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Olanzapine long-acting injection is a commonly used antipsychotic drug formulation in the treatment of schizophrenia. Postinjection delirium/sedation syndrome (PDSS) is a potential side effect of this intramuscular depot, for which patients are often presented at the ED. In this article, we give an overview of the current literature outlining the key aspects of managing this syndrome in a critical care setting, illustrated by a typical fictional clinical case. We discuss several useful and practical aspects of PDSS for emergency physicians and critical care physicians, including pharmacological background, common symptoms, diagnostic criteria and therapeutic options., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Dexamethasone is an antiemetic drug widely used to prevent nausea and vomiting caused by anticancer drugs. However, dexamethasone can cause several side effects even after short-term administration. Therefore, the development of dexamethasone-free antiemetic therapies has been recognized as an important challenge. The objective of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine. Patients who were chemotherapy-naïve and scheduled to receive highly emetogenic chemotherapy for breast cancer were enrolled and assessed for nausea and vomiting occurring within 120 h after the start of chemotherapy. The primary endpoint was the total control (TC) rate of overall phases. Secondary endpoints included the complete response (CR) rate, which was evaluated during the acute, delayed, and overall phases. A total of 88 patients were enrolled from eight centers in Japan, of whom 84 were included in the analysis. The proportion of patients achieving TC throughout the overall period was 17.1%. Similarly, CR and CC rates for the overall period were 43.4% and 39.5%, respectively. Frequently reported adverse events were loss of appetite and constipation, with rates of 52.4% and 50.0%, respectively. The primary endpoint was not achieved. Therefore, antiemetic therapy without dexamethasone shows an inadequate effect on nausea, and it is generally advisable to avoid omitting dexamethasone. However, in the overall period, both CR and CC were comparable to conventional three-drug combination therapy. Thus, in patients unable to use dexamethasone, replacing it with olanzapine could be an option.Trial registration number: UMIN 000038644, November 20, 2019. The date of first trial registration: 13/03/2020., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval This study was conducted in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects published by Japan’s Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare, Japan, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Written, informed consent was obtained from all participants., (© 2024. The Author(s).)

Background: Japan's super-aged society presents significant challenges, particularly with regard to managing aspiration pneumonia among older adults. We aimed to investigate the link between anticholinergic drug use and the incidence of aspiration pneumonia, primarily utilizing data from the Japanese Adverse Drug Event Report (JADER) database., Methods: The primarily analysis included JADER data from the first quarter of 2004 through the third quarter of 2023, focusing on 2367 cases of aspiration pneumonia in individuals aged ≥60 years. The study examined the association of aspiration pneumonia with 49 drugs listed in the Anticholinergic Risk Scale, using the Reporting Odds Ratio for signal detection. A scoping review incorporating findings from MEDLINE and the Cochrane Library was conducted to validate these associations., Results: The primary analysis identified an increased risk of aspiration pneumonia associated with specific drugs, including clozapine, haloperidol, risperidone, quetiapine, and olanzapine. A total of 20 drugs were significantly associated with an increased risk of aspiration pneumonia. Our results emphasize the importance of considering the dopamine-blocking effects of these drugs, particularly in at-risk populations, such as older adults, and those with conditions, such as schizophrenia or Parkinson's disease., Conclusions: The study highlights the importance of careful monitoring of anticholinergic drugs with potent dopamine-blocking effects, such as clozapine, haloperidol, risperidone, quetiapine, and olanzapine, to reduce the risk of aspiration pneumonia. Future research should include observational and interventional studies to further investigate these findings., Ethics and Dissemination: As this study utilized pre-existing anonymized information, approval from an ethics committee was not required., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Olanzapine is prescribed as prophylaxis for chemotherapy-induced nausea and vomiting at a dose of 2.5 or 5 mg in Asian countries. We compared the effectiveness of olanzapine 2.5 mg and 5 mg in preventing chemotherapy-induced nausea and vomiting among patients receiving high-emetogenic chemotherapy for lung cancer., Methods: Using a Japanese national inpatient database, we identified patients who received olanzapine doses of 2.5 or 5 mg during high-emetogenic chemotherapy for lung cancer between January 2016 and March 2021. We conducted a 1:1 propensity score-matched analysis with adjustment for various factors, including those affecting olanzapine metabolism. The outcomes were additional antiemetic drug administration (within 2-5 days after chemotherapy initiation), length of hospital stay, and total hospitalization costs., Results: Olanzapine 2.5 and 5.0 mg were used in 2905 and 4287 patients, respectively. The propensity score-matched analysis showed that olanzapine 2.5 mg administration was significantly associated with a higher proportion of additional antiemetic drug administration (36% vs. 31%, p < 0.001) than olanzapine 5 mg. The median length of hospital stay was 8 days in both groups. Total hospitalization cost did not differ significantly between the two doses of olanzapine (5061 vs. 5160 USD, p = 0.07). The instrumental variable analysis demonstrated compatible results., Conclusion: Prophylactic use of olanzapine 2.5 mg during chemotherapy for lung cancer was associated with a higher rate of additional antiemetic drugs than olanzapine 5 mg., (© 2024. The Author(s).)

