A randomized, double-blind, placebo-controlled phase II study of olanzapine based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B).

BACKGROUND: Nausea and vomiting are common adverse events associated with trastuzumab deruxtecan (T-DXd). We evaluated the efficacy of an olanzapine-based triplet regimen for preventing nausea and vomiting in patients receiving first cycle T-DXd. PATIENTS AND METHODS: This multi-institutional, randomized, double-blind, placebo-controlled (ERICA) phase II study enrolled patients with HER2-positive/HER2-low metastatic breast cancer receiving their first cycle of T-DXd. Patients were randomized to olanzapine 5 mg or placebo once daily (1:1 ratio) from Day 1 to 6, plus a 5-hydroxytryptamine type 3-receptor antagonist (5-HT3RA) and dexamethasone 6.6 mg intravenously or 8 mg orally on Day 1. The total observation period was 504 hours (21 days) from the first T-DXd administration. The primary endpoint was complete response (CR), defined as no emetic events and no rescue medications, in the delayed phase (24-120 hours post-T-DXd), with the type I error rate of 0.2 (one-sided) for the comparison. Secondary endpoints included no nausea rate in the delayed and persistent phases (120-504 hours), adverse event by CTCAE and PRO-CTCAE. RESULTS: In total, 168 patients were enrolled at 43 sites in Japan (Nov 2021-Sep 2023) with 162 patients (olanzapine, n = 80; placebo, n = 82) included in the per protocol set. The primary endpoint was met as the delayed phase CR rate was significantly greater with olanzapine than placebo (70.0% versus 56.1%, P = 0.047). Efficacy was maintained in the persistent phase (63.9% versus 44.4%). No nausea rate was also greater with olanzapine (delayed phase: 57.5% versus 37.8%; persistent phase: 51.4% versus 31.9%). CR rates in the delayed phase favored olanzapine across subgroups. Appetite loss was also decreased with olanzapine. Hyperglycemia and somnolence were mostly of low-grade severity. CONCLUSION: Olanzapine 5mg for 6 days with 5-HT3RA and dexamethasone appears effective for T-DXd-treated patients to prevent delayed and persistent nausea and vomiting.

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.

Mechanisms of adverse mammary effect induced by olanzapine and therapeutic interventions in rat model.

BACKGROUND: Olanzapine antagonizes dopamine receptors and is prescribed to treat multiple psychiatric conditions. The main side effect of concern for olanzapine is weight gain and metabolic syndrome. Olanzapine induces hyperprolactinemia, however its effect on the mammary gland is poorly documented. METHODS: Rats received olanzapine by gavage or in drinking water at 1, 3, and 6 mg/kg/day for 5-40 days or 100 days, with and without coadministration of bromocriptine or aripiprazole and using once daily or continuous administration strategies. Histomorphology of the mammary gland, concentrations of prolactin, estradiol, progesterone, and olanzapine in serum, mammary gland and adipose tissue, and mRNA and protein expressions of prolactin receptors were analyzed. RESULTS: In adult and prepubescent female rats and male rats, olanzapine induced significant development of mammary glands in dose- and time-dependent manners, with histopathological hyperplasia of mammary ducts and alveoli with lumen dilation and secretion, marked increase of mammary prolactin receptor expression, a marker of breast tissue, and with mild increase of circulating prolactin. This side effect can be reversed after medication withdrawal, but long-term olanzapine treatment for 100 days implicated tumorigenic potentials indicated by usual ductal epithelial hyperplasia. Olanzapine induced mammary development was prevented with the coaddition of the dopamine agonist bromocriptine or partial agonist aripiprazole, or by continuous administration of medication instead of a once daily regimen. CONCLUSIONS: These results shed light on the previously overlooked effect of olanzapine on mammary development and present experimental evidence to support current clinical management strategies of antipsychotic induced side effects in the breast.

Olanzapine suppresses mPFC activity-norepinephrine releasing to alleviate CLOCK-enhanced cancer stemness under chronic stress.

