PCSK9 dysregulates cholesterol homeostasis and triglyceride metabolism in olanzapine-induced hepatic steatosis via both receptor-dependent and receptor-independent pathways.

Schizophrenia, affecting approximately 1% of the global population, is often treated with olanzapine. Despite its efficacy, olanzapine's prolonged use has been associated with an increased risk of cardiovascular diseases and nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism remains unclear. Proprotein convertase subtilisin kexin type 9 (PCSK9) plays a crucial role in lipid metabolism and is involved in NAFLD pathogenesis via an unknown mechanism. This study aims to investigate the role of PCSK9 in olanzapine-induced NAFLD. C57BL/6J mice and HepG2 and AML12 cell lines were treated with varying concentrations of olanzapine to examine the effects of olanzapine on PCSK9 and lipid metabolism. PCSK9 levels were manipulated using recombinant proteins, plasmids, and small interfering RNAs in vitro, and the effects on hepatic lipid accumulation and gene expression related to lipid metabolism were assessed. Olanzapine treatment significantly increased PCSK9 levels in both animal and cell line models, correlating with elevated lipid accumulation. PCSK9 manipulation demonstrated its central role in mediating hepatic steatosis through both receptor-dependent pathways (impacting NPC1L1) and receptor-independent pathways (affecting lipid synthesis, uptake, and cholesterol biosynthesis). Interestingly, upregulation of SREBP-1c, rather than SREBP-2, was identified as a key driver of PCSK9 increase in olanzapine-induced NAFLD. Our findings establish PCSK9 as a pivotal factor in olanzapine-induced NAFLD, influencing both receptor-related and metabolic pathways. This highlights PCSK9 inhibitors as potential therapeutic agents for managing NAFLD in schizophrenia patients treated with olanzapine.

Low-dose versus standard-dose olanzapine with triple antiemetic therapy for prevention of highly emetogenic chemotherapy-induced nausea and vomiting in patients with solid tumours: a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial.

BACKGROUND: Olanzapine is an effective antiemetic agent but it results in substantial daytime somnolence when administered at the standard dose. Our aim was to compare the efficacy of low-dose versus standard-dose olanzapine after highly emetogenic chemotherapy in patients with solid tumours. METHODS: This was a single-centre, open-label, non-inferiority, randomised, controlled, phase 3 trial done in a tertiary care referral centre in India (Tata Memorial Centre, Homi Bhabha National Institute, Mumbai). Patients aged 13-75 years with an Eastern Cooperative Oncology Group performance status of 0-2, who were receiving doxorubicin-cyclophosphamide or high-dose cisplatin for a solid tumour were eligible. Patients were randomly assigned (1:1), with block randomisation (block sizes of 2 or 4) and stratified by sex, age (≥55 or <55 years), and chemotherapy regimen, to receive low-dose (2·5 mg) oral olanzapine or standard-dose (10·0 mg) oral olanzapine daily for 4 days, in combination with a triple antiemetic regimen. Study staff were masked to treatment allocation but patients were aware of their group assignment. The primary endpoint was complete control, defined as no emetic episodes, no rescue medications, and no or mild nausea in the overall phase (0-120 hours), assessed in the modified intention-to-treat (mITT) population (ie, all eligible patients who received protocol-specified treatment, excluding those who had eligibility violations and who withdrew consent after randomisation). Daytime somnolence was the safety endpoint of interest. Non-inferiority was shown if the upper limit of the one-sided 95% CI for the difference in the complete control proportions between the treatment groups excluded the non-inferiority margin of 10%. This study is registered with the Clinical Trial Registry India, CTRI/2021/01/030233, is closed to accrual, and this is the final data analysis. RESULTS: Between Feb 9, 2021, and May 30, 2023, 356 patients were pre-screened for eligibility, of whom 275 patients were enrolled and randomly assigned (134 to the 2·5 mg olanzapine group and 141 to the 10·0 mg olanzapine group). 267 patients (132 in the 2·5 mg group and 135 in the 10·0 mg group) were included in the mITT population, of whom 252 (94%) were female, 15 (6%) were male, and 242 (91%) had breast cancer. 59 (45%) of 132 patients in the 2·5 mg olanzapine group had complete control in the overall phase versus 59 (44%) of 135 in the 10·0 mg olanzapine group (difference -1·0% [one-sided 95% CI -100·0 to 9·0]; p=0·87). In the overall phase, there were significantly fewer patients in the 2·5 mg olanzapine group than in the 10·0 mg olanzapine group with daytime somnolence of any grade (86 [65%] of 132 vs 121 [90%] of 135; p<0·0001) and of severe grade on day 1 (six]5%] vs 54 [40%]; p<0·0001). INTERPRETATION: Our findings suggest that olanzapine 2·5 mg is non-inferior to 10·0 mg in antiemetic efficacy and results in reduced occurrence of daytime somnolence among patients receiving highly emetic chemotherapy and should be considered as a new standard of care. FUNDING: Progressive Ladies Welfare Association.