Introduction: Olanzapine use for chemotherapy-induced nausea and vomiting (CINV) in hematological malignancies, for multi-day chemotherapy, and with a steroid-sparing antiemetic strategy is poorly understood. This study investigated if olanzapine is associated with improved prevention of CINV when added to a steroid-sparing antiemetic regimen in patients with acute leukemia receiving intensive, moderately emetogenic, multi-day chemotherapy., Methods: This was a single-center, retrospective cohort study in patients with acute leukemia. Patients who received olanzapine for CINV prevention were compared to those who did not. All patients received a 5-HT3 antagonist. Adult patients receiving moderately emetogenic, multi-day, intensive chemotherapy for acute leukemia were included. Patients were excluded if they received steroids greater than physiological doses during the study period. The primary endpoint was the complete response of CINV (no emesis or rescue antiemetic usage)., Results: This study included 58 patients, 12 patients received olanzapine and 46 patients were in the control group. Baseline demographics were similar. In the study population, 89.7% had acute myeloid leukemia, median age was 54 (interquartile range 42-63) years, 34.5% were female, 27.6% had prior CINV. Complete response of CINV was similar between groups, 4 (33.3%) and 15 (32.6%) patients in the olanzapine and control groups, respectively. Safety events were similar between groups., Conclusion: Patients with acute leukemia receiving multi-day intensive chemotherapy are at high risk for CINV. The limited data in this study suggests that olanzapine use within a steroid-sparing antiemetic regimen was well tolerated and associated with similar incidence and severity of CINV compared to the control group., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Long-term studies are lacking, and previous observational studies have limitations, such as failure to account for confounding factors and short follow-up durations., Aims: To compare the long-term anthropometric and metabolic side effects of seven SGAs in a Chinese population, using a within-subject approach to reduce the risk of confounding., Method: We collected longitudinal data of SGA prescriptions, concomitant medications, fasting blood glucose (BG), lipid profiles, and BMI in a cohort of 767 patients with SCZ, with follow-up lasting up to 18.7 years (median ∼6.2 years). A total of 192,152 prescription records were retrieved, with 27,723 metabolic measures analysed. Linear mixed models were used to estimate the effects of SGA on BG, lipid profiles and BMI. Besides studying the effects of SGA medications (as binary predictors), we also investigated the effects of SGA dosage on metabolic profiles., Results: Considering SGA medications as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI. A significant increase in BG was observed with clozapine only. Amisulpride, paliperidone and quetiapine were associated with worsened lipid profiles and increased BMI. Conversely, aripiprazole was associated with significant improvement in lipid profiles but a small increase in BMI. When SGA dosage was considered, the model showed consistent results overall. At the minimum effective dose, clozapine was associated with the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole showed the least metabolic side effects, with aripiprazole being significantly associated with lower lipids., Conclusions: This study clarified the long-term and dose-dependent effects of different SGAs on anthropometric and metabolic parameters in Chinese SCZ patients. Our findings may inform clinicians and SCZ patients of SGA choices., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Intranasal (IN) delivery offers potential to deliver antipsychotic drugs with improved efficacy to the brain. However, the solubilization of such drugs and the frequency of required re-application both represent challenges to its practical implementation in treating various mental illnesses including schizophrenia. Herein, we report a sprayable nanoparticle network hydrogel (NNH) consisting of hydrophobically-modified starch nanoparticles (SNPs) and mucoadhesive chitosan oligosaccharide lactate (COL) that can gel in situ within the nasal cavity and release ultra-small penetrative SNPs over time. Hydrophobization of the SNPs enables enhanced uptake and prolonged release of poorly water soluble drugs such as olanzapine from the NNH depot through mucous and ultimately into the brain via the nose-to-brain (N2B) pathway. The hydrogel shows high in vitro cytocompatibility in mouse striatal neuron and human primary nasal cell lines and in vivo efficacy in an amphetamine-induced pre-clinical rat schizophrenia model, with IN-delivered NNH hydrogels maintaining successful attenuation of locomotor activity for up to 4 h while all other tested treatments (drug-only IN or conventional intraperitoneal delivery) failed to attenuate at any time point past 0.5 h. As such, in situ-gelling NNHs represent a safe excipient for the IN delivery of hydrophobic drugs directly to the brain using customized SNPs that exhibit high penetration and drug complexing properties to maximize effective drug delivery., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Todd Hoare reports financial support was provided by The Natural Sciences and Engineering Research Council of Canada (CHRPJ-508393-2017). Todd Hoare reports financial support was provided by Canadian Institutes of Health Research (CPG-151963). Todd Hoare reports financial support was provided by Milken Institute (2021-0825). Todd Hoare has patent In situ gelling polysaccharide-based nanoparticle hydrogel compositions, and methods of use thereof pending to 17323659. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cancer cachexia affects more than half of all cancer patients, reducing survival rates. Evidence-based approaches are urgently needed to optimize treatment., Methods: A systematic review and network meta-analysis were conducted to assess the effectiveness and safety of different pharmacotherapies for cancer cachexia. Three databases (PubMed, Cochrane Library, and Web of Science) were searched for the period from January 1, 2000, to March 20, 2024. The netmeta package in R software was used to calculate the pooled effect, employing a random effects model., Results: Seven placebo-controlled randomized trials involving 1421 patients were analyzed. Pairwise analysis showed that body weight increases were 4.6 kg (95% confidence interval [CI] 0.83-8.37 kg) for olanzapine, 3.82 kg (95% CI 0.73-6.91 kg) for espindolol (20 mg), 2.36 kg (95% CI 1.84-2.89 kg) for anamorelin (100 mg), and 1.31 kg (95% CI 0.42-2.19 kg) for anamorelin (50 mg). In terms of safety profiles, olanzapine demonstrated the lowest odds ratio when compared to placebo, at 0.26 (95% CI 0.07-0.94), followed by anamorelin (50 mg) at 0.86 (95% CI 0.30-2.48), and anamorelin (100 mg) at 0.89 (95% CI 0.42-1.88). However, network meta-analysis could not confirm the superiority of olanzapine over anamorelin in terms of efficacy and safety., Conclusion: Both olanzapine and anamorelin are useful in improving body weight in patients with cancer cachexia. Personalization may be helpful for different patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs., Methods: We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280., Results: We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82-1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09-1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92-2.25])., Conclusion: In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs., Competing Interests: Declaration of competing interest The authors declare that no actual or potential conflicts of interest exist, including any financial, personal, or other relationships with other people or organizations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Study Objective: United States prescribing information recommends against coadministration of injectable olanzapine with injectable benzodiazepines due to a risk of cardiorespiratory depression, whereas European prescribing information recommends the 2 drugs not be administered within 60 minutes of each other. In contrast, a recently published American College of Emergency Physicians clinical policy recommends injectable olanzapine and benzodiazepines be coadministered for treating severe agitation. We sought to compare injectable olanzapine with and without injectable benzodiazepines for evidence of cardiorespiratory depression., Methods: We performed a retrospective study of patients in an urban emergency department from January 2017 through November 2019 who received parenteral olanzapine with or without parenteral benzodiazepines. We included patients receiving 2 total medication doses, either olanzapine+benzodiazepine or 2 doses of olanzapine, coadministered within 60 minutes. The primary outcome was tracheal intubation in the emergency department. Secondary outcomes included hypotension (systolic blood pressure less than 90 mmHg) and hypoxemia (SpO 2 less than 90%)., Results: We identified 693 patients (median [alcohol]=210 mg/dL, median age=37 years [IQR 29 to 49]). In total, 549 received 2 doses of olanzapine, and 144 patients received olanzapine and a benzodiazepine. We found no difference in intubation rates between the olanzapine-only group (21/549, 3.8%) and the olanzapine+benzodiazepine group (5/144, 3.5%; difference=0.3%, 95% confidence interval -3.0% to 3.7%). Rates of hypoxemia (2% olanzapine-only and 3% olanzapine+benzodiazepine) and hypotension (9% both groups) also were not different between groups., Conclusion: We found no difference in cardiorespiratory depression between patients receiving only olanzapine versus olanzapine plus a benzodiazepine., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT 3 ) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy., Patients and Methods: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT 3 RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours). Secondary end points included the proportion of patients free of nausea and safety., Results: In total, 355 patients (78.6% male, median age 72 years, 100% thoracic cancer), including 175 and 180 patients in the olanzapine and placebo groups, respectively, were evaluated. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3% (95% CI, -1.3 to 13.9). The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in the olanzapine group v 75.0% in the placebo group) and delayed (89.7% v 75.6%, respectively) phases were significantly higher in the olanzapine group than in the placebo group (both P < .001). Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in the olanzapine and placebo groups, respectively, and no events were grade ≥3 in severity., Conclusion: The addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.

