Class of 2013 Abstract / Specific Aims: To describe the outcomes of olanzapine in the treatment of refractory chemotherapy-induced nausea and vomiting (CINV). Methods: Data were collected regarding demographic information, chemotherapy regimen, CINV prophylaxis, rescue antiemetics, and olanzapine usage for subjects, age 18-79, who were admitted to the University of Arizona Medical Center for chemotherapy and received at least one dose of olanzapine for CINV between January 2008 and January 2012. The primary outcome measure was the number of rescue antiemetics required following the first dose of olanzapine (greater than 10 doses was considered treatment failure). Comparisons using chi square to determine if differences existed with respect to the level of chemotherapy emetogenicity and demographic information were conducted. Main Results: No statistical difference between chemotherapy regimens of high versus low-to-moderate emetogenicity was seen (P=0.79). However, 7 of 10 (70%) subjects receiving highly emetogenic chemotherapy achieved success and 15 of 23 (65%) subjects receiving low-to-moderately emetogenic chemotherapy achieved success. No statistical differences appeared when evaluating usage of 1 versus 2 or more prophylactic antiemetics (P=0.77), men versus women (P=0.08), and age over 50 versus 50 years or younger (P<0.99). Conclusion: This study demonstrated a trend towards greater emetic control with the addition of olanzapine in patients failing first-line antiemetic pharmacotherapy. Additionally, a trend towards greater emetic control was seen in women. The rates of success among all groups may suggest benefit to adding olanzapine to subjects experiencing refractory CINV. Due to the limited sample size and retrospective methodology of the study, the use of olanzapine in refractory CINV merits further research with large, prospective studies directly comparing addition of olanzapine to other appropriate antiemetics.

MMed, Psychiatry, University of the Witwatersrand, Faculty of Health Sciences / Introduction Antipsychotics are used for the treatment of psychotic disorders, most commonly schizophrenia, as well as mood disorders e.g. bipolar mood d isorder. The efficacy of the newer second generation (atypical) antipsychotics is equivalent to first generation antipsychotics. The apparent advantage of the second generation antipsychotics is related to their purported reduced side effect profile, thus making them more desirable due to improved compliance and relapse prevention. The limiting factor with this class of drugs, especially in the state sector in South Africa, has been the cost. However, reports of treatment-emergent adverse events such as diabetes mellitus, diabetic ketoacidosis, hyperglycaemia and dyslipidaemia in patients receiving second generation antipsychotics have increased in recent times. This has lead to growing concern about the link between metabolic complications and their use, with consequent reconsideration of the implications of prescribing. Aims The study aimed to establish the extent to which metabolic and cardiovascular screening and monitoring has been undertaken on patients who have been prescribed olanzapine, a second generation antipsychotic. Specifically the extent to which the American Diabetes Association Consensus Conference monitoring protocols were being implemented in a specialist psychiatric South African setting i.e.: at Tara: The H. Moross Centre’s outpatient department. Objectives The study objectives were to describe the demographic profile, clinical diagnosis and risk factors for metabolic complications in a sample of patients receiving olanzapine. Further, to establish the extent to which metabolic and cardiovascular screening and monitoring has been undertaken on patients prescribed olanzapine as well as to what extent the patients’s demographics, diagnosis and metabolic risk factors influenced the treating doctor’s adherence to screening guidelines. Method This study was undertaken at Tara: The H. Moross Centre (outpatient department). A convenience sample of patients prescribed olanzapine were selected as the study group. The study involved a review of case records. It was a retrospective descriptive study. Relevant data was entered on a data sheet, designed for the study in accordance with the objectives and adapted from the American Diabetes Association Consensus Development Conference on Antipsychotic Drugs, Obesity and Diabetes. The data sheet is based on an existing protocol for monitoring metabolic status. v Frequencies for the presence or absence of evidence of screening or monitoring for metabolic complications were established, as per American Diabetes Association monitoring protocol requirements. Although the study involved outpatients, not all patients were intiated on olanzapine as outpatients i.e. some of the prescribing was inpatient initiated. Results The sample comprised of 19 females and 20 males. 48.72% female and 51.28% male. The mean age of females in the sample was 52.38 years (SD=16.20) and the mean age of males was 41.28 (SD=17.05) years. The sample were predominantly single ( 61.54% n=24 ) with the majority being white (79.49% n=31 ); most had either tertiarty (43% n=17 ) or secondary (53.85% n =21 ) level of education. Only 2.56% (n=1) had only primary level education. With regards to the diagnoses of patients in the sample, 17,95% (n=7) were diagnosed with bipolar 1 disorder, 7.69% (n=3) with major depressive disorder with psychosis, 20,51% (n=8) schizoaffective disorder and 53,84% (n=21) with schizophrenia. The percentage of screening for all the parameters was generally less than 20% and it continued to decline to less than 20% until 4 months. The exception was weight, where frequency increased slightly over time. Comparing inpatient vesus outpatient initiated treatment there were apparent differences in the extent of screening i.e. greater for inpatient initiated treatment, specifically with respect to weight and blood pressure. Conclusion The current study was conducted in a very specific setting, but the findings demonstrated an area requiring attention i.e. adherence to acceptable clinical guidelines. Whilst one can only speculate on the basis for non-adherence, having established the status quo, there is a requirement for an appropriate strategy to address the deficit, given the implications of inadequate monitoring.

