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The Journal of Toxicological Sciences 2023Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a...
Olanzapine is widely used as a treatment for schizophrenia and other psychiatric disorders. Its metabolic side effects, including weight gain and hyperglycemia, are a clinical problem; however, their full mechanism is not yet clearly understood. Recently, it was reported that the accumulation of oxidative stress in the hypothalamus may cause obesity and diabetes mellitus. Epidemiologically, metabolic side effects are known to be more likely to occur in women. In the present study, we investigated and tested the hypothesis that olanzapine induces oxidative stress in the hypothalamus and induces metabolic side effects. We also examined its association with sex differences. Olanzapine was administered intraperitoneally to male and female C57BL/6 mice, and the expression levels of oxidative stress-responsible genes in the hypothalamus and cerebral cortex were measured by qRT-PCR. In addition, olanzapine was administered intraperitoneally to C57BL/6 and Nrf2 KO mice, and the expression level of total glutathione was measured. Gene expressions induced by the Keap1-Nrf2-regulated system showed different responses to olanzapine for each gene. Under the conditions of this experiment, cystine-glutamate transporter was decreased although heme oxygenase-1 and γ-glutamylcysteine synthetase were increased. It was also clear that these responses were not hypothalamus-specific. Long-term feeding with olanzapine suppressed weight gain in males but not females. No glucose intolerance was observed at 13 weeks of administration. Furthermore, deaths occurred only in females. In conclusion, this study failed to provide evidence that olanzapine induces oxidative stress in a hypothalamic-specific manner. Instead, sex differences were observed in response to long-term and high-dose olanzapine administration, suggesting that individual susceptibility to olanzapine toxicity occurred in female mice.
Topics: Female; Male; Mice; Animals; Olanzapine; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Sex Characteristics; Mice, Inbred C57BL; Weight Gain; Antipsychotic Agents
PubMed: 37005277
DOI: 10.2131/jts.48.191 -
Pharmacy (Basel, Switzerland) Nov 2023This systematic review compared the efficacy and tolerance of oral antipsychotics (APDs) used in the treatment of schizophrenia following the PRISMA-P© statement ( =... (Review)
Review
This systematic review compared the efficacy and tolerance of oral antipsychotics (APDs) used in the treatment of schizophrenia following the PRISMA-P© statement ( = 21). The primary outcomes of interest were clinical response measured with symptoms' improvement, tolerance to side effects and discontinuation reasons. There was better individual patients' response to aripiprazole vs. ziprasidone and quetiapine ((CDSS = 0.04), BPRS = 0.02, YMRS = 0.001) and ziprasidone vs. quetiapine (CGI = 0.02, CDSS = 0.02). Aripiprazole was more tolerated than risperidone, ziprasidone and quetiapine ( < 0.05). Quetiapine was more tolerated than aripiprazole, ziprasidone and risperidone ( < 0.05). Ziprasidone was more tolerated than quetiapine haloperidol and olanzapine ( < 0.05). Risperidone was more tolerated than olanzapine ( = 0.03) and haloperidol was more tolerated than olanzapine and quetiapine ( < 0.05). Olanzapine caused less discontinuation than quetiapine; quetiapine caused less discontinuation than ziprasidone, aripiprazole and haloperidol; ziprasidone caused less discontinuation than quetiapine, aripiprazole and haloperidol; aripiprazole caused less discontinuation than quetiapine, ziprasidone and olanzapine and olanzapine caused less discontinuation than ziprasidone and haloperidol ( < 0.05). It was concluded that individual patient clinical response, tolerance to side effects and life-threatening side effects remain the most reliable basis for selecting and continuing the use of APD.
PubMed: 37987385
DOI: 10.3390/pharmacy11060175 -
Neuropsychopharmacology : Official... Feb 2022A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or... (Randomized Controlled Trial)
Randomized Controlled Trial
A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine's unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.
Topics: Adult; Antipsychotic Agents; Glucose; Healthy Volunteers; Humans; Insulin; Naltrexone; Narcotic Antagonists; Olanzapine; United States
PubMed: 34887529
DOI: 10.1038/s41386-021-01244-7 -
Oman Medical Journal Sep 2023In clinical experience, selecting atypical antipsychotics optimally balancing their benefits and potential side effects is seen to improve treatment adherence in...
OBJECTIVES
In clinical experience, selecting atypical antipsychotics optimally balancing their benefits and potential side effects is seen to improve treatment adherence in patients. This study aimed to compare the effectiveness and side effect profiles of aripiprazole and olanzapine in patients with psychotic disorders.