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis.

Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that EVs are also a source of DAMPs in the induction of the immune response preceding drug-induced agranulocytosis, the proteome and immunogenicity of clozapine- (agranulocytosis-associated drug) and olanzapine- (non-agranulocytosis-associated drug) exposed EVs were compared in two preclinical models: THP-1 macrophages and Sprague-Dawley rats. Compared with olanzapine, clozapine induced a greater increase in the concentration of EVs enriched from both cell culture media and rat serum. Moreover, treatment of drug-naïve THP-1 cells with clozapine-exposed EVs induced an inflammasome-dependent response, supporting a potential role for EVs in immune activation. Proteomic and bioinformatic analyses demonstrated an increased number of differentially expressed proteins with clozapine that were enriched in pathways related to inflammation, myeloid cell chemotaxis, wounding, transforming growth factor-ß signaling, and negative regulation of stimuli response. These data indicate that, although clozapine and olanzapine exposure both alter the protein cargo of EVs, clozapine-exposed EVs carry mediators that exhibit significantly greater immunogenicity. Ultimately, this supports the working hypothesis that drugs associated with a risk of IDRs induce cell stress, release of proinflammatory mediators, and early immune activation that precedes severe reaction onset. Further studies characterizing EVs may elucidate biomarkers that predict IDR risk during development of drug candidates. SIGNIFICANCE STATEMENT: This work demonstrates that clozapine, an idiosyncratic drug-induced agranulocytosis (IDIAG)-associated drug, but not olanzapine, a safer structural analogue, induces an acute proinflammatory response and increases extracellular vesicle (EV) release in two preclinical models. Moreover, clozapine-exposed EVs are more immunogenic, as measured by their ability to activate inflammasomes, and contain more differentially expressed proteins, highlighting a novel role for EVs during the early immune response to clozapine and enhancing our mechanistic understanding of IDIAG and other idiosyncratic reactions.

A multicenter phase II trial of the triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for a cisplatin-containing regimen. - PATROL-I.

Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application.

Group-Based Trajectory Modeling to Identify Patterns of Antipsychotic-Associated Weight Gain Among Children and Adolescents.

