Males had a significantly higher homocysteine levels than females (7.69 +/- 1.42 microM vs. 6.63 +/- 1.40 microM; P = 0.02). Comparing subjects with normal fasting glucose (NFG) (glucose < 100 mg/dl) and impaired fasting glucose (IFG) (> or = 100 mg/dl) subjects with IFG (mean 8.2 +/- 1.5 microM) had significantly higher homocysteine levels than those with NFG (mean 7.2 +/- 1.4 microM, P = 0.03). IFG was also associated with greater mean values for a Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) (P = 0.002) and diastolic blood pressure (P = 0.045).. The group with IFG had higher fasting serum homocysteine concentrations than those with NFG which supports a connection to an important cardiovascular risk factor.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Chronic Disease; Clozapine; Community Mental Health Centers; Female; Folic Acid; Homeostasis; Homocysteine; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Nutrition Assessment; Olanzapine; Prediabetic State; Psychotic Disorders; Reference Values; Risk Factors; Risperidone; Schizophrenia; Sex Factors; Statistics as Topic; Waist-Hip Ratio

Treatment of schizophrenia with olanzapine and other atypical antipsychotic agents is associated with insulin resistance and diabetes mellitus. The mechanism for this is not understood. Adiponectin is an insulin-sensitizing cytokine secreted by adipocytes. It is present in serum in multimers of varying size. Trimers and hexamers are referred to as low molecular weight (LMW) adiponectin. Larger multimers (12-, 18-, and 24-mers) have been designated high molecular weight (HMW) adiponectin and seem responsible for the insulin-sensitizing action of this adipokine. The aim of this study was to examine total adiponectin and LMW and HMW multimers in serum from patients with schizophrenia treated with either olanzapine (n = 9) or other typical antipsychotics (n = 9) and compare results with 16 healthy sex-, body mass index-, and age-matched controls. The effects of olanzapine on adiponectin protein expression and secretion in in vitro-differentiated primary human adipocytes were also examined. Patients receiving olanzapine had significantly lower total serum adiponectin as compared with those on conventional treatment and controls (5.23 +/- 1.53 ng/mL vs. 8.20 +/- 3.77 ng/mL and 8.78 +/- 3.8 ng/mL; P < 0.05 and P < 0.01, respectively). The HMW adiponectin was also reduced in patients on olanzapine as compared with the disease and healthy control groups (1.67 +/- 0.96 ng/mL vs. 3.87 +/- 2.69 ng/mL and 4.07 +/- 3.2 ng/mL; P < 0.05 for both). The LMW adiponectin was not different between patient groups (P = 0.15) but lower in patients on olanzapine as compared with controls (3.56 +/- 0.85 ng/mL vs. 4.70 +/- 1.4 ng/mL; P < 0.05). In vitro, short duration (up to 7 days) olanzapine exposure had no effect on total adiponectin expression or multimer composition of secreted protein. In summary, this study demonstrates a correlation between olanzapine treatment and reduced serum adiponectin, particularly HMW multimers. This may not be a direct effect of olanzapine on adipocyte expression or secretion of adiponectin. These observations provide insights into possible mechanisms for the association between olanzapine treatment and insulin resistance.

Topics: Adipocytes; Adiponectin; Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cells, Cultured; Female; Humans; Insulin Resistance; Male; Molecular Weight; Olanzapine; Schizophrenia

Clozapine and olanzapine treatment has been associated with insulin resistance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism.. A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls using a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analysis (7 quetiapine, 8 olanzapine, 9 normal controls).. There was a significant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin sensitivity index (SI) differed significantly among groups (p = .039); olanzapine subjects exhibited significant insulin resistance compared to normal controls (p = .01), but there was no significant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin resistance calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) also differed significantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a significant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049).. Our findings are consistent with our previous report that nonobese olanzapine-treated subjects showed insulin resistance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Body Mass Index; Body Weight; Cross-Sectional Studies; Dibenzothiazepines; Female; Follow-Up Studies; Glucose; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Nutrition Assessment; Olanzapine; Quetiapine Fumarate; Risk Factors; Schizophrenia

In the present study, we examined the effect of olanzapine on weight gain, systolic blood pressure and metabolic changes in rats. Female Sprague Dawley rats were treated with either vehicle or olanzapine (1 and 2 mg/kg i.p, twice daily) for 20 days. Body weight, food and water intake, systolic blood pressure, plasma glucose, insulin and lipid were measured. Olanzapine (1 and 2 mg/kg) significantly increased the body weight and systolic blood pressure. Whereas, food intake and plasma insulin and insulin resistance index, were elevated only at 1 mg/kg. In conclusion, olanzapine induced weight gain in rats is associated with elevation of systolic blood pressure.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Blood Pressure; Dose-Response Relationship, Drug; Drinking; Eating; Female; Insulin; Insulin Resistance; Lipids; Models, Animal; Olanzapine; Rats; Rats, Sprague-Dawley; Systole; Time Factors; Weight Gain

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

Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S(I)), and pancreatic beta-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules (n = 6) for 4-6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 +/- 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 +/- 24%; P = 0.0001) and visceral (+84 +/- 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S(I) [pre- versus postdrug]: 6.05 +/- 0.98 vs. 1.53 +/- 0.93 dl . min(-1) . kg(-1)/[microU/ml], respectively; P = 0.009). beta-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 +/- 0.15, post-drug: 1.07 +/- 0.25 microU . ml(-1)/[mg/dl]; P = 0.6). OLZ-induced beta-cell dysfunction was further demonstrated when beta-cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that beta-cell compensation is under neural control.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Body Weight; Dietary Fats; Dogs; Insulin Resistance; Islets of Langerhans; Male; Olanzapine; Risperidone

