Olanzapine Group Research Articles

Olanzapine for the Prevention of Postdischarge Nausea and Vomiting after Ambulatory Surgery: A Randomized Controlled Trial.

Postdischarge nausea and vomiting after ambulatory surgery is a common problem that is not adequately addressed in current practice. This prospective, randomized, double-blind, parallel-group, placebo-controlled study was designed to test the hypothesis that oral olanzapine is superior to placebo at preventing postdischarge nausea and vomiting. In a single-center, double-blind, randomized, placebo-controlled trial, the authors compared a single preoperative dose of olanzapine 10 mg to placebo, in adult female patients 50 years old or less, undergoing ambulatory gynecologic or plastic surgery with general anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and ondansetron. The primary composite outcome was nausea and/or vomiting in the 24 h after discharge. Secondary outcomes included severe nausea, vomiting, and side effects. A total of 140 patients were randomized and evaluable. The primary outcome occurred in 26 of 69 patients (38%) in the placebo group and in 10 of 71 patients (14%) in the olanzapine group (relative risk, 0.37; 95% CI, 0.20 to 0.72; P = 0.003). Severe nausea occurred in 14 patients (20%) in the placebo group and 4 patients (6%) in the olanzapine group (relative risk, 0.28; 95% CI, 0.10 to 0.80). Vomiting occurred in eight patients (12%) in the placebo group and two patients (3%) in the olanzapine group (relative risk, 0.24; 95% CI, 0.05 to 1.10). The median score for sedation (scale 0 to 10, with 10 being highest) in the 24 h after discharge was 4 (interquartile range, 2 to 7) in the placebo group and 6 (interquartile range, 3 to 8) in the olanzapine group (P = 0.023). When combined with ondansetron and dexamethasone, the addition of olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 hafter discharge from ambulatory surgery by about 60% with a slight increase in reported sedation.

Feasibility of olanzapine at reduced dose in highly emetogenic chemotherapy: A randomised controlled trial against aprepitant in triple therapy (FORESIGHT).

12087 Background: Olanzapine is used as an adjunct antiemetic in oncology as salvage therapy and in four-drug prophylaxis. Growing literature supports its effectiveness in initial three-drug prophylaxis in highly emetogenic chemotherapy (HEC). Methods: This prospective, multi-centre, open-label study evaluated the feasibility of a large-scale randomized controlled trial comparing the effectiveness and tolerability of 5 mg olanzapine once daily for four days (starting the night before chemotherapy) versus standard dose aprepitant (in tritherapy with standard ondansetron and dexamethasone) in treatment-naive patients receiving the first cycle of a HEC. Secondary outcomes included: complete response (no nausea, no emesis, no use of rescue medication), complete remission (no emesis, no rescue medication), intensity of patient-reported nausea and emesis on a visual analog scale, quality of life (scored with the Functional Living Index Emesis [FLIE]), and incidence of adverse events. Results: We randomized 30 patients in an intent-to-treat analysis. The large-scale trial was deemed not feasible without support from a research centre. Complete response rates were significantly higher in the olanzapine group in the delayed phase (24-120h post-chemotherapy) (86,7% v 21,4%, p < 0,001) and overall phase (0-120h post-chemotherapy) (60,0% v 21,4%, p = 0,04). Similar results were observed for complete remission. Intensity of patient-reported nausea was significantly lower in the olanzapine group in the delayed phase (p = 0,001). FLIE scores were significantly lower for the nausea domain (mean 62,3 v 60,9, p = 0,004) and overall score (124,3 v 108,8, p = 0,006). Depression on the ESAS-R was more common in the aprepitant group (0% v 38%, p = 0,01). Other adverse events were not significantly different. Conclusions: Support from a research centre must be ensured for study feasibility. Tritherapy olanzapine significantly improved complete response and remission in the delayed and overall phases post-chemotherapy among patients receiving HEC. It was also associated with higher quality of life and a reassuring safety profile. This feasibility trial, despite its small sample size, is one of the first prospective randomised trials to suggest similar efficacy of 5 mg olanzapine to aprepitant and to measure a difference in patient quality of life with this regimen. Clinical trial information: NCT04075955 .

Effects of Atypical Antipsychotics on Neuroactive Vitamins in Patients With Schizophrenia.