BACKGROUND: Olanzapine (OLZ) reverses chronic stress-induced anxiety. Chronic stress promotes cancer development via abnormal neuro-endocrine activation. However, how intervention of brain-body interaction reverses chronic stress-induced tumorigenesis remains elusive. METHODS: KrasLSL-G12D/WT lung cancer model and LLC1 syngeneic tumor model were used to study the effect of OLZ on cancer stemness and anxiety-like behaviors. Cancer stemness was evaluated by qPCR, western-blotting, immunohistology staining and flow-cytometry analysis of stemness markers, and cancer stem-like function was assessed by serial dilution tumorigenesis in mice and extreme limiting dilution analysis in primary tumor cells. Anxiety-like behaviors in mice were detected by elevated plus maze and open field test. Depression-like behaviors in mice were detected by tail suspension test. Anxiety and depression states in human were assessed by Hospital Anxiety and Depression Scale (HADS). Chemo-sensitivity of lung cancer was assessed by in vivo syngeneic tumor model and in vitro CCK-8 assay in lung cancer cell lines. RESULTS: In this study, we found that OLZ reversed chronic stress-enhanced lung tumorigenesis in both KrasLSL-G12D/WT lung cancer model and LLC1 syngeneic tumor model. OLZ relieved anxiety and depression-like behaviors by suppressing neuro-activity in the mPFC and reducing norepinephrine (NE) releasing under chronic stress. NE activated ADRB2-cAMP-PKA-CREB pathway to promote CLOCK transcription, leading to cancer stem-like traits. As such, CLOCK-deficiency or OLZ reverses NE/chronic stress-induced gemcitabine (GEM) resistance in lung cancer. Of note, tumoral CLOCK expression is positively associated with stress status, serum NE level and poor prognosis in lung cancer patients. CONCLUSION: We identify a new mechanism by which OLZ ameliorates chronic stress-enhanced tumorigenesis and chemoresistance. OLZ suppresses mPFC-NE-CLOCK axis to reverse chronic stress-induced anxiety-like behaviors and lung cancer stemness. Decreased NE-releasing prevents activation of ADRB2-cAMP-PKA-CREB pathway to inhibit CLOCK transcription, thus reversing lung cancer stem-like traits and chemoresistance under chronic stress.

Modulatory effect of olanzapine on neuronal nitric oxide synthase (nNOS) expression in the rat striatum.

Nitric oxide (NO) has been thought to be a novel factor involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about potential crosstalk between neuronal NO signaling and neuroleptics action. The present work was, therefore, focused on gene expression of neuronal NO synthase (nNOS) in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain, and for both descriptive and quantitative analysis of nNOS protein distribution in selected brain structures. Long-term treatment with olanzapine is reflected in different changes in the number of enzyme-expressing cells in the rat brain. Olanzapine decreased the number of nNOS-expressing cells and possibly reduced NO synthesis in the rat striatum. Olanzapine can be taken into account as a potential inhibitor of NO synthesis in the rat striatum.

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.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Effectiveness of antipsychotics for managing agitated delirium in patients with advanced cancer: a secondary analysis of a multicenter prospective observational study in Japan (Phase-R).

PURPOSE: Delirium is a common and serious comorbidity in patients with advanced cancer, necessitating effective management. Nonetheless, effective drugs for managing agitated delirium in patients with advanced cancer remain unclear in real-world settings. Thus, the present study aimed to explore an effective pharmacotherapy for this condition. METHODS: We conducted a secondary analysis of a multicenter prospective observational study in Japan. The analysis included patients with advanced cancer who presented with agitated delirium and received pharmacotherapy. Agitation was defined as a score of the Richmond Agitation-Sedation Scale for palliative care (RASS-PAL) of ≥ 1. The outcome was defined as -2 ≤ RASS-PAL ≤ 0 at 72 h after the initiation of pharmacotherapy. Multiple propensity scores were quantified using a multinomial logistic regression model, and adjusted odds ratios (ORs) were calculated for haloperidol, chlorpromazine, olanzapine, quetiapine, and risperidone. RESULTS: The analysis included 271 patients with agitated delirium, and 87 (32%) showed -2 ≤ RASS-PAL ≤ 0 on day 3. The propensity score-adjusted OR of olanzapine was statistically significant (OR, 2.91; 95% confidence interval, 1.12 to 7.80; P = 0.030). CONCLUSIONS: The findings suggest that olanzapine may effectively improve delirium agitation in patients with advanced cancer.