METHODS
In this double-blind clinical trial, the subjects were patients with psychotic disorders treated with aripiprazole and olanzapine. The subjects were randomly divided into two equally sized groups. One group was treated with olanzapine and the other group with aripiprazole. All participants were assessed using the positive and negative syndrome scale and side effects were monitored over a two-month follow-up period.
RESULTS
The participants comprised N = 76 patients (65 male; 11 female). Treatments with both aripiprazole (n = 38) and olanzapine (n = 38) were associated with a significant decrease in the severity of psychotic symptoms over the two-month treatment period. This decrease was achieved faster in the olanzapine group. There were no significant differences in the changes in body mass index, waist circumference, blood sugar, triglyceride, or cholesterol between the two groups. A qualitative difference between the groups was found in their total sleep duration.
CONCLUSIONS
Olanzapine was more effective than aripiprazole in reducing psychotic symptoms. There were no significant differences between the overall side effect profiles of the two drugs.
PubMed: 38249132
DOI: 10.5001/omj.2023.109 -
Journal of Psychopharmacology (Oxford,... Oct 2019Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and...
BACKGROUND
Olanzapine, regarded as one of the most efficacious antipsychotic medications for the treatment of schizophrenia, is associated with a high risk of weight gain and metabolic dysfunction. ALKS 3831, a clinical candidate for treatment of schizophrenia, is a combination of olanzapine and samidorphan, an opioid receptor antagonist. The addition of samidorphan is intended to mitigate weight gain and the metabolic dysregulation associated with the use of olanzapine.
METHODS
Non-clinical studies were conducted to assess the metabolic effects of olanzapine and samidorphan alone and in combination at clinically relevant exposure levels.
RESULTS
Chronic olanzapine administration in male and female rats shifted body composition by increasing adipose mass, which was accompanied by an increase in the rate of weight gain in female rats. Co-administration of samidorphan normalized body composition in both sexes and attenuated weight gain in female rats. In hyperinsulinemic euglycemic clamp experiments conducted prior to measurable changes in weight and/or body composition, olanzapine decreased hepatic insulin sensitivity and glucose uptake in muscle while increasing uptake in adipose tissue. Samidorphan appeared to normalize glucose utilization in both tissues, but did not restore hepatic insulin sensitivity. In subsequent studies, samidorphan normalized olanzapine-induced decreases in whole-body glucose clearance following bolus insulin administration. Results from experiments in female monkeys paralleled the effects in rats.
CONCLUSIONS
Olanzapine administration increased weight gain and adiposity, both of which were attenuated by samidorphan. Furthermore, the combination of olanzapine and samidorphan prevented olanzapine-induced insulin insensitivity. Collectively, these data indicate that samidorphan mitigates several metabolic abnormalities associated with olanzapine in both the presence and the absence of weight gain.
Topics: Adipose Tissue; Animals; Antipsychotic Agents; Drug Combinations; Female; Glucose Metabolism Disorders; Macaca fascicularis; Male; Naltrexone; Narcotic Antagonists; Olanzapine; Rats; Rats, Sprague-Dawley; Sex Factors; Weight Gain
PubMed: 31294646
DOI: 10.1177/0269881119856850 -
The Primary Care Companion For CNS... Apr 2023
Topics: Humans; Olanzapine; Schizophrenia; Antipsychotic Agents; Psychotic Disorders; Weight Loss; Benzodiazepines
PubMed: 37027805
DOI: 10.4088/PCC.21cr03113 -
Scientific Reports Oct 2023Olanzapine is a commonly prescribed atypical antipsychotic agent for treatment of patients with schizophrenia and bipolar disorders. Previous in vitro studies using...
Olanzapine is a commonly prescribed atypical antipsychotic agent for treatment of patients with schizophrenia and bipolar disorders. Previous in vitro studies using human liver microsomes identified CYP1A2 and CYP2D6 enzymes being responsible for CYP-mediated metabolism of olanzapine. The present work focused on the impact of CYP1A2 and CYP2D6 genetic polymorphisms as well as of CYP1A2 metabolizing capacity influenced by non-genetic factors (sex, age, smoking) on olanzapine blood concentration in patients with psychiatric disorders (N = 139). CYP2D6 genotype-based phenotype appeared to have negligible contribution to olanzapine metabolism, whereas a dominant role of CYP1A2 in olanzapine exposure was confirmed. However, CYP1A2 expression rather than CYP1A2 genetic variability was demonstrated to be associated with olanzapine concentration in patients. Significant contribution of - 163C > A (rs762551), the most common SNP (single nucleotide polymorphism) in CYP1A2 gene, to enhanced inducibility was confirmed by an increase in CYP1A2 mRNA expression in smokers carrying - 163A, and smoking was found to have appreciable impact on olanzapine concentration normalized by the dose/bodyweight. Furthermore, patients' olanzapine exposure was in strong association with CYP1A2 expression; therefore, assaying CYP1A2 mRNA level in leukocytes can be an appropriate tool for the estimation of patients' olanzapine metabolizing capacity and may be relevant in optimizing olanzapine dosage.