In schizophrenia, neuroactive vitamins A/D/E play vital neuroprotective roles in its pathophysiological processes. During medical treatment, atypical antipsychotics, including aripiprazole, amisulpride, olanzapine, and paliperidone, were widely used at present. However, their impact on vitamin metabolism in vivo remained unclear. In this study, we conducted a case-control research to investigate the impacts of antipsychotics on vitamin metabolism. Schizophrenic patients (n = 163), who were divided into 5 groups (aripiprazole group, amisulpride group, olanzapine group, paliperidone group, nonmedication group) according to their different medication patterns, and healthy controls (n = 75) were involved. The concentrations of vitamin A/D/E and antipsychotics were measured using liquid chromatography-tandem mass spectrometry methods. Compared with healthy controls, significantly lower vitamin D and E concentrations were found in the nonmedication group after covariance analysis adjusting for age, sex, albumin, bilirubin, triglyceride, and cholesterol. We found that aripiprazole could affect vitamin D concentrations in vivo, and a positive correlation between aripiprazole concentrations and vitamin D concentrations (r = 0.319, P = 0.025) was observed in aripiprazole group. Such result revealed the very first observation for the influence of atypical antipsychotics medication toward vitamin status in vivo. Our study showed that low concentrations of vitamin D and E in vivo could be associated with schizophrenia, suggesting that hypovitaminosis may lead to a vulnerability to schizophrenia. More importantly, aripiprazole may potentially benefit the patients through improving their vitamin D status in vivo.

M207. REVEALING HYPOTHALAMIC PATHWAYS CONTRIBUTION TO OLANZAPINE- INDUCED METABOLIC SYNDROME: FROM MURINE MODEL TO HUMAN TRANSLATION

BackgroundOlanzapine (OL) represents one of the main choices for the treatment of psychotic symptoms. However, OL increase the risk of metabolic syndrome (MS). The mechanism of Olanzapine induced MS remains still unclear but hypothalamic pathways seem to be involved. The purpose of our study is to validate an innovative approach for translational studies to investigate the hypothalamic pathways contribution to OL induced MS.MethodsTo establish a murine model of Olanzapine induced MS, OL compounded in chow (54mg/Kg of HFD food) has been administered for 30 days to C57BL/6J female mice of 10 weeks old (20 mice/group). Food intake and weight gain are tested.After the 4 weeks of treatment, mice are sacrificed by rapid cervical dislocation. Blood is collected for Glucose, Insulin and Leptin evaluation. Hypothalamus and Liver are rapidly dissected and analyzed with qPCR. Fatty liver is histologically tested with Red Oil-O- staining.The identification of mice hypothalamic coexpression network with a Genome-wide Weighted Genes Co-expression Network Analysis (WGCNA) is performed using a publicly available mice hypothalamic RNASeq a dataset.From the RNASeq data obtained from Perez-Gomez et al. study (PMID: 30532051) a differential gene expression (DGE) analysis is performed to identify the gene impacted by Olanzapine and verified with qPCR on our sample. The segregation of differentially expressed genes in specific modules of the mice hypothalamic network is tested.Human hypothalamic network identification is performed using the publicly available GTEx dataset of Hypothalamic RNASeq data for a WGCNA. The segregation of differentially expressed genes of mice model in human network has been studied. An eigengene network approach is used to study the relationship between the human affected modules.ResultsFrom the 2nd week of treatment, the weight gain shows a significant increase (p= 0.02) in OL group compared to Control. The difference in weight gain remains unchanged until the 30th day. Likewise Blood glucose, Insuline and Leptine levels appear increased in Olanzapine group compared to control (p= 0,0089, p= 0,01, p= 0,0012 respectively). The percentage of liver parenchyma occupied by lipid droplets shows a statistically significant increase in OL treated group (p=0,0001).14 of the 29 identified hypothalamic differentially expressed genes between OL- treated mice compared to control clusters in a single module of the WGCNA. The pathway analysis of this module reveals that Wnt signaling pathway reaches the statistical significance (FDR= 0,02 p value = 0,00006).The co-occurrence of OL-induced hypothalamic differentially expressed genes, previously identified in mice, is analyzed on human WGCNA on hypothalamic RNASeq data. The impacted module in humans seems to be three with no identifiable pathways involved. From the eigengene analysis results that two of the three impacted modules cluster in a single hierarchical module. The pathway analysis performed on the whole eigengine module reveals that Wnt signaling pathway reaches the statistical significance (FDR= 0,01 p value = 0,00003).DiscussionOur study firstly demonstrates the full MS-phenotype induced by Olanzapine avoiding the use of weight gain as a proxy of OL-MS as shown in previous literature. The high comparability shows by hypothalamic network analysis in mice and humans underlines the highly interspecies conservation of hypothalamic functional pathways. So the present study represents an innovative approach for translational studies on hypothalamic pathway contribution to MS induced by OL. Combining a murine model, network analysis and human translation it proposes a reliable method for translation of pre-clinical studies.