Pragmatic clinical trials to advance research in children and adolescents with eating disorders.

OBJECTIVE: To discuss the utility of pragmatic clinical trials (PCTs) to help advance research in eating disorders (EDs). METHODS: We describe challenges associated with traditional explanatory research trials and examine PCTs as an alternative, including a review of the PRECIS-2 tool. RESULTS: There are many challenges associated with the design and completion of traditional RCTs within the field of EDs. Pragmatic clinical trials are studies that closely align with conditions available in everyday practice and focus on outcomes that are relevant to patients and clinicians. Results of PCTS maximize applicability and generalizability to clinical settings. DISCUSSION: Available therapies established for the treatment of EDs provide remission rates that rarely exceed 50%, implying a need for additional research on new or adjunctive treatments. In addition to a general overview of PCTs, we draw upon published literature and our own experiences involving adjunctive olanzapine for the treatment of children and youth with anorexia nervosa to help highlight challenges associated with randomized controlled trial (RCT) design and implementation, and offer pragmatic suggestions that would allow patients greater choice in treatment trials, while at the same time capturing outcomes that are most likely to advance treatment efforts. CONCLUSIONS: Pragmatic clinical trials provide alternatives to RCT design that can help bolster research in EDs that aims to explore real-world effects of interventions. PUBLIC SIGNIFICANCE: Available therapies established for the treatment of eating disorders (EDs) in children and adolescents provide remission rates that rarely exceed 50%, implying a need for additional research on new or adjunctive treatments. In this article, we discuss the utility of pragmatic trials to help promote research that can help advance knowledge that is relevant to clinical care settings.

Vitamin D3 and zinc supplements augment the antimanic efficacy of lithium and olanzapine treatments in an animal model of mania.

Objective: Bipolar disorder (BD) is a challenging psychiatric disorder and a complex disease. The associated reduction in serum vitamin D3 (VitD3) levels in BD patients and the contribution of zinc (Zn) to the treatment, along with the severe side effects of lithium (Li) treatment, were encouraging to assess the efficacy of different correlated combinations of therapeutic/nutraceutical treatments such as olanzapine (Oln), VitD3, and Zn against Li. Methods: Mania was induced in C57BL/6 mice by administering methylphenidate (MPH) for 14 consecutive days. On the 8th day of MPH injection, different treatment regimens were administered, Li, Oln, VitD3/Zn, VitD3/Zn/Oln, VitD3 + Zn + Oln + Li50mg/kg (C50), and VitD3 + Zn + Oln + Li100mg/kg (C100). Both VitD3 (850 IU/kg) and Zn (180 mg/kg) were supplied with food for 2 weeks before starting the induction of mania, which continued until the end of MPH administration. Behavioral, brain oxidative stress, thyroid hormones, VitD3, Zn, GsK-3ß, and Bcl2 levels, as well as brain histopathological alterations, were assessed. Results: Manic mice exhibited alterations in all tested parameters, and the histopathological examination of the cortex and hippocampus confirmed these results. The VitD3/Zn/Oln, C50, and C100 treatment regimens reversed most of the behavioral and pathophysiological alterations; however, the C50 treatment regimen was the most efficient. Conclusions: This study emphasizes the importance of combining different antimanic medications like Li and Oln with nutraceutical supplements to increase their antimanic efficacy, reduce their adverse effects, and, ideally, improve the BD patient's quality of life.

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.

Effects of atypical antipsychotics on serum asprosin level and other metabolic parameters in patients with schizophrenia.