Olanzapine (OLZ) is an antipsychotic medication used to treat postpartum psychiatric symptoms. It aimed to evaluate the effects of administering OLZ to lactating rats on testicular parameters of adult Wistar rats. Mothers received 2.5, 5 or 10 mg/kg until weaning. Adult male rats showed decrease in body weight, weight of testes, epididymis, prostate, seminal gland and gonadosomatic index when higher doses of OLZ were administered. Testicular volumetric parameters, as well as the length of seminiferous tubules, were also reduced in animals treated with the highest doses of OLZ. The diameter of the seminiferous tubules and the height of the seminiferous epithelium were reduced. There was also a relevant decrease in the population of Sertoli cells and a relevant reduction in the volume of individual Leydig cells. Histopathological analysis of the testes showed lesions compatible with testicular degeneration in rats treated with the highest dose of OLZ. There was a significant reduction in plasma testosterone levels in all treatments. It is noted, therefore, that the adverse impact on the testes of the highest doses of the drug during the neonatal period persisted into adulthood, with the dose of 2.5 mg/kg of OLZ proving to be safer than the others.

Background: Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics., Aims: This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics., Methods: Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups., Results: Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups., Conclusion: Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To develop and validate a population pharmacokinetic (PPK) model of oral olanzapine in pediatric Chinese patients in order to individualize therapy in this population., Methods: A total of 897 serum concentrations from 269 pediatric patients taking oral olanzapine (ages 8-17 years) were collected. Demographic parameters, biological characteristics and concomitant medications were investigated as covariates. The data were analyzed using a nonlinear mixed-effects modeling approach. Bootstrapping (1000 runs), normalized prediction distribution error (NPDE), and external validation of 62 patients were employed. Simulations were performed to explore the individualized dosing regimens in various situations., Results: The one-compartment model with first-order absorption and elimination had an apparent clearance (CL/F) of 10.38 L/h, a distribution volume (V/F) of 9.41 L/kg and an absorption rate constant (K a ) fixed at 0.3 h -1 . The equation was CL∕F (L∕h) = 10.38 × (body weight∕60) 0.25 ×1.33 (if male) × 0.71 (if co-occurrence of infection) × 0.51 (if co-therapy with fluvoxamine) × 1.27 (if co-therapy with sertraline) × 1.43 (if co-therapy with valproate). The final model had satisfactory stability, robustness, and predictive ability. The results from a simulation suggested the oral olanzapine doses required for male and female pediatric patients weighing between 40 and 60 kg without co-medication were 10-15 mg/day and 7.5-10 mg/day, respectively, and dosage adjustments should be based on sex and body weight; and co-administrated with valproate, sertraline, or fluvoxamine., Conclusion: This model may help individualize optimum dosing of oral olanzapine for pediatric patients.

One of the major discoveries in recent research on antipsychotic drugs is that antipsychotic treatment in adolescence could induce robust long-term alterations in antipsychotic sensitivity that persist into adulthood. These long-term impacts are likely influenced by various factors, including the "diseased" state of animals, sex, type of drugs, mode of drug administration, and age of treatment onset. In this study we compared the short- and long-term behavioral effects of 21-day continuous oral olanzapine (7.5 mg/kg/day) or clozapine (30.0 mg/kg/day) administration in heathy or maternal immune activated adolescent (33-53 days old) or adult (80-100 days old) rats of both sexes. We used a conditioned avoidance response model to assess the drug-induced alterations in antipsychotic sensitivity. Here, we report that while under the chronic drug treatment period, olanzapine progressively increased its suppression of avoidance responding over time, especially when treatment was initiated in adulthood. Clozapine's suppression depended on the age of drug exposure, with treatment initiated in adulthood showing a suppression while that initiated in adolescent did not. After a 17-day drug-free interval, in a drug challenge test, olanzapine treatment initiated in adolescence caused a decrease in drug sensitivity, as reflected by less avoidance suppression (a tolerance effect); whereas that initiated in adulthood appeared to cause an increase (more avoidance suppression, a sensitization effect). Clozapine treatments initiated in both adolescence and adulthood caused a similar tolerance effect. Our findings indicate that the same chronic antipsychotic treatment regimen initiated in adolescence or adulthood can have differential short- and long-term impacts on drug sensitivity., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to assess the clinical efficacy of a 5 mg dosage of olanzapine in preventing chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC) among female patients diagnosed with gastrointestinal tract tumors., Methods: Patients undergoing the oxaliplatin/irinotecan chemotherapy regimen were enrolled in this prospective controlled study. The olanzapine group received a 5 mg dosage of olanzapine along with palonosetron and dexamethasone, while the control group received a standard two-combination regimen consisting of dexamethasone and palonosetron. The primary endpoints included the total protection (TP) rates for the entire age group and the subgroup aged 60 years and above. Secondary endpoints encompassed the total protection rates during the acute and delayed phases within the two age brackets, as well as the total control (TC) rates and complete remission (CR) rates across all three phases (total, acute, and delayed). Additionally, the study involved the assessment of quality of life and the collection of adverse events associated with the interventions., Results: 1) Regarding the primary endpoint, the total phase TP rates within both the entire age group and the age group exceeding 60 years demonstrated superiority in the olanzapine group when compared to the control group (66.7% vs 37.25%, P = 0.003; 68.8% vs 44.4%, P = 0.044). 2) In terms of secondary endpoints, the olanzapine group exhibited superior acute phase TP rates in both age brackets when compared to the control group (P < 0.05). The olanzapine group also demonstrated higher delayed-phase TP rates, TC rates across all three phases, and CR rates within the two age brackets, although the differences were not statistically significant (P > 0.05). Furthermore, the quality of life in the olanzapine group surpassed that of the control group for both age brackets (P < 0.05), characterized by enhanced appetite and a higher incidence of drowsiness in the patients treated with olanzapine when compared to those in the control group (P < 0.05)., Conclusion: Olanzapine can enhance CINV induced by MEC regimen in female patients across all age groups, including the elderly, and therefore improve the quality of life for these patients., Clinical Trial Registration: https://www.chictr.org.cn/index.html , identifier: ChiCTR20000368269, 25/08/2020., (© 2024. The Author(s).)