A comparative study of effectiveness, safety and cost effectiveness of olanzapine, risperidone and aripiprazole therapy in schizophrenia

Background: Schizophrenia is the most common psychotic disorder and responsible for approximately half of long-term psychiatric hospitalizations. Antipsychotic medications reduce the psychotic symptoms and prevent relapses. The choice of drug for treatment of schizophrenia depends on many issues, including effectiveness, cost, side-effect burden, availability, and tolerability. Many studies have compared antipsychotic drugs with one another, but no broad consensus has been reached. Our study compares the clinical effectiveness, safety and cost effectiveness of atypical antipsychotics in our setting.Methods: This was an observational, prospective study in which schizophrenia patients receiving either olanzapine, risperidone or aripiprazole were enrolled. Patients were followed up for 3 months. Evaluation of effectiveness was done by analysing mean reduction in PANSS score. Analysis of ADRs was done using WHO causality scale and Hartwig and Siegel severity scale. Cost analysis was done by comparing all three groups in term of cost range of antipsychotic drugs per improvement in PANSS score during the study period.Results: In the present study, the average dose of antipsychotic drugs received by a patient per day was 8.83±2.98 mg in olanzapine group, 4.76±1.12 mg in risperidone group and 20.43±8.5 mg in aripiprazole group. Mean reduction in PANSS score from baseline to 12 weeks was 23.79% in olanzapine group, 25.41% in risperidone group and 24.65% in aripiprazole group. Conclusions: All the groups were equally effective in reduction in PANSS score while risperidone was the most cost effective.

Olanzapine-induced liver injury in mice: aggravation by high-fat diet and protection with sulforaphane

Olanzapine is effective to treat for schizophrenia and other mood disorders, but limited by side effects such as weight gain, dyslipidemia, and liver injury. Obesity in the US is at epidemic levels, and is a significant risk factor for drug-induced liver injury. Obesity incidence in the psychiatric population is even higher than in the US population as a whole. The purpose of this study was to test the hypothesis that obesity worsens olanzapine-induced hepatic injury, and to investigate the potential protective effects of sulforaphane. 8-week old female C57BL/6 mice were fed either a high-fat or low-fat control diet (HFD and LFD). Mice also received either olanzapine (8 mg/kg/d) or vehicle by osmotic minipump for 4 weeks. A subset of mice in the HFD + olanzapine group was administered sulforaphane, a prototypical Nrf2 inducer (90 mg/kg/d). Olanzapine alone increased body weight, without a commensurate increase in food consumption. Olanzapine also caused hepatic steatosis and injury. Combining olanzapine and HFD caused further dysregulation of glucose and lipid metabolism. Liver damage from concurrent HFD and olanzapine was worse than liver damage from high-fat diet or olanzapine alone. Sulforaphane alleviated many metabolic side effects of olanzapine and HFD. Taken together, these data show that olanzapine dysregulates glucose and lipid metabolism and exacerbates hepatic changes caused by eating a HFD. Activation of the intrinsic antioxidant defense pathway with sulforaphane can partially prevent these effects of olanzapine and may represent a useful strategy to protect against liver injury.

High-protein diet and omega-3 fatty acids improve redox status in olanzapine-treated rats.