<p>Olanzapine is an atypical antipsychotic drug exhibiting a low incidence of extrapyramidal side effects. It is not only effective in treating positive symptoms of schizophrenia, but also more efficacious against negative and depressive symptoms than classical antipsychotics. Olanzapine has been recommended as the first-line drug for the treatment of schizophrenia. Unfortunately, a common side effect of olanzapine, namely weight gain, has also been observed. A comprehensive literature analysis revealed that olanzapine induced higher weight gain than most other antipsychotics, only second to clozapine. The incidence of olanzapine-induced weight gain and related diseases, such as diabetes and cardiovascular diseases, is higher than that of the general population. These unwanted side effects have decreased the adherence to treatment. Many clinical observations and preliminary animal studies have attempted to elucidate the possible mechanism involved. To date, the mechanism for olanzapine-induced weight gain remains unclear.</p><p>This research project utilizes an animal model to investigate the possible mechanism of olanzapine-induced weight gain. The specific research objectives include: 1) does olanzapine affect feeding behavior; 2) can olanzapine influence the levels of glucose and triglyceride; 3) are cytokines, such as insulin, leptin, and TNF-Ñ involved in olanzapine-induced weight gain; 4) how does olanzapine affect adipose tissue?</p><p> An olanzapine-induced weight gain animal model has been established in the present investigation. An increase in food and water intake and increase in fat deposition accompanied with weight gain after treatment were observed. No significant increase in levels of glucose and triglyceride was detected. The changes of insulin and leptin levels in blood suggest that olanzapine may affect the endocrine system. A dramatic morphological alteration of adipose tissue by olanzapine was serendipitously observed. Immunohistochemical staining revealed that olanzapine stimulated collagen VI expression and deposition in the extracellular matrix suggesting that adipocyte differentiation may be enhanced. The effect of olanzapine on fat deposition might play a critical role in olanzapine-induced weight gain. The data from adipose tissue have provided a new clue on future research in understanding the mechanism of olanzapine-induced weight gain. Due to limitation of small number of animals and relatively short term of treatment, a large variation in groups diminished the power of analysis regarding the effects of olanzapine related to weigh gain.

<p>Olanzapine is an atypical antipsychotic drug exhibiting a low incidence of extrapyramidal side effects. It is not only effective in treating positive symptoms of schizophrenia, but also more efficacious against negative and depressive symptoms than classical antipsychotics. Olanzapine has been recommended as the first-line drug for the treatment of schizophrenia. Unfortunately, a common side effect of olanzapine, namely weight gain, has also been observed. A comprehensive literature analysis revealed that olanzapine induced higher weight gain than most other antipsychotics, only second to clozapine. The incidence of olanzapine-induced weight gain and related diseases, such as diabetes and cardiovascular diseases, is higher than that of the general population. These unwanted side effects have decreased the adherence to treatment. Many clinical observations and preliminary animal studies have attempted to elucidate the possible mechanism involved. To date, the mechanism for olanzapine-induced weight gain remains unclear.</p><p>This research project utilizes an animal model to investigate the possible mechanism of olanzapine-induced weight gain. The specific research objectives include: 1) does olanzapine affect feeding behavior; 2) can olanzapine influence the levels of glucose and triglyceride; 3) are cytokines, such as insulin, leptin, and TNF-Ñ involved in olanzapine-induced weight gain; 4) how does olanzapine affect adipose tissue?</p><p> An olanzapine-induced weight gain animal model has been established in the present investigation. An increase in food and water intake and increase in fat deposition accompanied with weight gain after treatment were observed. No significant increase in levels of glucose and triglyceride was detected. The changes of insulin and leptin levels in blood suggest that olanzapine may affect the endocrine system. A dramatic morphological alteration of adipose tissue by olanzapine was serendipitously observed. Immunohistochemical staining revealed that olanzapine stimulated collagen VI expression and deposition in the extracellular matrix suggesting that adipocyte differentiation may be enhanced. The effect of olanzapine on fat deposition might play a critical role in olanzapine-induced weight gain. The data from adipose tissue have provided a new clue on future research in understanding the mechanism of olanzapine-induced weight gain. Due to limitation of small number of animals and relatively short term of treatment, a large variation in groups diminished the power of analysis regarding the effects of olanzapine related to weigh gain.