Topics: Humans; Olanzapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Antipsychotic Agents; Genotype; RNA, Messenger
PubMed: 37898643
DOI: 10.1038/s41598-023-45752-6 -
Basic & Clinical Pharmacology &... Apr 2022Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose-dependent effects on metabolic parameters with changes for...
Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose-dependent effects on metabolic parameters with changes for weight, blood pressure, lipid and glucose profiles being modelled using linear mixed-effects models. The risk of metabolic abnormalities including early weight gain (EWG) (≥5% during first month) was assessed using mixed-effects logistic regression models. In 392 olanzapine-treated patients (median age 38.0 years, interquartile range [IQR] = 26.0-53.3, median dose 10.0 mg/day, IQR = 5.0-10.0 for a median follow-up duration of 40.0 days, IQR = 20.7-112.2), weight gain was not associated with olanzapine dose (p = 0.61) although it was larger for doses versus ≤10 mg/day (2.54 ± 5.55 vs. 1.61 ± 4.51% respectively, p = 0.01). Treatment duration and co-prescription of >2 antipsychotics, antidepressants, benzodiazepines and/or antihypertensive agents were associated with larger weight gain (p < 0.05). Lower doses were associated with increase in total and HDL cholesterol and systolic and diastolic blood pressure (p < 0.05), whereas higher doses were associated with glucose increases (p = 0.01). Patients receiving >10 mg/day were at higher EWG risk (odds risk: 2.15, 1.57-2.97). EWG might be prominent in high-dose olanzapine-treated patients with treatment duration and co-prescription of other medications being weight gain moderators. The lack of major dose-dependent patterns for weight gain emphasizes that olanzapine-treated patients are at weight gain risk regardless of the dose.
Topics: Adult; Antipsychotic Agents; Benzodiazepines; Humans; Olanzapine; Prospective Studies; Weight Gain
PubMed: 35150056
DOI: 10.1111/bcpt.13715 -
The American Journal of Case Reports Nov 2021BACKGROUND Drug-induced acute angle closure glaucoma is an uncommon ocular emergency that may follow the administration of certain topical and systemic medications....
BACKGROUND Drug-induced acute angle closure glaucoma is an uncommon ocular emergency that may follow the administration of certain topical and systemic medications. Acute angle closure can be triggered by various classes of drugs, including adrenergic agonists, anticholinergics, and serotonergic medications. Here, we report a rare case of drug-induced acute angle closure glaucoma secondary to olanzapine. CASE REPORT A 59-year-old male patient of Arabian Peninsula descent, known to have schizophrenia, presented to our Emergency Department with a 3-day history of right ocular pain and decrease in vision. He was started recently on olanzapine 5 mg once daily by his psychiatrist 1 week prior to the onset of his symptoms. The diagnosis of drug-induced pupillary block was made based on clinical and radiological findings. The patient was started on topical and systemic IOP-lowering agents. A therapeutic Nd: YAG laser peripheral iridotomy for the right eye was performed. On follow-up, his symptoms alleviated and clinical examination showed significant improvement. CONCLUSIONS The reported case highlights the importance of systemic medical history in secondary acute angle closure glaucoma. Physicians from other specialties should be aware of drugs triggering pupillary block and therefore be able to educate patients about symptoms of acute angle closure glaucoma.
Topics: Glaucoma, Angle-Closure; Humans; Intraocular Pressure; Iris; Laser Therapy; Male; Middle Aged; Olanzapine
PubMed: 34803156
DOI: 10.12659/AJCR.934432 -
Journal of Clinical Pharmacology Nov 2021A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I...
A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure.
Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Body Weight; Cigarette Smoking; Cytochrome P-450 CYP3A; Drug Combinations; Female; Food-Drug Interactions; Humans; Liver Failure; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Olanzapine; Racial Groups; Renal Insufficiency; Rifampin; Schizophrenia; Sex Factors; Young Adult
PubMed: 34018607
DOI: 10.1002/jcph.1911