The present study aimed to estimate the effects of high-protein diet (PD)-isolated whey protein and omega-3 fatty acids-docosahexaenoic and eicosapentaenoic acid on oxidative parameters of rats treated with Olanzapine (OLZ). Experiments were carried out on 8-week-old Wistar albino male rats (n = 64) weighing 200 ± 20g. By dietary and pharmacological treatment, all animals were divided into 8 groups: 1. CTRL group; 2. CTRL + OLZ group; 3. CTRL + FA group; 4. CTRL + OLZ + FA group; 5. PD group; 6. PD + OLZ group; 7. PD + FA group; 8. PD + OLZ + FA group. After 6 weeks of pharmacological/diet treatment, all animals were sacrificed to collect blood samples and determine the biomarkers of oxidative stress. The following oxidative stress markers were measured spectrophotometrically: superoxide anion radical (O2-), hydrogen peroxide (H2O2), nitric oxide (NO-), index of lipid peroxidation measured as TBARS, reduced glutathione, catalase and superoxide dismutase. The study has shown that Olanzapine treatment was associated with increased release of pro-oxidants and diminished activity of anti-oxidant markers. Additional supplementation with PD and FA succeeded in abolishing the negative influence in most of the measured parameters. However, these beneficial impacts were stronger in the case of their separate application, which could be the practical and clinical importance of these results.

Comparison of Mirtazapine and Olanzapine on Nausea and Vomiting following Anthracycline-cyclophosphamide Chemotherapy Regimen in Patients with Breast Cancer.

We evaluated and compared the efficacy and safety of mirtazapine (MTZ) with olanzapine (OLP) for preventing chemotherapy-induced nausea and vomiting (CINV) following anthracycline plus cyclophosphamide (AC) regimen. Eligible participants were chemotherapy-naive early-stage breast cancer patients who were scheduled to undergo adjuvant AC. The patients were randomized to take oral MTZ or OLP in combination with aprepitant (A), dexamethasone (D), and granisetron (G), (ADG). The endpoints included rates of complete response (CR), complete control (CC), total control (TC), and adverse events during the acute, delayed, and overall phases in the two cycles of chemotherapy. The influence of CINV on the quality of life (QoL) was evaluated on day 6 of chemotherapy. Of 82 patients, 60 were randomized. In the first cycle, CR rates in cycle 1 were 83.3% and 76.6% during the acute period, 80% and 86.6% during the delayed period, and 66.6% and 63.3% during the overall period, for the ADG-M and ADG-O, respectively. High efficacy of both groups was maintained over 2 cycles. More patients in the ADG-M group noted minimal or no impact of CINV on daily life in cycle 2 (89.7% vs. 67.9%; p = 0.044). Incidence of somnolence and fatigue was more frequent with the olanzapine group. In this study, there was no substantial difference between mirtazapine and olanzapine in preventing CINV. Further large randomized trials are essential to demonstrate the anti-emetic effect of mirtazapine in chemotherapy.

TO STUDY EFFICACY OF AMISULPRIDE IN TREATMENT OF SCHIZOPHRENIA.

The study was performed at the Department of Pharmacology in collaboration with Department of Psychiatry, NSCB Medical College, Jabalpur. The maximum numbers of patients in were in reproductive age group that is in between 20 to 49 years. The mean age in Amisulpride group was 33.26(±10.23) years while in Olanzapine group it was 31.25 (±12.22) years.
 Schizophrenia was more common (80%) in younger (20-49years) age group. In our study the male /female ratio was 1.7. Our study supports the notion that Schizophrenia is more common in Married and Urban population. Only one patient from Olanzapine Group suffered Extrapyramidal symptoms of moderate severity requiring withdrawal from study.2 patients from Olanzapine group and 1 patient from Amisulpride group had Tremors and Akathesia of mild severity. There was no emergence of Extrapyramidal symptoms in rest of the patients (p>.05)
 Keywords: Efficacy, Amisulpride, Olanzapine & Schizophrenia.

The efficacy and safety of the addition of olanzapine to ondansetron and dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy.