PURPOSE/BACKGROUND: Antipsychotic-associated weight gain (AAWG) is a common adverse effect of second-generation antipsychotic (SGA) medications among children and adolescents. This study applied group-based trajectory modeling to identify latent trajectories of AAWG among children and adolescents and associated risk factors. PROCEDURES: This was a retrospective analysis of the IQVIA Ambulatory EMR-US database from 2016 to 2021. The cohort consisted of patients aged 6 to 19 years who were SGA naive and received at least 90 days of continuous SGA prescriptions. Group-based trajectory modeling was used to identify latent trajectories of AAWG development during a 24-month period since SGA initiation, and multinomial logistic regression analysis was conducted to examine the risk factors associated with the identified AAWG trajectories. FINDINGS/RESULTS: A total of 16,262 patients were included. Group-based trajectory modeling identified the following 4 distinctive AAWG trajectories: persistent severe weight gain (4.2%), persistent moderate weight gain (20.1%), minor weight change (69.6%), and gradual weight loss (6.1%). Compared with the minor weight change group, younger age (12-17 vs 5-11: odds ratio [OR], 0.634; 95% confidence interval [CI], 0.521-0.771), lower baseline body mass index z -score (OR, 0.216; 95% CI, 0.198-0.236), and receiving olanzapine as the initial SGA (olanzapine vs aripiprazole: OR, 1.686; 95% CI, 1.673-1.699) were more likely to follow severe weight gain trajectories. The area under the receiver operating characteristic curves for comparing severe weight gain versus minor weight change groups and moderate weight vs minor weight change groups in the multinomial regression model were 0.91 and 0.8, respectively. IMPLICATIONS/CONCLUSIONS: A quarter of pediatric SGA recipients experienced persistent weight gain during the SGA treatment. The risk of having persistent AAWG can be predicted using patient characteristics collected before SGA initiation and the initial SGA agent.

Nuclear receptor 5A2 regulation of Agrp underlies olanzapine-induced hyperphagia.

Antipsychotic (AP) drugs are efficacious treatments for various psychiatric disorders, but excessive weight gain and subsequent development of metabolic disease remain serious side effects of their use. Increased food intake leads to AP-induced weight gain, but the underlying molecular mechanisms remain unknown. In previous studies, we identified the neuropeptide Agrp and the transcription factor nuclear receptor subfamily 5 group A member 2 (Nr5a2) as significantly upregulated genes in the hypothalamus following AP-induced hyperphagia. While Agrp is expressed specifically in the arcuate nucleus of the hypothalamus and plays a critical role in appetite stimulation, Nr5a2 is expressed in both the CNS and periphery, but its role in food intake behaviors remains unknown. In this study, we investigated the role of hypothalamic Nr5a2 in AP-induced hyperphagia and weight gain. In hypothalamic cell lines, olanzapine treatment resulted in a dose-dependent increase in gene expression of Nr5a2 and Agrp. In mice, the pharmacological inhibition of NR5A2 decreased olanzapine-induced hyperphagia and weight gain, while the knockdown of Nr5a2 in the arcuate nucleus partially reversed olanzapine-induced hyperphagia. Chromatin-immunoprecipitation studies showed for the first time that NR5A2 directly binds to the Agrp promoter region. Lastly, the analysis of single-cell RNA seq data confirms that Nr5a2 and Agrp are co-expressed in a subset of neurons in the arcuate nucleus. In summary, we identify Nr5a2 as a key mechanistic driver of AP-induced food intake. These findings can inform future clinical development of APs that do not activate hyperphagia and weight gain.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

AIMS: To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. MATERIALS AND METHODS: Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. RESULTS: We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. CONCLUSIONS: These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Refeeding syndrome and psychopharmacological interventions in children and adolescents with Anorexia Nervosa: a focus on olanzapine-related modifications of electrolyte balance.