Thesis (M.A.)--University of North Carolina Wilmington, 2009. / Title from PDF title page (February 22, 2010) Includes bibliographical references (p. 55-58)

Reports have linked atypical antipsychotics (AAPs) with weight gain. The polymorphic CYP2D6 involved in metabolism has been associated with medication morbidity. Eleven subjects receiving olanzapine were genotyped for CYP2D6 to examine the relationship between 2D6 and AAP weight gain. Using a linear regression, the dependent variable was percent change in body mass index (BMI). Genotype, dose and duration of treatment were independent. Genotype was significant (P < 0.0097) for those with a *1/*3 or *4 genotype experiencing a larger percent BMI change than those with a *1/*1 genotype. This may be due to increased olanzapine concentrations leading to increased exposure, which may trigger AAP weight gain.

Schizophrenia affects 1-1.5% of people in the United States alone. Haloperidol (HP), a butyrophenone and a typical antipsychotic, has been used as an antipsychotic drug in human. Unfortunately, the therapeutic effects of HP also come with severe extrapyramidal side effects, resulting in movement disorders in patients. Olanzapine, a new atypical neuroleptic, seems to have better efficacy, with less severe adverse effects. There has been increasing evidence of the role of reactive oxygen species (ROS) and oxidative stress in the pathogenesis of Schizophrenia. We therefore hypothesized that the differences between HP and Olz could be partly because of the differences in the oxidative stress they cause. We studied the pro-oxidant and antioxidant effects of these two drugs in vitro and examined the mechanism of their cytotoxicity in a neuronal cell model using PC-12 cells. HP was found to be ineffective as a superoxide radical scavenger but appeared to be a potent scavenger of hydroxyl radicals with a rate constant of ~6.78 X 109 M-1s-1. Olz on the other hand was found to scavenge hydroxyl radical at a rate of 34.1 X 109 M-1s-1. This was shown using the hydroxyl radical dependent deoxyribose degradation assay and EPR spin trapping methods. HP was also found to quench singlet oxygen in a dose-dependent manner. HP was found to enhance the microsomal lipid peroxidation in a dose-dependent manner and at 10 µM it augmented the lipid peroxide accumulation by 100% whereas Olz, at the same concentrations had trivial effects. Light microscopy and two cytometric apoptotic/viability probes (7-aminoactinomycin D and Annexin-V) were employed to evaluate mechanisms of drug-induced cell death in PC-12 pheochromocytoma cells exposed to HP or Olz. At low dose (50 µM), HP was more cytotoxic than Olz. At high concentrations (150 mM) each of these antipsychotic drugs caused a significant increase in cell death that was readily detectable by all the techniques. Light microscopy with trypan blue staining indicated that necrosis was the predominate form of cell death with both drugs. Apoptotic cells were rarely observed by microscopy in vehicle or drug-exposed cells. Further, no increase in early cellular apoptosis was observed using the Annexin-V probe. 7AAD and Annexin-V both showed drug-related increases in the late apoptotic/necrotic cell death window. These data, along with the cytologic evaluations suggest that cell death in PC-12 pheochromocytoma cells exposed to HP or Olz may primarily be necrotic in nature, rather than apoptotic. Because Olz at a low dose was less cytotoxic and was found to have lower pro-oxidant action than HP the secondary effects manifested in patients with chronic treatment with HP may, at least in part, be attributed to the pro-oxidant effects of the drug. / Master of Science

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT 2A/5-HT2C-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT2-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia - a clinical syndrome linked to enhanced sensitivity to N-methyl-D-aspartate (NMDA)-receptor antagonists.