To evaluate the efficacy and safety of the addition of olanzapine to ondansetron and dexamethasone for chemotherapy-induced nausea vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy (HEC). In this randomized, double-blind, placebo-controlled, crossover study, we randomly assigned chemotherapy-naïve patients receiving HEC to receive olanzapine or placebo in addition to ondansetron and dexamethasone. All subjects were crossed over to another treatment arm on second-cycle chemotherapy. The primary endpoint was complete response (CR) rate defined as no vomiting and no use of rescue drugs. At the first cycle, there were significantly more patients with CR in the olanzapine group than in the placebo group in overall phase (68.7% vs. 25.0%, p < 0.001), acute phase (0-24h) (75.0% vs. 31.2%, p < 0.001) and delayed phase (24-120h) (68.7% vs. 43.7%, p = 0.038). After crossover, there were significantly more patients with CR in the olanzapine group than in the placebo group in overall phase (67.2% vs. 25.0%, p < 0.001), acute phase (71.9% vs. 32.8%, p < 0.001) and delayed phase (67.2% vs. 37.5%, p < 0.001). In crossover analysis, the olanzapine group had significantly lower mean nausea (1.28 vs. 3.05, p < 0.001) and fatigue (3.5 vs. 4.58, p < 0.001) scores but higher mean appetite (2.5 vs. 1.55, p = 0.003) and sleepiness (3.26 vs. 2.2, p < 0.001) scores. There were no grade 3 and 4 anti-emetic-drug-related toxicities. Mean QT interval changes did not different between two groups (-4.30 vs. -1.86, p = 0.69). The addition of olanzapine to ondansetron and dexamethasone significantly improved CINV prevention and was safe in patients receiving HEC.

Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

419O - Olanzapine combined with 5-HT3 RA plus dexamethasone for prevention and treatment of chemotherapy-induced nausea and vomiting in cancer patients: A systematic review and meta-analysis of randomized controlled trials

BackgroundWe conducted a review to evaluate the efficacy and adverse events (AEs) of olanzapine combined with 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist (RA) plus dexamethasone compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapyinduced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomized controlled trials (RCTs). MethodsPubMed, Web of Science, EMBASE, and The Cochrane Library, WanFang Database, China Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), and Chinese Science and Technology Periodical Database (VIP) (inception to April 2019) were searched to recognize relevant articles. Relative risk (RR) with 95% confidence intervals (CIs) for CINV and AEs were all extracted. Results11 studies with 1107 cancer patients were involved in this review. The pooled RR of any level acute CINV (RR = 0.60, 95%CI: 0.48–0.75, Z=-4.57, P < 0.01) and any level delayed CINV (RR = 0.50, 95%CI: 0.38-0.66, Z=-4.87, P < 0.01) were significantly decreased in olanzapine group. While only CINV III and CINV IV were significantly decreased in olanzapine groups. Subgroup analysis indicated that there was no significant difference between 5mg and 10mg for olanzapine. Moreover, the occurrence of insomnia (RR = 0.12, 95%CI: 0.06-0.26, Z=-5.44, P < 0.01) was statistically decreased in the olanzapine group. ConclusionsOlanzapine significantly decreased the occurrence of moderate-severe CINV (CINV III and IV) and insomnia for the prevention and treatment of CINV in high and moderately emetogenic chemotherapy. Compared with 10mg per day, 5mg oral may be more appropriate for cancer patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

The Effect of Valproic Acid on Olanzapine Serum Concentration: A Study Including 2791 Patients Treated With Olanzapine Tablets or Long-Acting Injections.

The combination of olanzapine and valproic acid (VPA) is regularly prescribed in the treatment of bipolar or schizoaffective disorders. The VPA has been shown to reduce olanzapine concentration, but the mechanism behind this interaction remains unknown. We aimed to investigate the effect of VPA on olanzapine concentration during oral versus long-acting injectable (LAI) formulation in a real-life setting. From a therapeutic drug monitoring service, prescribed doses and serum concentrations from 2791 olanzapine-treated patients (9433 measurements) were included. The number of patients on olanzapine-LAI treatment was 328, whereas 2463 were using oral olanzapine. The frequency of patients comedicated with VPA was 9.4% for olanzapine tablets and 5.8% for olanzapine-LAI. The VPA had no effect on olanzapine dose-adjusted concentrations in LAI users (1.6 vs 1.7 [ng/mL]/[mg/d]; P = 0.38), whereas in the oral group the dose-adjusted olanzapine concentration was lower in VPA users (2.2 vs 2.7 [ng/mL]/[mg/d]; P < 0.001). For smokers in the oral olanzapine group using VPA, 8.7% of the measurements were in the subtherapeutic range (<10 ng/mL) compared with 6.0% in nonusers (P = 0.003). These findings show that the VPA-olanzapine interaction involves a presystemic mechanism and is therefore restricted to oral olanzapine treatment. For oral treatment of olanzapine, comedication with VPA implies a risk of insufficient effect, which may be of clinical relevance in smokers in particular. Thus, it is important to be aware of the interaction potential with VPA during oral olanzapine use, whereas for LAI-treated patients fewer precautions are required from a pharmacokinetic point of view.