This study aims to investigate the potential correlation between the use of olanzapine, a psychopharmacological intervention commonly prescribed in Anorexia Nervosa treatment, and the occurrence of Refeeding Syndrome. Despite the acknowledged nutritional and biochemical impacts of olanzapine, the literature lacks information regarding its specific association with Refeeding Syndrome onset in individuals with Anorexia Nervosa. This is a naturalistic, retrospective, observational study, reporting the occurrence of Refeeding Syndrome in children and adolescents with Anorexia Nervosa, treated or untreated with olanzapine. Dosages and serum levels of olanzapine were assessed for potential associations with the occurrence of Refeeding Syndrome and specific variations in Refeeding Syndrome-related electrolytes. Overall, 113 patients were enrolled, including 46 (41%) who developed a Refeeding Syndrome. Mild (87%), moderate (6.5%), and severe (6.5%) Refeeding Syndrome was described, at a current average intake of 1378 ± 289 kcal/day (39 ± 7.7 kcal/kg/die), frequently associated with nasogastric tube (39%) or parenteral (2.2%) nutrition. Individuals receiving olanzapine experienced a more positive phosphorus balance than those who did not (F(1,110) = 4.835, p = 0.030), but no difference in the occurrence of Refeeding Syndrome was documented. The mean prescribed doses and serum concentrations of olanzapine were comparable between Refeeding Syndrome and no-Refeeding Syndrome patients.    Conclusion: The present paper describes the occurrence of Refeeding Syndrome and its association with olanzapine prescriptions in children and adolescents with Anorexia Nervosa. Olanzapine was associated with a more positive phosphorus balance, but not with a different occurrence of Refeeding Syndrome. Further, longitudinal studies are required. What is Known: • Refeeding Syndrome (RS) is a critical complication during refeeding in malnourished patients, marked by electrolyte (phosphorus, magnesium, potassium) imbalances. • Olanzapine, an atypical antipsychotic with nutritional and biochemical impacts, is used in Anorexia Nervosa (AN) treatment, however data concerning its association with RS are lacking. What is New: • The study observed RS in 46/113 (41%) young patients with AN. • Olanzapine-treated individuals showed a higher improvement in serum phosphate levels than untreated ones, although no impact on the occurrence of Refeeding Syndrome was observed.

Weight Gain and Metabolic Changes in Patients With First-Episode Psychosis or Early-Phase Schizophrenia Treated With Olanzapine: A Meta-Analysis.

BACKGROUND: Patients with first-episode psychosis or early-phase schizophrenia are susceptible to olanzapine-associated weight gain and cardiometabolic dysregulation. This meta-analysis characterized weight and metabolic effects observed during olanzapine treatment in randomized clinical trials in this vulnerable patient population. METHODS: PubMed, EMBASE, and Dialog were searched for randomized controlled trials (RCTs) reporting weight or cardiometabolic outcomes associated with olanzapine treatment in first-episode psychosis or early-phase schizophrenia. Random-effects meta-analysis and meta-regression were conducted using R v4.0.5. RESULTS: Of 1203 records identified, 26 RCTs informed the analyses. The meta-analytic mean (95% CI) weight gain was 7.53 (6.42-8.63) kg in studies (n = 19) that reported weight gain with olanzapine treatment. Stratified by duration, the mean (95% CI) weight gain was significantly higher in studies >13 weeks in duration than in those lasting ≤13 weeks: 11.35 (10.05-12.65) vs 5.51 (4.73-6.28) kg, respectively. Despite between-study variability, increases from baseline in most glycemic and lipid parameters were generally small in studies of both ≤13 and >13 weeks. There were no correlations, however, between weight gain and metabolic parameter changes when stratified by study duration. CONCLUSIONS: In RCTs enrolling patients with first-episode psychosis or early-phase schizophrenia, olanzapine was consistently associated with weight gain that was greater in studies lasting >13 weeks compared with those of ≤13 weeks. Metabolic changes observed across studies suggest that RCTs may underestimate metabolic sequelae vs real-world treatment observations. Patients with first-episode psychosis or early-phase schizophrenia are vulnerable to olanzapine-associated weight gain; strategies minimizing olanzapine-associated weight gain should be carefully considered.

Case series profile of olanzapine post-injection delirium/sedation syndrome.

Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called post-injection delirium/sedation syndrome (PDSS), characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information Centre between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (interquartile range [IQR]: 38-58) and male predominance (89%). Median onset time post injection was 30 min (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 h (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n = 10), benzodiazepine (n = 4) and benztropine (n = 3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage antidopaminergic and anticholinergic symptoms respectively. This proposed treatment combination could potentially alleviate some of the symptoms but needs further studies to validate the findings. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anticholinergic with similar onset (<1 h) and duration (<72 h). Bromocriptine is proposed to manage PDSS if patients develop severe dopamine blockade and physostigmine followed by rivastigmine for anticholinergic delirium.

Patterns of suboptimal antipsychotic use and misuse in Australia: What can routinely collected data tell us?

AIMS: There are increasing concerns about harms related to suboptimal antipsychotic use. Here we describe recent population-based trends in antipsychotic use and harms in Australia and identify population groups exhibiting patterns of use likely to contribute to these harms. METHODS: Using population-based data from the Australian Pharmaceutical Benefits Scheme (2015-2020), poisoning calls to the New South Wales (NSW) Poisons Information Centre (2015-2020) and poisoning deaths in all coronial records (2005-2018) in Australia, we measured trends in the prevalence of antipsychotic use and related deaths and poisonings. We applied latent class analyses to identify patterns of antipsychotic use that may contribute to harms. RESULTS: Quetiapine and olanzapine had the highest prevalence of use between 2015 and 2020. Noteworthy trends included increases of 9.1% and 30.8% in quetiapine use and poisonings, while olanzapine use decreased by 4.5% but poisonings increased by 32.7%. Quetiapine and olanzapine poisonings and related deaths had the highest rates of co-ingestion of opioids, benzodiazepines and pregabalin compared to other antipsychotics. We identified six distinct population groups using antipsychotics: (i) ongoing high-dose use with sedatives (8%), (ii) ongoing use (42%), (iii) ongoing use with analgesics and sedatives (11%), (iv) long-term low-dose use (9%), (v) sporadic use (20%) and (vi) sporadic use with analgesics (10%). CONCLUSION: Ongoing potentially suboptimal antipsychotic use and associated harms highlight the need to monitor such patterns of use, for example through prescription monitoring systems.

Atypical antipsychotics olanzapine and clozapine increase bone loss in female rats with experimental periodontitis.

BACKGROUND AND OBJECTIVES: Periodontitis is a highly prevalent disease in psychiatric patients, including those undergoing symptomatic treatment with second-generation antipsychotics. Some of these drugs, such as clozapine (CLO) and olanzapine (OLA), have prominent metabolic effects such as weight gain, hyperglycemia, and dyslipidemia, which are risk factors for periodontitis. In addition to the metabolic effects, there are reports of changes in salivary flow, gingival bleeding, and caries. In this context, we aimed to evaluate if the metabolic effects of OLA and CLO alter periodontal parameters in an animal model of periodontitis without the environmental and psychosocial biases inherent to human diseases. METHODS: In the first set of experiments, male and female adult Wistar rats received oral administration of CLO, OLA, or vehicle for 45 days. They were evaluated for body mass composition and weight gain, blood glucose parameters (fasting and glucose tolerance and insulin resistance tests), and lipid profile (HDL, total cholesterol, and triglycerides). In a second set of experiments, the same measurements were performed in female rats exposed to the antipsychotics for 45 days and ligature-induced periodontitis on the 30th day of treatment. Macroscopic measurements of exposed roots, microtomography in the furcation region of the first molar, and histological evaluation of the region between the first and second molars were evaluated to assess bone loss. Additionally, gingival measurements of myeloperoxidase activity and pro-inflammatory cytokine TNF-α were made. RESULTS: Only females exposed to OLA had more significant weight gain than controls. They also exhibited differences in glucose metabolism. Ligature-induced periodontitis produced intense bone retraction without changing the density of the remaining structures. The bone loss was even higher in rats with periodontitis treated with OLA or CLO and was accompanied by a local increase in TNF-α caused by CLO. These animals, however, did not exhibit the same metabolic impairments observed for animals without periodontitis. CONCLUSION: The use of clozapine and olanzapine may be a risk factor for periodontal disease, independent of systemic metabolic alterations.