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D 2 ), histamine 1 (H 1 ), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D 2 , H 1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D 2 , H 1 , and mACh receptor occupancy is possible using LC-MS/MS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with schizophrenia often face challenges related to cognitive function, affecting their daily functioning and overall quality of life. The choice of antipsychotic treatment may play a crucial role in determining cognitive outcomes., Study Question: Our study aimed to investigate whether there was a difference in cognitive ability between the patients with schizophrenia receiving oral antipsychotics (OAP) versus long-acting injectable antipsychotics (LAI-APs)., Study Design: We conducted a cross-sectional study using analytical methods between January 1, 2020, and January 1, 2022. Participants were divided into 2 groups: patients undergoing treatment with OAP and patients undergoing treatment with LAI-AP. All participants underwent version A of Brief Assessment of Cognition in Schizophrenia (BACS)., Measures and Outcomes: The primary objective was to compare cognitive function in patients with schizophrenia treated with LAI antipsychotics versus OAP using BACS. Primary outcome measures include overall BACS score, with secondary measures focusing on specific cognitive domains. This study contributes to the understanding of the cognitive effects of different antipsychotic formulations in schizophrenia treatment., Results: Although there was a slightly higher intelligence quotient in the LAI-AP group (102.2 vs. 101.32, P = 0.5401), it was not statistically significant. Olanzapine was the most commonly prescribed antipsychotic, with 48% of patients in the LAI-AP group and 40% in the OAP group. The LAI-AP group outperformed in all BACS evaluations. The most notable difference was in the token motor task (57.78 ± 17.03 vs. 50.04 ± 18.82, P = 0.0335), while the Tower of London test showed the smallest difference (17.26 ± 2.61 vs. 15.48 ± 3.47, P = 0.0046). Regression analysis revealed no significant variance in intelligence quotient scores; however, a significant discrepancy in BACS scores was evident, favoring the LAI treatment for better cognitive outcomes., Conclusions: The use of long-acting antipsychotic treatment in individuals with schizophrenia offers promising advantages in preserving cognitive function., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To describe haematological adverse effects in adolescents with anorexia nervosa who are taking olanzapine., Methods: Case series report., Case Report: The reported cases (two female patients and one male) were found to have blood test abnormalities after starting olanzapine and to rapidly recover their platelet and neutrophil values after the drug was discontinued. Low haemoglobin values persisted longer than observed in other series. These abnormalities became more noticeable when the dose of olanzapine was increased to 5 mg/day (initial dose 2.5 mg/day). It should be noted that two of the patients already had values indicative of mild neutropenia before they started the antipsychotic drug, and that these worsened as they continued taking the drug. In one of the patients there was only a decrease in neutrophil values, as well as mild anaemia., Conclusions: This first case series of haematological abnormalities in adolescents with anorexia nervosa who are taking olanzapine found values corresponding to pancytopenia in two of the three cases reported. It would be worthwhile to consider heightening haematological surveillance in this population when starting treatment with olanzapine and rethinking our knowledge regarding the frequency of these side effects., (Copyright © 2021 Asociación Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Evidence for the efficacy of a low dose of olanzapine (OLA) in combination with antidepressants has been limited and without positive trials in first-episode (FE) patients with schizophrenia (SCH). This study aimed to compare the efficacy in treating negative and depressive symptoms between those FE patients with SCH treated with a combination of OLA plus sertraline and those treated with OLA monotherapy., Methods: One hundred and ninety-six first-episode and drug naïve patients with SCH were randomized to receive low-dose OLA (7.5-10 mg/day) combined with sertraline (50-100 mg/day) (OS group) or normal-dose OLA monotherapy (12.5-20 mg/day) (NO group). Clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS), and the depressive symptoms were evaluated by the Hamilton Depression Scale (HAMD). Psychosocial functioning was assessed by the Personal and Social Performance Scale (PSP)., Results: In the intent-to-treat efficacy analysis, the OS group had greater decreases in negative and depressive symptoms (pall < 0.01) and a greater increase in PSP total score compared with the NO group (p < 0.01). Moreover, reductions in HAMD total score and PANSS negative subscore and sex were associated with the improvements in psychosocial functioning from baseline to week 24, after controlling for baseline psychosocial function, age, and onset age., Conclusion: This study demonstrates that low-dose OLA in combination with sertraline had clinically meaningful improvements not only in the negative and depressive symptoms but also in psychosocial functioning in patients with FE-SCH, while not affecting positive symptoms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Clinical observations of cancer patients treated with selinexor have reported high incidence of nausea and anorexia. The study objective was to investigate the adoption of prophylactic olanzapine for the prevention of nausea, vomiting and anorexia in cancer patients receiving selinexor and standard chemotherapy., Methods: We retrospectively reviewed supportive care interventions in patients receiving selinexor and recorded frequency of adverse events (NCI-CTAE). Association between categorical variables were analyzed using Fisher's exact tests; repeated measures analysis was performed to assess weight changes over time., Results: Of 124 evaluable patients, 83 (66.9%) were female, 93 were white (75.0%), and the most common cancer was ovarian (N = 30, 24.2%). One hundred and four patients (83.9%) received olanzapine, of which 93 (89.4%) were prophylactically treated, the majority (86.5%) receiving low 2.5 mg daily dose. Other anti-emetics included ondansetron in 90 patients (72.6%), dexamethasone prescribed in 50 patients (40.3%) and metoclopramide in 49 patients (39.5%), while aprepitant/fosaprepitant (N = 2, 1.6%) were prescribed infrequently. Cancer patients receiving prophylactic olanzapine (N = 93) compared to patients who never received olanzapine (N = 20) had more Grade 1 + anorexia (31.2% vs 20.0%), less nausea (53.8% vs 70.0%), less vomiting (33.3% vs 40.0%), and increased hyperglycemia (29.0% vs 10.0%), but differences were non-statistically significant. In addition, there was minimal weight loss over time in both groups and no statistically significant differences in weight loss between groups., Conclusion: Prophylactic olanzapine decreased nausea, vomiting and maintained weight over 3 months but did not prevent anorexia in patients receiving selinexor and chemotherapy. Low dose olanzapine was well tolerated but associated with hyperglycemia., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Clinical and preclinical studies have shown dysfunctions in genetic expression and neurotransmission of γ-Aminobutyric acid (GABA), GABA A receptor subunits, and GABA-synthesizing enzymes GAD 67 and GAD 65 in schizophrenia. It is well documented that there is significant weight gain after chronic neuroleptic treatment in humans. While there are limited studies on the effects of diet on GABA signaling directly, a change in diet has been used clinically as an adjunct to treatment for schizophrenic relief. In this study, rats chronically consumed either a chow diet (CD) or a 60% high-fat diet (HFD) and drank from bottles that contained one of the following solutions: water, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg) for four weeks. Rats were then euthanized and their brains were processed for GABA A in-vitro receptor autoradiography using [ 3 H] flunitrazepam. A chronic HFD treatment yielded significantly increased [ 3 H] flunitrazepam binding in the rat cerebellum independent of neuroleptic treatment. The desynchronization between the prefrontal cortex and the cerebellum is associated with major cognitive and motor dysfunctions commonly found in schizophrenic symptomatology, such as slowed reaction time, motor dyscoordination, and prefrontal activations related to speech fluency and cognitive alertness. These data support the notion that there is a dietary effect on GABA signaling within the cerebellum, as well as the importance of considering nutritional intervention methods as an adjunct treatment for patients chronically treated with neuroleptics. Finally, we indicate that future studies involving the analysis of individual patient's genetic profiles will further assist towards a precision medicine approach to the treatment of schizophrenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common., Methods: We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications., Results: Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher., Conclusions: The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Olanzapine, an FDA-approved atypical antipsychotic, is widely used to treat schizophrenia and bipolar disorder. In this study, the inhibitory effect of olanzapine on voltage-dependent K + (Kv) channels in rabbit coronary arterial smooth muscle cells was investigated., Methods: Electrophysiological recordings were performed in freshly isolated coronary arterial smooth muscle cells., Results: Olanzapine inhibited the Kv channels in a concentration-dependent manner with an IC 50 value of 7.76 ± 1.80 µM and a Hill coefficient of 0.82 ± 0.09. Although olanzapine did not change the steady-state activation curve, it shifted the inactivation curve to a more negative potential, suggesting that it inhibited Kv currents by affecting the voltage sensor of the Kv channel. Application of 1 or 2 Hz train pulses did not affect the olanzapine-induced inhibition of Kv channels, suggesting that its effect on Kv channels occurs in a use (state)-independent manner. Pretreatment with DPO-1 (Kv1.5 subtype inhibitor) reduced the olanzapine-induced inhibition of Kv currents. In addition, pretreatment with guangxitoxin (Kv2.1 subtype inhibitor) and linopirdine (Kv7 subtype inhibitor) partially decreased the degree of Kv current inhibition. Olanzapine induced membrane depolarization., Conclusion: From these results, we suggest that olanzapine inhibits the Kv channels in a concentration-dependent, but state-independent, manner by affecting the gating properties of Kv channels. The primary Kv channel target of olanzapine is the Kv1.5 subtype., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

Valproic acid is an anticonvulsant, which is also widely used for treating psychiatric disorders. Some clinical trials have demonstrated benefits of valproic acid augmentation therapy in schizophrenia. Interindividual variability in valproic acid dose and serum concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between serum concentrations of valproic acid and single nucleotide polymorphisms of the cytochrome P450 (CYP) 2C19 gene in patients with schizophrenia. All patients had been receiving fixed dose of valproic acid for at least 2 weeks. The daily doses were 0.5-1.5 g. No other drugs except olanzapine were coadministered. Serum concentrations of valproic acid were measured using the ultra-high performance liquid chromatography method with mass-spectrometric detection. The CYP2C19 (CYP2C19*2 G681A rs4244285 and CYP2C19*3 G636A rs4986893) genotypes were identified by real-time PCR analyses. The mean concentration/dose ratios of valproic acid were significantly higher in patients with CYP2C19 *1/*2 genotype (P < 0.01) or CYP2C19 *2/*3 genotype (P < 0.01) than in those with CYP2C12 *1/*1 genotype. The mean concentration/dose ratios of valproic acid were significantly higher in patients with 1 (P < 0.01) or 2 (P < 0.01) mutated alleles for CYP2C19 than in those without mutated alleles. And the post hoc analysis revealed that the result has acceptable statistical (power (1 - β) = 0.8486 at type I  level of 0.05) to support the observed significant associations for CYP2C19 SNPs and serum C/D ratios of valproic acid. The findings of this study suggest that the genetic polymorphisms of CYP2C19 significantly affect the steady-state serum concentrations of valproic acid in Chinese Han population. The determination of the CYP2C19 genotypes may be useful for dosing adjustment in schizophrenia patients on valproic acid therapy., (© 2021. The Author(s).)

Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) and Mdr1a/b gene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (C max , 44.1 ± 5.1 ng/mL in the combination group vs 9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC 0-t , 235.8 ± 22.7 h × ng/mL in the combination group vs 47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination group vs 49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased the in vivo exposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cells in vitro as well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The selective activation of the muscarinic M 1 receptor (M 1 R) may be a promising approach for treating cognitive impairment associated with cholinergic dysfunction. We previously reported that low cooperativity (α-value) is associated with a favorable cholinergic side effect profile of M 1 R positive allosteric modulators (M 1 PAMs), as well as being a crucial factor for the cognitive improvement observed after combining M 1 PAMs with donepezil, in rodents. In this study, we preclinically characterized TAK-071, a novel M 1 PAM with low cooperativity (α-value = 199), as a new therapy for schizophrenia. We tested TAK-071 in the offspring of polyriboinosinic-polyribocytidylic acid-treated dams, which is a maternal immune activation model of schizophrenia. TAK-071 improved sociability deficits and working memory in this model. In a genetic mouse model of schizophrenia, miR-137 transgenic (Tg) mice, TAK-071 improved deficits in working memory, recognition memory, sociability, and sensorimotor gating. Patients with schizophrenia usually take several antipsychotics to treat positive symptoms. Thus, we also investigated the combined effects of TAK-071 with currently prescribed antipsychotics. Among the 10 antipsychotics tested, only olanzapine and quetiapine showed M 1 R antagonistic effects, which were counteracted by TAK-071 at possible effective concentrations for cognitive improvement in vitro. Moreover, haloperidol did not affect the ability of TAK-071 to improve working memory in miR-137 Tg mice, suggesting a low risk of losing efficacy when combined with dopamine D 2 receptor antagonists. In conclusion, TAK-071 can exert beneficial effects on social behavior and cognitive function and could be a new therapy for schizophrenia., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Somnambulism, or sleepwalking (SW), is one of the most common forms of arousal parasomnias. It is characterized by different complex motor behaviors leading to unwanted movements in bed or walking during sleep. It can be the consequence of psychological stress, abnormal breathing during sleep, high fever, or drug adverse effects. There is evidence of an association between antipsychotic treatment, including olanzapine, and SW., Methods: We present the case of a patient experiencing treatment-resistant anorexia nervosa whose somnambulism re-exacerbated after the addition of a low dose of olanzapine, following the CARE (CAse REport) Statement and Checklist. We also conducted a systematic review of the literature on olanzapine-induced somnambulism following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, PsychINFO, and the Cochrane Library databases were independently reviewed up to January 2021 for articles reporting olanzapine-related somnambulism cases, without language or time restriction., Results: We describe a case of somnambulism in a patient initially admitted to our hospital for anorexia nervosa and treated with a low dose of olanzapine. This is the first case of SW induced by olanzapine in eating disorders to be reported. Up-to-date olanzapine-related somnambulism was described in 8 patients experiencing psychiatric disorders (ie, schizophrenia and bipolar disorder)., Conclusions: To provide a reliable estimate of incidence and prevalence for olanzapine-related somnambulism, large-scale, pharmacovigilance studies are required, to allow for comparisons of overall clinical characteristics, outcomes, including time to recovery, between different treatment options. Clinician awareness should be enhanced, and attention should be given to such infrequent adverse effects associated with antipsychotics., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Antipsychotic medications, including olanzapine, are associated with substantial weight gain and metabolic disturbances. We sought to determine whether coadministration of miricorilant, a selective glucocorticoid receptor modulator, with olanzapine can ameliorate these effects., Methods: Sixty-six healthy men were enrolled in a 2-week, randomized, double-blind, placebo-controlled trial. The primary objective was to evaluate changes in body weight after 14 days coadministration of olanzapine (10 mg) + miricorilant (600 mg) compared with olanzapine (10 mg) + placebo. Secondary objectives included evaluating (a) the safety and tolerability of the combination; (b) the effects of the combination on glucose, insulin, insulin resistance, and triglycerides; and (c) the impact of the combination on hepatic enzymes., Results: Subjects administered olanzapine + miricorilant gained less weight than subjects administered olanzapine + placebo (mean weight gain on day 15, 3.91 kg vs 4.98 kg; difference between groups, -1.07 kg; 95% confidence interval, -1.94 to -0.19; P = 0.017]). Compared with the placebo group, coadministration of miricorilant with olanzapine was associated with smaller increases in insulin (difference, -3.74 mIU/L; P = 0.007), homeostatic model assessment of insulin resistance (difference, -0.47; P = 0.007), triglycerides (difference, -0.29 mmol/L; P = 0.057), aspartate aminotransferase (difference, -32.24 IU/L; P = 0.009), and alanine aminotransferase (difference, -49.99 IU/L; P = 0.030)., Conclusions: Miricorilant may provide a promising option for ameliorating the detrimental effects of olanzapine, and investigation of this medication in patients affected by antipsychotic-induced weight gain is warranted. Two phase 2 studies of miricorilant in patients with recent and long-standing antipsychotic-induced weight gain are currently in progress., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