Should Olanzapine be Advocated Over Conventional Anti-Emetics for the Prevention of Chemotherapy-Induced Nausea and Vomiting? An Updated Meta-Analysis of Randomized Control Trials

Objective: The aim of this study is to synthesize the evidence about the efficacy of Olanzapine for the prevention of CINV. Methods: A computer literature search of PubMed, EBSCO, Ovid, and Cochrane CENTRAL databases has been conducted. Studies were screened for eligibility and data were extracted. The proportion of patients with complete response (CR) and those with no nausea were pooled as risk ratio (RR) in a fixed effect model meta-analysis using Review Manager Version 5.3 for windows. Results: Nine randomized controlled trials (n=1572) were pooled in the final analysis. In all studies, olanzapine was given as 10 mg PO. Olanzapine was superior to active control in terms of CR rate in acute phase (RR 1.12, 95% CI [1.02, 1.22], p=0.01]), delayed phase (RR 1.31, 95% CI [[1.10, 1.56], p=0.002), and overall phase (RR 1.30, 95% CI [1.09, 1.55], p=0.004). Rates of no nausea were significantly higher in olanzapine 10 mg group compared to active control group in acute phase (RR 1.20, 95% CI [1.04, 1.38], p=0.01), delayed phase (RR 1.72, 95% CI [1.42, 2.08], p&lt;0.00001), and overall phase (RR 1.57, 95% CI [1.39, 1.77], p &lt;0.00001). The incidence of adverse events was similar in olanzapine and control groups, with the most frequently reported treatment-related emergent adverse events being fatigue, constipation, and headache. Conclusion: Olanzapine is a well-tolerated drug for cancer patients and has shown superiority against conventional antiemetics for the prevention of CINV.

1605P - Olanzapine combined with 5-HT3 RA plus dexamethasone for prevention and treatment of chemotherapy-induced nausea and vomiting in high and moderate emetogenic chemotherapy: A systematic review and meta-analysis of randomized controlled trials

BackgroundWe conducted a review to evaluate the efficacy and adverse events (AEs) of olanzapine combined with 5-hydroxytryptamine type 3 (5-HT3) RA plus dexamethasone compared with 5-HT3 RA plus dexamethasone for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in high and moderate emetogenic chemotherapy based on randomized controlled trials (RCTs). MethodsPubMed, Web of Science, The Cochrane library, and EMBASE, China National Knowledge Infrastructure (CNKI), WanFang Database, China Biomedical Literature database (CBM), and Chinese Science and Technology Periodical Database (VIP) (inception to April 2019) were searched to recognize relevant articles. Relative risk (RR) with 95% confidence intervals (CIs) for CINV and AEs were all extracted. Results11 studies with 1107 cancer patients were involved in this review. The pooled RR of acute CINV (RR=0.60, 95%CI: 0.48–0.75, Z=-4.57, P<0.01) and delayed CINV (RR=0.50, 95%CI: 0.38-0.66, Z=-4.87, P<0.01) were significant decreased. While only CINV III and CINV IV were significant deceased in olanzapine groups. Subgroup analysis indicated that there was no significant difference between 5mg and 10mg for olanzapine. Moreover, the occurrence of insomnia was statistically decreased in olanzapine group. ConclusionsOlanzapine significant decreased the occurrence of moderate-severe CINV (CINV III and IV) and insomnia for the prevention and treatment of CINV in high and moderate emetogenic chemotherapy. Compared with 10mg per day, 5mg oral may be more appropriate for cancer patients. Legal entity responsible for the studyThe author. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Up-regulation of hepatic fatty acid transporters and inhibition/down-regulation of hepatic OCTN2 contribute to olanzapine-induced liver steatosis

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic β-hydroxybutyrate level (indicator of fatty acid β-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 μM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.