BACKGROUND: In this cross-sectional study, we compared fasting serum asprosin levels and metabolic parameters between patients receiving one of three atypical antipsychotics (olanzapine, risperidone, or aripiprazole) and healthy subjects. METHODS: The study population included 62 adult outpatients with schizophrenia and 22 healthy controls, matched for age and gender. Patients were in remission and had been on stable monotherapy with one of these atypical antipsychotics for over 6 months. Body Mass Index (BMI) and fasting serum levels of asprosin, glucose, HA1c, insulin, and lipid profile were compared across the investigated groups. Additionally, the number of participants meeting the insulin resistance criterion, defined as homeostasis model assessment for insulin resistance (HOMA-IR) >2.5, as well as the number of participants with elevated BMI levels (men >27 kg/m2, women >25 kg/m2) were compared among the groups. RESULTS: We observed statistically significant differences in BMI and fasting serum levels of glucose, HA1c, insulin, triglyceride (TG), high-density lipoprotein cholesterol, and asprosin among patients receiving olanzapine or risperidone, as compared to those receiving aripiprazole and healthy subjects. Patients on aripiprazole exhibited values comparable to healthy subjects, whereas those on risperidone or olanzapine showed significantly higher values, with the highest observed in the olanzapine group. Additionally, the prevalence of participants meeting the insulin resistance criterion and those with elevated BMI was also greater in individuals receiving olanzapine or risperidone compared to those on aripiprazole and healthy subjects. Serum asprosin levels showed a significant positive correlation with BMI and several metabolic parameters, including HbA1c, fasting insulin, HOMA-IR, and TG. No significant differences were observed among the investigated groups in terms of serum levels of total cholesterol and low-density lipoprotein cholesterol. CONCLUSIONS: Our cross-sectional study highlights the association between elevated asprosin levels, weight gain, and metabolic disorders in patients treated with olanzapine and risperidone. Given the bidirectional nature of the relationship between serum asprosin levels and these metabolic disturbances, further research is warranted to elucidate potential causative pathways.

Comparison of olanzapine 2.5 mg and 5 mg in the prevention of chemotherapy-induced nausea and vomiting: a Japanese nationwide database study.

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.

Precipitated opioid withdrawal in a patient started on olanzapine/samidorphan.

BACKGROUND: Olanzapine/Samidorphan (Lybalvi®) is a novel oral agent for the treatment of schizophrenia and bipolar I disorder. It was designed to reduce weight gain associated with olanzapine. Samidorphan is an analog of naltrexone, initially intended to treat substance use disorders by antagonizing mu, delta, and kappa opioid receptors. CASE REPORT: We present the case of a 36-year-old who took their first dose of olanzapine/samidorphan shortly before calling for emergency services. The patient took diphenhydramine and an epinephrine autoinjector for what they thought was an allergic reaction but continued to have symptoms. EMS reported involuntary muscle movements thought to be due to dystonia from olanzapine. In the ED, they experienced generalized muscle spasms lasting for several seconds and diaphoresis. Initially, the staff treated for a presumed dystonic reaction to olanzapine and administered diphenhydramine 25 mg IV, diazepam 2 mg IV, midazolam 5 mg IV, and benztropine 1 mg IV without improvement. It was later determined that the patient took 16 mg of buprenorphine SL daily. With this information, precipitated opioid withdrawal was felt to be the likely cause of symptoms. The patient received 16 mg of buprenorphine for an initial Clinical Opiate Withdrawal Scale (COWS) score of 11 with repeat COWS of 6. Why should an emergency physician be aware of this? Initiating olanzapine/samidorphan in the setting of chronic opioid therapy may result in precipitated opioid withdrawal. Additional SL buprenorphine may be a reasonable treatment modality.

Olanzapine-induced weight gain and lipid dysfunction in mice between different gender.