Thymoquinone attenuates olanzapine-induced metabolic disorders in rats.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Efficacy and Safety of Olanzapine for the Prevention of Chemotherapy-induced Nausea and Vomiting in Children: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Chemotherapy-induced nausea and vomiting (CINV) remain the most distressing event in patients receiving highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC). This meta-analysis was conducted to evaluate the efficacy and safety of olanzapine containing regimen in preventing CINV in children on HEC and MEC. We searched PubMed, Embase, and Cochrane central register of controlled trials electronic databases to identify randomized clinical trials that compared 2 groups who either got olanzapine (olanzapine group) or placebo/no olanzapine (control group) for the prevention of CINV in children. The primary outcome was to determine the efficacy of olanzapine (complete response). The secondary outcomes were nausea control, the need for rescue medications, and adverse events of olanzapine. Three randomized clinical trials (n=394 patients) were included in this meta-analysis (olanzapine group, n=194, and placebo/control group, n=200). The pooled analysis of this meta-analysis found that olanzapine had a higher complete response in all phases of emesis in the HEC group and only in the acute phase in HEC/MEC groups compared with the control group. Olanzapine had higher nausea control in all phases of HEC but no nausea control in HEC/MEC. Olanzapine also reduced the need for rescue medications. A significant number of patients in the olanzapine group experienced somnolence (grades 1 and 2), but none of the participants discontinued the study due to side effects. In conclusion, this meta-analysis showed that olanzapine significantly prevented CINV in HEC. There was also a lesser need for rescue medications in the olanzapine group. Somnolence was higher in the olanzapine group, but it was clinically insignificant.

The impact of adjunctive aripiprazole on QT interval: A 12-week open label study in patients on olanzapine, clozapine or risperidone.

OBJECTIVE: To evaluate the effect of adjunct aripiprazole on QT of patients clinically stabilized on atypical antipsychotics. METHODS: The dataset was from an open-label 12-week prospective trial that evaluated adjunctive use of 5 mg/day of aripiprazole on metabolic profile in patients with schizophrenia, or schizoaffective disorder stabilized on olanzapine, clozapine, or risperidone. Bazett-corrected QT (QTc) was manually calculated from ECGs measured at baseline (before aripiprazole) and week 12, by two doctors blind to the diagnosis and atypical antipsychotic. The change in QTc (∆QTc: baseline QTc-week 12 QTc) and the number of participants in normal, borderline, prolonged, and pathological groups after 12 weeks were analyzed. RESULTS: Fifty-five participants, mean age of 39.3 (SD 8.2) years, were analyzed. The ∆QTc after 12 weeks was 5.9 ms (p = 0.143) for the whole sample; 16.4 ms (p = 0.762), 3.7 ms (p = 0.480) and 0.5 ms (p = 0.449), for the clozapine, risperidone and olanzapine group, respectively. There was no significant statistical difference comparing the change in QTc overall, and between atypical antipsychotic groups, when evaluating from baseline to endpoint. However, stratifying the sample based on sex-dependent QTc cut-offs showed a 45% decrease in abnormal QTc readings (p = 0.049) after aripiprazole initiation; 20 subjects had abnormal QTc at baseline, while only 11 subjects had abnormal QTc at 12 weeks. 25.5% of participants showed a reduction in at least one QTc severity group, while 65.5% had no change and 9.0% worsened in QTc group, after 12 weeks of adjunct aripiprazole. CONCLUSION: Low-dose adjunctive aripiprazole did not prolong QTc in patients stabilized on either olanzapine, risperidone, or clozapine. More controlled studies evaluating the QTc effect of adjunctive aripiprazole should be done to confirm and support these findings.

Olanzapine as an add-on, pre-operative anti-emetic drug for postoperative nausea or vomiting: a randomised controlled trial.