Olanzapine 5mg in Combination with Standard Antiemetic Therapy for the Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Cisplatin-Based Chemotherapy (J-FORCE): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial

Background: Olanzapine 10 mg added to standard antiemetic therapy, including aprepitant, palonosetron, and dexamethasone, has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg may be considered to prevent sedation. In several phase II studies, olanzapine 5 mg has shown equivalent activity and a favourable safety profile in relation to somnolence. We conducted a randomised, double-blinded, placebo-controlled, phase III study (J-FORCE) to evaluate olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. Methods: This was a multicentre, phase III study to evaluate olanzapine 5 mg with triplet-combination therapy. Patients receiving cisplatin ((≥50 mg/m2) were randomly assigned to receive oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). The primary endpoint was the proportion of complete response (CR), defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 hours). Findings: Between February 9, 2017 and July 13, 2018, 710 patients were enrolled from 26 hospitals in Japan. Of those, 356 and 354 patients were randomly assigned to the olanzapine and placebo groups, respectively. In the delayed phase, CR was 79% (95% CI: 75-83) in the olanzapine 5 mg group and 66% (95% CI: 61-71)a€€in the placebo group (p<0.001). Grade 3 adverse events (i.e., constipation and somnolence) were reported in the olanzapine group. Interpretation: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. Trial Registration: This study is registered at UMIN Clinical Trials Registry, number UMI24676.gbv. Funding Statement: The study was supported in part by the Japan Supportive, Palliative and Psychosocial Oncology Group and funded by the Japan Agency for Medical Research and Development under Grant Number JP18ck0106214h0003. Declaration of Interests: TY reports grants from AC MEDICAL INC., grants from A2 Healthcare Corporation, grants and personal fees from CAC Croit Corporation, grants from FMD KL SI reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; grants and personal fees from Eli Lily, personal fees from Taiho, grants and personal fees from Chugai, grants from Novartis, grants from Merck-Serono, grants from Daiichi-Sankyo, grants from Bristol-Myers Squibb, grants from Bayer, personal fees from ONO PHARMACEUTICAL CO., LTD. , grants from Eisai, outside the submitted work; . NY reports grants from Chugai, grants from Taiho, grants from Eisai, grants from Lilly, grants from Quintiles, grants from Astellas, grants from BMS, grants from Novartis, grants from Daiichi-Sankyo, grants from Pfizer, grants from Boehringer Ingelheim, grants from Kyowa-Hakko Kirin, grants from Bayer, grants from ONO PHARMACEUTICAL CO., LTD, grants from Takeda, personal fees from ONO PHARMACEUTICAL CO., LTD, personal fees from Chugai, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Lilly, personal fees from BMS, personal fees from Eisai, personal fees from Otsuka, personal fees from Takeda, personal fees from Boehringer Ingelheim, personal fees from Cimic, grants from Janssen Pharma, grants from MSD, grants from Merck, outside the submitted work; . YU reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; . YO reports grants and personal fees from AstraZeneca, grants and personal fees from Chugai, grants and personal fees from Lilly, grants and personal fees from ONO, grants and personal fees from BMS, grants and personal fees from Pfizer, grants and personal fees from MSD, personal fees from Celltrion, personal fees from Amgen, grants and personal fees from Kyorin, grants and personal fees from Takeda, personal fees from Boehringer Ingelheim, grants from Kissei, grants and personal fees from Novartis, grants from Dainippon-Sumitomo, grants from Ignyta, grants from ROXO, outside the submitted work. Ethics Approval Statement: The study was conducted in compliance with the Declaration of Helsinki, and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (guidelines established by the Japanese government), and the protocol was approved by the Ethics Committees of all participating institutions. All patients included in this study provided written informed consent.

Combination of olanzapine and aprepitant in the prevention of chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients.