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

Some novel antipsychotics, including olanzapine, induce weight gain and metabolic abnormalities, which represent the major adverse effects of these drugs. However, the mechanism(s) involved in such effects are unclear.. The aim of this study was to develop, in female rats, a parametric model of olanzapine-induced weight gain and metabolic abnormalities and evaluate it against clinical findings.. Female rats were administered olanzapine b.i.d. at doses of 0, 1, 2 and 4 mg/kg over 20 days, and a wide range of variables were recorded during and after drug administration.. Olanzapine increased both 24 h and total food intake. This was associated with rapid onset weight gain and increased adiposity (assessed by visceral fat pad masses). Insulin, but not glucose, concentrations were elevated, with a significant increase in the HOMA-IR index, indicative of insulin resistance. A nonsignificant trend towards higher levels of leptin was observed. Paradoxically, there was a significant increase in adiponectin. All of these variables showed maximal increases at either 1 or 2 mg/kg and attenuated effects at 4 mg/kg. Prolactin levels were also increased by olanzapine. However, for this variable, there was a clear dose-response curve, with the maximal effect at the highest dose (4 mg/kg).. These data suggest that aspects of olanzapine-induced weight gain and metabolic abnormalities can possibly be modelled in female rats. It is suggested that olanzapine-induced hyperphagia acts as an initial stimulus which leads to weight gain, enhanced visceral adiposity and subsequent insulin resistance, although the latter may be ameliorated by compensatory responses in adiponectin levels. Prolactin elevation appears likely not to be involved in the weight gain, adiposity and metabolic changes seen in this model.

Topics: Adipose Tissue; Animals; Antipsychotic Agents; Benzodiazepines; Dose-Response Relationship, Drug; Drinking; Eating; Estradiol; Female; Homeostasis; Hyperinsulinism; Insulin Resistance; Leptin; Metabolic Diseases; Olanzapine; Prolactin; Rats; Rats, Wistar; Statistics as Topic; Weight Gain

Second-generation antipsychotic agents (SGAs) are increasingly replacing first-generation antipsychotic agents due to their superior activity against the negative symptoms of schizophrenia, decreased extrapyramidal symptoms and better tolerability. However, some SGAs are associated with adverse metabolic effects as significant weight gain, lipid disorders and diabetes mellitus. The pathogenesis of SGA-induced disturbances of glucose homeostasis is unclear. In vivo studies suggest a direct influence of SGAs on peripheral insulin resistance. To this end, we analyzed whether olanzapine might alter glycogen synthesis and the insulin-signaling cascade in L6 myotubes. Glycogen content was diminished in a dose- and time-dependent manner. Within the insulin-signaling cascade IRS-1 tyrosine phosphorylation was induced several fold by insulin and was diminished by preincubation with olanzapine. IRS-1-associated PI3K activity was stimulated by insulin three-fold in L6 myotubes. Olanzapine inhibited insulin-stimulated IRS-1-associated PI3K activity in a dose-dependent manner. Protein mass of AKT, GSK-3 and GS was unaltered, whereas phosphorylation of AKT and GSK-3 was diminished, and pGS was increased. Finally, we compared olanzapine with amisulpride, an SGA clinically not associated with the induction of diabetes mellitus. Glycogen content was diminished in olanzapine-preincubated L6 cells, whereas this effect was not observed under the amisulpride conditions. We conclude that olanzapine impairs glycogen synthesis via inhibition of the classical insulin-signaling cascade and that this inhibitory effect may lead to the induction of insulin resistance in olanzapine-treated patients.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Cell Line; Dose-Response Relationship, Drug; Glucose Metabolism Disorders; Glycogen; Insulin; Insulin Resistance; Muscle Fibers, Skeletal; Muscle, Skeletal; Olanzapine; Rats; Signal Transduction

Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.

Topics: Antipsychotic Agents; Benzodiazepines; Carbohydrate Metabolism; Case-Control Studies; Clozapine; Dibenzothiazepines; Female; Ghrelin; Humans; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Obesity; Olanzapine; Overweight; Peptide Hormones; Quetiapine Fumarate; Resistin; Risperidone; Tumor Necrosis Factor-alpha; Weight Gain

The metabolic effect of atypical antipsychotic drugs may manifest itself in weight gain, disturbances in glucose homeostasis and dyslipidemia. One confounding factor is that psychotic disorders themselves make the patients prone to specific metabolic changes. Nevertheless clinical studies have confirmed that atypical anti-psychotic drugs have a different metabolic effect. In the present prospective case-series, four male antipsychotic drug-naive psychiatric patients without any familial history of metabolic disorder were studied. The patients received risperidone or olanzapine monotherapy for 12 weeks; weight, plasma levels of triglyceride, cholesterol, HDL, and fasting glucose were measured in every 4th week. In two patients, oral glucose tolerance test (OGTT) was also performed at days 0 and 56. The average weight gain during the 12-week period was 12%. The cholesterol and triglyceride plasma concentrations were also elevated. The fasting glucose levels did not change during the observation period. In the OGTT performed in two patients, normal fasting glucose and insulin plasma levels were observed after 8 weeks; however, the plasma insulin concentrations were highly elevated after glucose intake, which may suggest the presence of insulin resistance. Our preliminary results confirmed the previous results on the metabolic effect of atypical anti-psychotic drugs, which may lead to metabolic syndrome. The regular control of the metabolic laboratory parameters, early intervention and the modification of the atypical antipsychotic treatment may help to avoid this adverse effect of the drugs.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Cholesterol, HDL; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Olanzapine; Prospective Studies; Risperidone; Serotonin Agents; Triglycerides; Weight Gain

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Blood Glucose; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulin Resistance; Male; Mental Disorders; Olanzapine; Pirenzepine; Triglycerides