A combination of olanzapine and samidorphan was recently approved by the US Food and Drug Administration for the treatment of patients with schizophrenia or bipolar I disorder. Population pharmacokinetic models for olanzapine and samidorphan were developed using data from 11 clinical studies in healthy subjects or patients with schizophrenia. A 2-compartment disposition model with first-order absorption and elimination and a lag time for absorption adequately described concentration-time profiles of both olanzapine and samidorphan. Age, sex, race, smoking status, and body weight were identified as covariates that impacted the pharmacokinetics of olanzapine. A moderate effect of body weight on samidorphan pharmacokinetics was identified by the model but was not considered clinically meaningful. The effects of food, hepatic or renal impairment, and coadministration with rifampin on the pharmacokinetics of olanzapine and samidorphan, as estimated by the population pharmacokinetic analysis, were consistent with findings from dedicated clinical studies designed to evaluate these specific covariates of interest. Food intake did not have a clinically relevant effect on the pharmacokinetics of olanzapine or samidorphan. Consistent with the known metabolic pathways for olanzapine (primarily via uridine 5'-diphospho-glucuronosyltransferase-mediated direct glucuronidation and cytochrome P450 [CYP]-mediated oxidation) and for samidorphan (predominantly mediated by CYP3A4), coadministration of olanzapine and samidorphan with rifampin, a strong inducer of CYP3A4 and an inducer of uridine 5'-diphospho-glucuronosyltransferase enzymes, significantly decreased the systemic exposure of both olanzapine and samidorphan. Severe renal impairment or moderate hepatic impairment resulted in a modest increase in olanzapine and samidorphan exposure., (© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Weight gain due to antipsychotics is a challenging clinical problem because, to date, no effective pharmacological strategies have been found. Bupropion is often used in people with schizophrenia for smoking cessation and is well tolerated. However, studies on its use as weight loss treatment are scarce. The aim of the study was to examine the effectiveness of bupropion as a single weight loss treatment in overweight individuals maintained on long-term olanzapine or risperidone., Methods: This randomized, double-blind, placebo-controlled, 8-week study included 26 overweight (body mass index ≥27 kg/m2) individuals with schizophrenia maintained on olanzapine (10-20 mg/d) or risperidone (2-4 mg/d). Participants were randomly allocated to a study group that received bupropion (150-300 mg/d) or to a placebo group. The positive and Negative Syndrome Scale and the Clinical Global Impression-Severity Scale were used to assess severity of psychosis at baseline and end of study (8 weeks)., Results: Bupropion addition, but not placebo, was associated with a significant reduction in body weight. Severity of psychotic symptoms was not altered in either group., Conclusions: The results demonstrate the efficacy of bupropion, compared with placebo, in patients maintained on chronic treatment with olanzapine or risperidone, both known to be major contributors to significant weight gain., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose/background: Although high-dose olanzapine might be a treatment option in patients with treatment-resistant schizophrenia, it can be reduced to the standard dose after symptoms are stabilized. We examined the rate of olanzapine reduction from high to standard dose and whether this change was successful., Methods/procedures: We included patients who received high-dose olanzapine (>20 mg/d) for 4 weeks or longer at our hospital. First, we retrospectively followed the patients for 6 years and estimated the percentage of those whose olanzapine was reduced from high to standard dose. Second, we followed patients who received olanzapine reduction for 1 year and estimated the rate of success based on the study-defined criteria for unsuccessful reduction. We also explored factors associated with the dose reduction and successful results., Findings/results: Among 110 patients who received high-dose olanzapine treatment, 72 had their olanzapine dose reduced to the standard dose for 6 years; the duration of high-dose olanzapine treatment was significantly and negatively associated with a reduction in olanzapine (hazard ratio, 0.98; 95% confidence interval, 0.98-0.99). Among the patients whose olanzapine was reduced, 50 achieved successful reduction for 1 year. Among the reasons for the reduction, an unknown reason was significantly associated with successful reduction (hazard ratio, 4.93; 95% confidence interval, 1.55-22.8)., Implications/conclusions: The findings suggest that high-dose olanzapine can be reduced to the standard dose after stabilization of symptoms in most patients with schizophrenia., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A combination of olanzapine and samidorphan (OLZ/SAM) was recently approved by the US Food and Drug Administration for treatment of patients with schizophrenia or bipolar I disorder. The effects of moderate hepatic impairment on the pharmacokinetics (PKs) of olanzapine and samidorphan after a single dose of OLZ/SAM were characterized in a clinical study. Physiologically-based pharmacokinetic (PBPK) modeling was used to extend the clinical findings to predict the effects of varying degrees of hepatic impairment on the PKs of olanzapine and samidorphan. A previously developed PBPK model for OLZ/SAM was refined to recover the observed pharmacokinetic differences between individuals with moderate hepatic impairment and healthy controls. The optimized model was applied to predict changes in olanzapine and samidorphan PKs after multiple once-daily doses of OLZ/SAM in subjects with mild, moderate, and severe hepatic impairment relative to healthy controls. Modifications to model parameters, including absorption rate constant and fraction unbound to plasma protein, were made to recover the observed change in the PKs of olanzapine and samidorphan in individuals with moderate hepatic impairment. In applying the optimized model, mild, moderate, and severe hepatic impairment were predicted to increase steady-state total systemic exposures by 1.1-, 1.5-, and 1.6-fold, respectively, for olanzapine, and by 1.2-, 1.9-, and 2.3-fold, respectively, for samidorphan. PBPK modeling allowed for prediction of untested clinical scenarios of varying degrees of hepatic impairment in lieu of additional clinical studies., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Schizophrenia is characterized by a high disease burden. Olanzapine is a common drug used in antipsychotic medication. Little is known about the population pharmacokinetics of olanzapine in elderly patients. Missed doses are a common and unavoidable issue during the treatment of psychiatric diseases, especially in elderly patients. This study aimed to identify what an elderly person should do if doses are inadvertently missed., Methods: Data were collected from 140 elderly psychiatric patients (aged ≥65 years) who received olanzapine therapy. Olanzapine concentrations were determined by high pressure liquid chromatographic tandem mass spectrometry (HPLC-MS/MS) and a population-based approach was used to quantify the characteristics of elderly patients. A non-linear mixed-effects model was used for data analysis. Simulations based on the final model were applied to predict situations involving a single missed dose or three consecutive missed doses under several remedial regimens., Results: A total of 474 samples from 140 elderly patients were included in the therapeutic drug monitoring (TDM) data analysis. A one-compartment model, with no significant covariates, was developed to describe the population pharmacokinetics of olanzapine in elderly patients. The population predicted systematic clearance (CL/F) and volumes of distribution (V/F) were 18 L/h and 785 L, respectively. The simulation demonstrated that in a missed dose situation, elderly patients should take the regular dose immediately; the refill dose used at the second remedial time point depends on the length of the time delay., Conclusion: Here, we used a simulation to provide a remedial regimen for missed doses of olanzapine in the elderly population. Our simulation can provide valuable suggestions for individualized therapy in elderly patients., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Xiao et al.)