As one of the most common antipsychotics, olanzapine may cause metabolic-related adverse effects, but it is still unknown how olanzapine alters lipid metabolism. In this study, we found that olanzapine-treated mice showed varying degrees of dyslipidemia, which was particularly pronounced in female mice. Based on ultra-performance liquid chromatography-quadrupole time-of-flight-MS (UPLC-Q-TOF-MS) technology and lipid metabolomics, we mapped the changes in lipid metabolism in olanzapine-treated mice and then compared the changes in lipid metabolism between male and female mice. There were 98 metabolic differentiators between the olanzapine-treated and control groups in females and 79 in males. These metabolites were glycerolipids, glycerophospholipids, fatty amides, and sphingolipids, which are involved in glycerolipid metabolism, glycerophospholipid metabolism, and fatty acid metabolism. These results suggest that olanzapine-induced changes in the levels of lipid metabolites are closely associated with disturbances in lipid metabolic pathways, which may underlie lipemia. This lipidome profiling study not only visualizes changes in lipid metabolism in liver tissue but also provides a foundation for understanding the regulatory pathways and mechanisms involved in olanzapine-induced lipid metabolism disorders. Furthermore, this study demonstrates differences in lipid metabolism between males and females, providing a reference for clinical treatment regimen selection.

An economic model to understand the cost-effectiveness of olanzapine orally dispersible tablets (ODT) and olanzapine film coated tablets as a group compared with other oral atypical antipsychotics for treating schizophrenia in Morocco.

BACKGROUND: Antipsychotic medications are the primary treatment for schizophrenia, with olanzapine being an effective medication for schizophrenia. The economic cost for each individual with schizophrenia is high, with antipsychotic medication being a major expense. This study aims to develop an economic decision model that compares different treatment options for schizophrenia patients, including olanzapine Orally Dispersible Tablets (ODT), olanzapine [ODT + Standard Oral Tablet (SOT)], risperidone (ODT + SOT), and aripiprazole (ODT + SOT), to determine their cost-effectiveness with an objective to optimize healthcare resource allocation in Morocco. METHODS: The study used published medical literature and a clinical expert panel to develop a decision analytic model. This model was designed to capture parameters such as adherence levels, treatment discontinuation, relapse with and without hospitalization, quality-adjusted life years (QALYs), treatment-related adverse events, healthcare resource utilization, and associated costs. The main outcomes of interest included the total annual direct cost per treatment, QALYs, and incremental cost-effectiveness ratio (ICER) per 1 QALY gained. One-way and probabilistic sensitivity analyses were employed to account for parameter uncertainty. RESULTS: According to the simulation model, the ODT and ODT + SOT as a group form of olanzapine was the most effective treatment option in terms of the lowest percentages of inpatient relapse, and patients who remained stable (11% and 79% respectively) than risperidone (19% and 62% respectively) and aripiprazole ODT (26% and 50% respectively) and ODT + SOT formulation groups. Olanzapine (ODT + SOT) therapy group was cost-effective when compared to the combined group of ODT + SOT forms of risperidone [ICER: Moroccan Dirham (MAD) 103,907], and aripiprazole (ICER: MAD 65,047). Additionally, olanzapine ODT was found to be cost-effective compared to olanzapine SOT with an ICER of MAD 3921, risperidone ODT with an ICER of MAD 1,02,298, risperidone SOT with an ICER of MAD 31,088, and aripiprazole ODT or SOT formulations. All the above ICERs fall under the willingness-to-pay threshold in Morocco of MAD 250,832.40. Sensitivity analyses confirmed the reliability of the findings. CONCLUSIONS: The model concluded that olanzapine ODT is the most cost-effective first-line treatment option for schizophrenia in Morocco when compared to other atypical antipsychotic medications in ODT and SOT formulations.

Olanzapine for young PEople with aNorexia nervosa (OPEN): A protocol for an open-label feasibility study.