Postoperative nausea or vomiting occurs in up to 40% in patients with multiple risk factors, despite prophylaxis. Olanzapine is an antipsychotic drug that is used to prevent nausea and vomiting in palliative care and to treat chemotherapy-induced nausea and vomiting. This study aimed to examine whether pre-operative olanzapine, as a prophylactic anti-emetic added to intra-operative dexamethasone, ondansetron and total intravenous anaesthesia, reduced the incidence of postoperative nausea or vomiting. We performed a multiply-blinded randomised controlled trial in patients aged 18-60 years with cancer at high risk of postoperative nausea or vomiting (three or four risk factors according to the Apfel criteria) plus a previous history of chemotherapy-induced nausea and vomiting. Patients were allocated at random to receive 10 mg olanzapine or placebo orally 1 h before surgery in addition to a two-drug regimen (dexamethasone and ondansetron) and propofol anaesthesia to prevent postoperative nausea or vomiting. The primary outcome was the incidence of postoperative nausea or vomiting in the first 24 h after surgery. In total, 100 patients were enrolled; 47 in the olanzapine group and 49 in the control group completed the study. The baseline characteristics of the groups were similar. The incidence of postoperative nausea or vomiting in the first 24 h after surgery was lower in the olanzapine group (12/47, 26%) than in the control group (31/49, 63%) (p = 0.008, RR 0.40 (95%CI 0.21-0.79)). Adding pre-operative oral olanzapine to intra-operative dexamethasone and ondansetron was highly effective in reducing the risk of postoperative nausea or vomiting in the first 24 hours after surgery in patients with a previous history of chemotherapy-induced nausea and vomiting and at least three Apfel risk factors for postoperative nausea or vomiting.

Therapeutic outcomes wide association scan of different antipsychotics in patients with schizophrenia: Randomized clinical trials and multi-ancestry validation.

AIM: This study identified discrepant therapeutic outcomes of antipsychotics. METHODS: A total of 5191 patients with schizophrenia were enrolled, 3030 as discovery cohort, 1395 as validation cohort, and 766 as multi-ancestry validation cohort. Therapeutic Outcomes Wide Association Scan was conducted. Types of antipsychotics (one antipsychotic vs other antipsychotics) were dependent variables, therapeutic outcomes including efficacy and safety were independent variables. RESULTS: In discovery cohort, olanzapine related to higher risk of weight gain (AIWG, OR: 2.21-2.86), liver dysfunction (OR: 1.75-2.33), sedation (OR: 1.76-2.86), increased lipid level (OR: 2.04-2.12), and lower risk of extrapyramidal syndrome (EPS, OR: 0.14-0.46); risperidone related to higher risk of hyperprolactinemia (OR: 12.45-20.53); quetiapine related to higher risk of sedation (OR = 1.73), palpitation (OR = 2.87), increased lipid level (OR = 1.69), lower risk of hyperprolactinemia (OR: 0.09-0.11), and EPS (OR: 0.15-0.44); aripiprazole related to lower risk of hyperprolactinemia (OR: 0.09-0.14), AIWG (OR = 0.44), sedation (OR: 0.33-0.47), and QTc prolongation (ß = -2.17); ziprasidone related to higher risk of increased QT interval (ß range: 3.11-3.22), nausea (OR: 3.22-3.91), lower risk of AIWG (OR: 0.27-0.46), liver dysfunction (OR: 0.41-0.38), and increased lipid level (OR: 0.41-0.55); haloperidol related to higher risk of EPS (OR: 2.64-6.29), hyperprolactinemia (OR: 5.45-9.44), and increased salivation (OR: 3.50-3.68). Perphenazine related to higher risk of EPS (OR: 1.89-2.54). Higher risk of liver dysfunction in olanzapine and lower risk of hyperprolactinemia in aripiprazole were confirmed in validation cohort, and higher risk of AIWG in olanzapine and hyperprolactinemia in risperidone were confirmed in multi-ancestry validation cohort. CONCLUSION: Future precision medicine should focus on personalized side-effects.