Study Objective: Intramuscular medications are commonly used to treat agitation in the emergency department (ED). The purpose of this study is to compare intramuscular droperidol and olanzapine for treating agitation., Methods: This was a prospective observational study of ED patients receiving intramuscular droperidol or olanzapine for acute agitation. The treating physician determined the medication and dose; however, over time drug shortages made either olanzapine (July to September 2019) or droperidol (November 2019 to March 2020) unavailable, creating a natural experiment. The primary outcome was time to adequate sedation, assessed by the Altered Mental Status Scale (AMSS), defined as time to AMSS score less than or equal to 0., Results: We analyzed 1,257 patients (median age 42 years; 73% men); 538 received droperidol (median dose 5 mg) and 719 received olanzapine (median dose 10 mg). The majority of patients (1,086; 86%) had agitation owing to alcohol intoxication. Time to adequate sedation was 16 minutes (interquartile range 10 to 30 minutes) for droperidol and 17.5 minutes (interquartile range 10 to 30 minutes) for olanzapine (absolute difference -0.7 minutes; 95% confidence interval -2.1 to 0.5 minutes). Adjusted Cox proportional hazard model analysis revealed no difference between groups in time to sedation (hazard ratio for adequate sedation for droperidol compared with olanzapine 1.12; 95% confidence interval 1.00 to 1.25). Patients receiving olanzapine were more likely to receive additional medications for sedation (droperidol 17%; olanzapine 24%; absolute difference -8% [95% confidence interval -12% to -3%]). We observed no difference between drugs regarding adverse effects except for extrapyramidal adverse effects, which were more common with droperidol (n=6; 1%) than olanzapine (n=1; 0.1%)., Conclusion: We found no difference in time to adequate sedation between intramuscular droperidol and olanzapine., (Copyright © 2021 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

This study examined the effects of chronic treatment of the antipsychotic drugs, haloperidol and olanzapine, on microglial activation in the brain. In addition, we explored the interaction of these antipsychotic drugs with normal and high-fat diet. In order to measure activated microglial expression, we used [ 3 H] PK11195 in vitro autoradiography. Male Sprague Dawley rats were given a diet of either regular chow diet or a high-fat diet, and assigned either water, haloperidol drinking solution (1.5 mg/kg), or olanzapine drinking solution (10 mg/kg) for four weeks. Following treatment, rats were euthanized and brains extracted for [ 3 H] PK11195 autoradiography. Rats on 4 weeks of a high-fat diet showed increased [ 3 H] PK11195 binding compared to rats on a normal diet in the temporal association cortex (19 %), ectorhinal cortex (17 %), entorhinal cortex (18 %), and perirhinal cortex (18 %), irrespective of drug treatment. These are regions associated with memory, sensory, and visual processing. Rats treated with either haloperidol or olanzapine showed no differences in [ 3 H] PK11195 binding compared to the control group. However, there were differences between the 2 different antipsychotic medications themselves. Haloperidol increased [ 3 H] PK11195 binding in the amygdala (23 %), ectorhinal cortex (24 %), and perihinal cortex (29 %), compared to olanzapine. These results corroborate a known role of a high-fat diet and central inflammatory changes but suggest no role of these antipsychotic drugs in promoting neuroinflammation across 4 weeks compared to normal control rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Most studies investigating antipsychotic effectiveness report either total psychopathology or symptom cluster findings. Studies focusing on a separate symptom, such as hallucinations, a hallmark symptom in schizophrenia, are scarce.Therefore, the current study aims to compare the antihallucinatory effectiveness of 3 pharmacologically different antipsychotics: olanzapine, amisulpride, and aripiprazole., Methods: The present study is part of the Bergen-Stavanger-Innsbruck-Trondheim study, a 12-month prospective, randomized, pragmatic antipsychotic drug trial in active-phase schizophrenia spectrum disorders. The primary outcome of the present study was change of hallucinations as measured by item P3 (hallucinatory behavior) from the Positive and Negative Syndrome Scale in the subgroup with hallucinations at baseline. Primary analyses were intention to treat., Results: A total of 144 participants were included in the study, where 105 (72%) had a score of 3 or more on the Positive and Negative Syndrome Scale P3 item at baseline, indicating the presence of hallucinations (HALL subgroup).In the HALL subgroup, a significantly less reduction of hallucinations was revealed for participants using olanzapine in weeks 12, 26, 39, and 52 when compared with amisulpride and in weeks 26 and 52 when compared with aripiprazole. In subanalyses for participants never exposed to antipsychotic drugs (antipsychotic-naive) and those who had used antipsychotics before entering the study, antihallucinatory differences were revealed only in the latter group., Conclusions: A differential antihallucinatory effect of the 3 study drugs was present. The inferior effect of olanzapine seems to be driven by the subgroup of participants exposed to antipsychotic treatment before entering the study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aims: Comparison of efficacy, safety and sedation between two doses of olanzapine in the control of chemotherapy-induced nausea and vomiting (CINV). Patients & methods: A prospective, randomized, double-blind, controlled study was conducted, enrolling 68 patients receiving a single-day cycle of high and moderately emetogenic chemotherapy. Patients received either of olanzapine 5 mg or 10 mg from day 1 through 3 in addition to ondansetron and dexamethasone. Control of CINV, nausea, sedation, quality of life (QoL) and adverse events were compared. Results: Nausea, emesis control and improvement of QoL were similar in both groups. Sedation severity was 133% higher with 10 mg olanzapine. Conclusions: Lower dose olanzapine is effective to control CINV with significantly reduced sedation.

Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 μm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3'-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses., Methods: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation)., Results: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone)., Conclusions: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Purpose: This study aimed to investigate the combined effects of dose, age, sex, body weight, and smoking on plasma concentrations of olanzapine (OLA) and N-desmethyl olanzapine (DMO) in Chinese inpatients with schizophrenia., Methods: A retrospective study including 185 inpatients was conducted. The steady-state plasma concentrations of OLA (COLA) and DMO (CDMO) were measured using high-performance liquid chromatography-tandem mass spectrometry. The combined effects of dose, age, sex, body weight, and smoking on COLA and CDMO were evaluated., Findings: Multiple linear regression analyses revealed that dose, age, body weight, and smoking had significant effects on COLA and CDMO in inpatients with schizophrenia treated with OLA. The dose was the most important determinant of COLA and CDMO and was positively correlated with both. Furthermore, smokers exhibited a significantly lower COLA and COLA + DMO, whereas higher body weight led to the reduction of COLA, CDMO, and COLA + DMO. Advanced age was associated with lower CDMO., Implications: These results suggest that dose, age, body weight, and smoking have a significant influence on the plasma concentration of OLA and its metabolite DMO. Clinicians should consider the combined effects when prescribing OLA to patients with schizophrenia., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting., Methods: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate., Results: Typical estimates for the absorption rate constant (K a ), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h -1 , 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise., Conclusion: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study compared weight and cardiometabolic changes after short-term treatment of olanzapine/samidorphan and olanzapine. Eligible criteria for an included trial were ≤ 24 weeks, randomized controlled trials (RCTs) that compared olanzapine/samidorphan and olanzapine treatments in patients/healthy volunteers and reported weight or cardiometabolic outcomes. Three databases were searched on October 31, 2020. Primary outcomes included weight changes and all-cause dropout rates. Standardized mean differences (SMDs) and risk ratios (RRs) were computed and pooled using a random-effect model. This meta-analysis included four RCTs (n = 1195). The heterogeneous data revealed that weight changes were not significantly different between olanzapine/samidorphan and olanzapine groups (4 RCTs, SDM = - 0.19, 95% CI - 0.45 to 0.07, I 2  = 75%). The whole-sample, pooled RR of all-cause dropout rates (4 RCTs, RR = 1.02, 95% CI 0.84 to 1.23, I 2  = 0%) was not significant different between olanzapine/samidorphan and olanzapine groups. A lower percentage of males and a lower initial body mass index were associated with the greater effect of samidorphan in preventing olanzapine-induced weight gain. Current evidence is insufficient to support the use of samidorphan to prevent olanzapine-induced weight gain and olanzapine-induced cardiometabolic abnormalities. Samidorphan is well accepted by olanzapine-treated patients.

Background: The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics., Methods: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone., Findings: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone., Interpretation: Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted., Funding: This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891)., Competing Interests: Declaration of Competing Interest BTG has spoken at events sponsored by AbbVie. CS receives funding from 4D Pharma, Dupont and Nutricia. GC has spoken at events sponsored by Janssen Ireland and Probi, and receives funding from Pharmavite. JFC has spoken at events sponsored by Janssen Ireland, Neuropharmex, Mead Johnson, Friesland Campina, has been a consultant for Nestle & Alkermes and receives funding from Mead Johnson, Cremo, 4D Pharma, Dupont, GSK, Suntory Wellness, Pharmavite, and Nutricia. NPH has spoken at events sponsored by Johnson & Johnson and Coloplast. TGD has spoken at events sponsored by Servier, Lundbeck, Janssen, AstraZeneca and receives funding from Mead Johnson, Cremo, 4D Pharma, Dupont, GSK, Suntory Wellness, Pharmavite, and Nutricia., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Olanzapine can decrease anxiety and impair memory, but there is limited information about length of treatment or sex differences in its effectiveness. Therefore, effects of 21-24 and 41-45 days of treatment and sex differences on anxiety-related behaviour and spatial memory were assessed in PVG/c (PVG/c is the internationally recognised way of referring to this rat strain) male and female rats. From 70 days after birth (PND70), all rats received no drug or 6, 11 or 15 mg/kg/day olanzapine via drinking water. From PND91, they were given four daily tests in an open field, light-dark box, zero maze and Y maze, and then again 21 days later from PND112. At PND91-94, all olanzapine doses decreased open-field ambulation and walking, and 6 and 15 mg/kg/day decreased rearing, increased immobility while 15 mg/kg/day decreased shuttles in the light/dark box (all suggesting higher anxiety). At PND112-115, 11 mg/kg/day increased open-field ambulation, walking, rearing, centre occupancy and light/dark-box shuttles and light-side entries while decreasing open-field immobility and corner occupancy (all suggesting lower anxiety). There were also several results in the open field and light/dark box suggesting olanzapine decreased anxiety for males but increased it for females. A significant olanzapine-related preference for the novel Y-maze arm either improved spatial memory, or decreased anxiety. Olanzapine thus appeared anxiogenic after 21 days' treatment, becoming anxiolytic after 42 days. This could depend on the sex of the rats (females more responsive to lower doses), and the dose (11 mg/kg/day being most effective). Therefore, while olanzapine was generally anxiolytic, it also had some treatment length- and sex-related anxiogenic effects., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Antipsychotic (AP) medications are associated with an increased risk for developing metabolic side effects including weight gain, dyslipidemia, hypertension, type 2 diabetes (T2D), and cardiovascular disease. Previous reviews have focused on the chronic metabolic side effects associated with AP use. However, an underappreciated aspect of APs are the rapid perturbations in glucose and lipid metabolism that occur with each dose of drug. The purpose of this narrative review is to summarize work examining the peripheral mechanisms of acute olanzapine-induced related metabolic disturbances. We also discuss recent studies that have attempted to elucidate treatment approaches to mitigate AP-induced impairments in fuel metabolism., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Olanzapine has exhibited efficacy as an antiemetic agent when used with 5-HT 3 receptor antagonists, dexamethasone, and NK 1 receptor antagonists for patients receiving highly emetogenic chemotherapy. In addition, several studies have reported the efficacy or safety of olanzapine in patients receiving moderately emetogenic chemotherapy, including carboplatin, irinotecan, and oxaliplatin. However, no reports of olanzapine use have focused on patients receiving oxaliplatin-based chemotherapy. Therefore, we analyzed the safety of antiemetic therapy using olanzapine, palonosetron, aprepitant, and dexamethasone in colorectal cancer patients undergoing oxaliplatin-based chemotherapy. This study was a prospective phase II single-institution study of 40 patients (median age 60 years, 23 patients were male). The primary endpoint was the incidence of adverse events, and the exploratory endpoints were the rate of chemotherapy-induced nausea and vomiting. Almost all patients (90%) had a performance status of 0. All patients received the scheduled antiemetic therapy. The most common adverse event was somnolence (n = 7 patients, 17.5%). All adverse events were grade 1. Thirty-six patients were included in the exploratory analysis of efficacy. No patients experienced vomiting during the first 120 h after chemotherapy, and complete response and complete control were both 86.1%. The rate of total control was 55.6% during the same time period. Olanzapine use with 5-HT 3 receptor antagonists, dexamethasone, and NK 1 receptor antagonists was safe for colorectal cancer patients receiving oxaliplatin-based chemotherapy.