Mise en contexte : Le délirium est une pathologie largement décrite dans la littérature scientifique chez les adultes, et elle est maintenant bien reconnue en pédiatrie. Les antipsychotiques sont fréquemment utilisés pour traiter le delirium, tant chez l’enfant que chez l’adulte, malgré le peu d’évidence supportant leur utilisation. L’objectif de cette étude est de décrire l’utilisation de l’olanzapine, un antipsychotique de deuxième génération, dans l’unité de soins intensifs pédiatrique au CHU Sainte-Justine, d’identifier les facteurs de risque prédisposants l’utilisation de cette médication, et son impact sur les doses de médicaments concomitantes, ainsi que sur les scores de delirium, de sédation et de douleur. Méthode : Il s’agit d’une étude rétrospective monocentrique. Une collecte de données a été réalisée sur l’ensemble des patients admis pendant une durée de 2,5 ans. Les caractéristiques des patients recevant de l’olanzapine ou non ont été comparées en utilisant les tests statistiques de Wilcoxon-Mann-Whitney, Khi-2, et de Student. Puis, une analyse multivariée par le biais de régression logistique a permis d’identifier les facteurs de risque prédisposants l’administration d’olanzapine. Finalement, les épisodes de delirium ont été isolés et évalués de plus près. Afin de décrire l’impact de l’olanzapine sur la prise de médicaments analgésiques et sédatifs et sur les scores de delirium et d’agitation, les tests de Wilcoxon-Mann-Whitney ont été utilisés pour comparer les valeurs 24 heures avant la première dose d’olanzapine, et 24, 48 et 72 heures suivant cette dose. Résultats : Environ 6% des admissions aux soins intensifs pédiatriques et 21% des épisodes de delirium ont été traités avec de l’olanzapine. Les facteurs de risque prédisposants l’administration de l’olanzapine inclus le sexe masculin, le delirium, la ventilation non-invasive ainsi que l’administration de benzodiazépines, de kétamine, de dexmédétomidine et de clonidine. Nous avons observé une diminution du score de delirium des patients (le Cornell Assessment of Pediatric Delirium, CAPD) à la suite de l’administration de l’olanzapine, mais également chez les patients non traités. Toutefois, les patients ayant reçu de l’olanzapine ont eu un épisode de delirium plus prolongé. Conclusion : À la lumière des résultats obtenus, des études randomisées sont nécessaires afin de démontrer l’efficacité de l’olanzapine dans le traitement du delirium pédiatrique. / Context: Delirium is a pathology widely documented in the scientific literature in adults, and increasingly recognized in pediatrics. Despite few evidence supporting their use, antipsychotics are often used to treat delirium in adults and children. This study aims to describe the use of olanzapine, a second-generation antipsychotic, in a pediatric intensive care unit at CHU Sainte-Justine, to identify the factors associated with the use of this medication, and its impact on concomitant drug doses, as well as delirium, sedation and pain scores. Method: This is a single-center retrospective study. Data were collected on all patients admitted to the CHU Sainte-Justine Pediatric Intensive Care Unit for a period of 2.5 years. Characteristics between patients receiving or not olanzapine were compared using the nonparametric statistical tests of Wilcoxon-Mann-Whitney, Chi-2 and Student test. Subsequently, a multivariate analysis using logistic regression made it possible to identify the factors associated with the administration of olanzapine. To describe the impact of olanzapine on analgesics and sedatives administration and delirium and agitation scores, Wilcoxon-Mann-Whitney tests were used comparing values prior to first dose and 24, 48, and 72 hours post-dose. Results: Nearly 6% of admissions to the pediatric intensive care unit and 21% of delirium episodes were treated with olanzapine. The factors associated with its use included male sex, delirium, non-invasive ventilation and administration of benzodiazepines, ketamine, dexmedetomidine and clonidine. We demonstrated a decrease in delirium scores (Cornell Assessment of Pediatric Delirium; CAPD) following the administration of olanzapine, but also in untreated patients. However, the length of the delirium episode was longer in children receiving olanzapine. Conclusion: In the light of the results obtained, randomized studies in children are needed to demonstrate olanzapine’s efficacy in pediatric delirium.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.