Evaluation of contemporary olanzapine- and netupitant/palonosetron-containing antiemetic regimens for chemotherapy-induced nausea and vomiting.

INTRODUCTION: This post-hoc analysis retrospectively assessed data from two recent studies of antiemetic regimens for chemotherapy-induced nausea and vomiting (CINV). The primary objective was to compare olanzapine-based versus netupitant/palonosetron (NEPA)-based regimens in terms of controlling CINV during cycle 1 of doxorubicin/cyclophosphamide (AC) chemotherapy; secondary objectives were to assess quality of life (QOL) and emesis outcomes over four cycles of AC. METHODS: This study included 120 Chinese patients with early-stage breast cancer who were receiving AC; 60 patients received the olanzapine-based antiemetic regimen, whereas 60 patients received the NEPA-based antiemetic regimen. The olanzapine-based regimen comprised aprepitant, ondansetron, dexamethasone, and olanzapine; the NEPA-based regimen comprised NEPA and dexamethasone. Patient outcomes were compared in terms of emesis control and QOL. RESULTS: During cycle 1 of AC, the olanzapine group exhibited a higher rate of 'no use of rescue therapy' in the acute phase (olanzapine vs NEPA: 96.7% vs 85.0%, P=0.0225). No parameters differed between groups in the delayed phase. The olanzapine group had significantly higher rates of 'no use of rescue therapy' (91.7% vs 76.7%, P=0.0244) and 'no significant nausea' (91.7% vs 78.3%, P=0.0408) in the overall phase. There were no differences in QOL between groups. Multiple cycle assessment revealed that the NEPA group had higher rates of total control in the acute phase (cycles 2 and 4) and the overall phase (cycles 3 and 4). CONCLUSION: These results do not conclusively support the superiority of either regimen for patients with breast cancer who are receiving AC.

Epigenetic Histone Methylation of PPARγ and CPT1A Signaling Contributes to Betahistine Preventing Olanzapine-Induced Dyslipidemia.

As a partial histamine H1 receptor agonist and H3 antagonist, betahistine has been reported to partially prevent olanzapine-induced dyslipidemia and obesity through a combination therapy, although the underlying epigenetic mechanisms are still not known. Recent studies have revealed that histone regulation of key genes for lipogenesis and adipogenesis in the liver is one of the crucial mechanisms for olanzapine-induced metabolic disorders. This study investigated the role of epigenetic histone regulation in betahistine co-treatment preventing dyslipidemia and fatty liver caused by chronic olanzapine treatment in a rat model. In addition to abnormal lipid metabolism, the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), as well as the downregulation of carnitine palmitoyltransferase 1A (CPT1A) in the liver induced by olanzapine, were significantly attenuated by betahistine co-treatment. In addition, betahistine co-treatment significantly enhanced the global expression of H3K4me and the enrichment of H3K4me binding on the promoter of Cpt1a gene as revealed by ChIP-qPCR, but inhibited the expression of one of its site-specific demethylases, lysine (K)-specific demethylase 1A (KDM1A). Betahistine co-treatment also significantly enhanced the global expression of H3K9me and the enrichment of H3K9me binding on the promoter of the Pparg gene, but inhibited the expression of two of its site-specific demethylases, lysine demethylase 4B (KDM4B) and PHD finger protein 2 (PHF2). These results suggest that betahistine attenuates abnormal adipogenesis and lipogenesis triggered by olanzapine through modulating hepatic histone methylation, and thus inhibiting the PPARγ pathway-mediated lipid storage, while at the same time promoting CP1A-mediated fatty acid oxidation.

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice.

AIMS/HYPOTHESIS: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. METHODS: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5-6.0 mg kg-1 day-1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. RESULTS: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. CONCLUSIONS/INTERPRETATION: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.