11577 Background: Olanzapine and Aprepitant have been shown to be a safe and effective agent for the prevention of CINV. This study aims to compare Olanzapine, Aprepitant and their combination in the prevention of CINV. Methods: Prospective randomized controlled study in breast cancer patients receiving doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 chemotherapy. Female patient; age, ≥ 18; chemotherapy naïve; were included. Patients with seizure disorder, brain metastasis were excluded. Olanzapine group received Tablet Olanzapine 10 mg on day 1 to 3. Aprepitant group received Tablet. Aprepitant 125mg on day 1, 80mg on days 2-3. The combination group received Aprepitant 125mg on day 1, 80mg on days 2-3 and Olanzapine 10mg on day 1. All groups received Palnosteron 0.25mg and Dexamethasone 8mg on day 1. The primary end point of the study was complete response (CR) for nausea that is no nausea in the acute, delayed and overall periods. Secondary endpoint was CR for vomiting and no use of rescue drugs in all periods. Beginning with the first day of chemotherapy and daily through day 5, patients were asked to record daily episodes of nausea using a visual analogue scale from 0 to 10, with 0 indicating no nausea and 10 indicating a maximal level of nausea. They were asked to record daily episodes of vomiting (number and time) and the utilization of rescue therapy. Results: A total of 141 patients were evaluated and consented for the study. The median age was 47 years; range 29-80; CR for nausea in the acute period (within 24 hours) was 83%, 63.8% and 78.7% (p=0.078); for the delayed period (days 2-5) 59.6%, 55.3% and 63.8% (p=0.702); for the overall period (0-120 hours) 57.4%, 53.2% and 59.6% (p=0.817) for the Olanzapine, Aprepitant and combination arm respectively. CR for vomiting in the acute period was 91.5%, 91.5% and 97.9.7% (p=0.344); for the delayed period 74.5%, 85.1% and 97.9% (p=0.005); for the overall period 70.2%, 85.1% and 97.9% (p=0.001) for the Olanzapine, Aprepitant and combination arm respectively. There were no Grade 3/4 toxicities. Conclusions: The combination strategy shows trend towards better prevention of CINV. Clinical trial information: CTRI/2017/12/010864.

Relation between hyponatremia and alteration in gross metabolic parameters after atypical antipsychotic therapy

Background: Weight gain and hyponatremia which is dilutional in nature, has been well known adverse effects associated with use of atypical antipsychotic medication but the plausible impact of dilutional hyponatremia on weight gain has not been explored.Methods: One hundred and three patients more than 18 years of age of either gender who were prescribed, olanzapine or risperidone, were tested for serum electrolytes (Na+ and K+) and gross metabolic parameters (weight and waist circumference) were measured for baseline and post drug testing.Results: Most common age group was 30-39 years of age in the patient study sample (n=103) with 38 (36.90%) patients were females while rest 63 (63.10%) were males. There was no significant association between serum sodium levels and weight gain was observed (p &gt;0.05). It was observed that in olanzapine group 64% of the studied cases had weight gain whereas in risperidone group only 20.8% reported weight gain (p &lt;0.001). There was significant association between olanzapine and increase in waist circumference over risperidone, irrespective to serum sodium status (x2=0.0148, p &gt;0.05).Conclusions: Olanzapine was primarily responsible for weight gain and increase in waist circumference over risperidone. These gross metabolic parameters were not influenced by hyponatremia.

Antiemetic prophylaxis with temozolomide: an audit from a tertiary care center.

In our previous experience, a significant proportion of patients who received 5-HT3 antagonist monotherapy with adjuvant temozolomide (150-200 mg/m2) had chemotherapy-induced nausea and vomiting (CINV). This is an audit comparing the multiple antiemetic therapies in the prevention of temozolomide-associated CINV. This was a retrospective audit. Adult glioma patients treated with temozolomide at a dose of 150-200 mg/m2 between October 2017 and June 2018 were selected for this analysis. Three antiemetic prophylaxis were used in this time period: ondansetron (October 2017 to November 2017), ondansetron + domperidone (December 2017 to February 2018), and ondansetron + olanzapine (March 2018 to June 2018). The rates of nausea and vomiting were compared among the 3 cohorts using the chi-squared test with Bonferroni correction. A P value of less than .016 was considered significant. A total of 360 patients were selected for this analysis. There were 91 patients in the ondansetron prophylaxis group (25.3%), 113 (31.4%) in the ondansetron plus domperidone group, and 156 (43.3%) in the ondansetron plus olanzapine group. The overall incidence of nausea and vomiting was 25.0% (n = 90) and 7.2% (n = 26). Overall the rates of nausea (P = .052) and vomiting (P = .481) were similar in all 3 cohorts. However, the rates of grade 2 and above nausea (P = .012) and vomiting (P = .015) were significantly lower in the olanzapine group. The combination of ondansetron with olanzapine leads to a statistically significant decrease in the rate of moderate-to-severe emesis and nausea and needs to be explored in a prospective study.