INTRODUCTION: Antipsychotics are routinely prescribed off-label for anorexia nervosa (AN) despite limited evidence. This article presents a protocol of a study aiming to assess the feasibility of a future definitive trial on olanzapine in young people with AN. METHODS AND ANALYSIS: In an open-label, one-armed feasibility study, 55 patients with AN or atypical AN, aged 12-24, receiving outpatient, inpatient or day-care treatment who are considered for olanzapine treatment will be recruited from NHS sites based in England. Assessments will be conducted at screening, baseline and at 8-, 16 weeks, 6- and 12 months. Primary feasibility parameters will be proportions of patients who agree to take olanzapine and who adhere to treatment and complete study assessments. Qualitative methods will be used to explore acceptability of the intervention and study design. Secondary feasibility parameters will be changes in body mass index, psychopathology, side effects, health-related quality of life, carer burden and proportion of participants who would enrol in a future randomised controlled trial. The study is funded by the National Institute for Health Research via Health Technology Assessment programme. DISCUSSION: Olanzapine for young PEople with aNorexia nervosa will inform a future randomised controlled trial on the efficacy and safety of prescribing olanzapine in young people with AN.

Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

Trial Sequential Analysis and Meta-Analysis of Olanzapine in Pediatric Patients for Chemotherapy-Induced Nausea and Vomiting (CINV).

Background and Objective: Olanzapine (OLZ) containing regimens are approved in adults for chemotherapy-induced nausea and vomiting (CINV) receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC), and the same has not been approved in the pediatric population. In order to generate data regarding the efficacy and safety of OLZ as an adjunct to the standard of care (SoC) for CINV in pediatric patients receiving HEC/MEC, the review authors performed this systematic review and meta-analysis. Methods: A systematic literature search was performed through the databases Cochrane Library, Pub Med, and clinicaltrials.gov, from inception to September 2023, using keywords: "chemotherapy" and "olanzapine," "nausea" and "vomiting." Randomized clinical trials published in English that analyzed the efficacy and safety of olanzapine as an adjunct to SoC were included. The essential outcomes included in this study were the proportion of patients with no emesis in the acute and delayed phase, patients with no nausea in the acute and delayed phase, the proportion of patients requiring rescue medication, and the proportion of patients with reduced CNS arousal. Results: In the OLZ group, a greater number of patients had no emesis both in the acute and delayed phase (RR = 1.22; 95% CI = 1.09-1.37; P = .0004); and (RR = 1.23; 95% CI = 0.92-1.63; P = .16) respectively. Similarly, a higher number of patients showed no nausea both in the acute and delayed phase (RR = 1.08; 95% CI = 0.78-1.48; P = .66) and (RR = 1.12; 95% CI = 0.79-1.61; P = .52) respectively. The use of rescue medication was significantly less in the OLZ group (RR = 0.62; 95% CI = 0.42-0.91; P = .01). More patients experienced reduced CNS arousal in the OLZ group (RR = 2.97; 95% CI = 2.02-4.38; P < .0001). Conclusions: Olanzapine as an adjunct to the SoC may be effective in acute emesis, which may also reduce the use of rescue medication. Reduced CNS alertness was the significant adverse effect observed. For other endpoints, more studies are required to substantiate its role in CINV.

Evaluation of the Impact of the Addition of Atypical Antipsychotics to Continuous Infusion Propofol Therapy.

Purpose: The administration of sedatives to critically ill patients is a common practice in intensive care units (ICU) and has been associated with negative outcomes. To mitigate this, atypical antipsychotics are utilized as adjunctive therapy. This study aims to review and quantify overall effectiveness of the atypical antipsychotics quetiapine, risperidone, and olanzapine on reduction in the amount of continuous infusion propofol utilized in the ICU. Methods: This was an observational study that took place from February 27, 2021 to December 31, 2022. The primary outcome of this study was the percentage change in average propofol infusion rate (mcg/kg/min) from baseline to the greater than 24 to 48 hours period after atypical antipsychotic initiation. Secondary outcomes included ICU length of stay, duration of mechanical ventilation, QTc interval monitoring, and continuation of the antipsychotic without a valid indication. Descriptive statistics were utilized for the statistical analysis. Results: A total of 47 patients were included in the study. The average baseline propofol rate was 31 mcg/kg/min, which reduced 8.6% to 28.35 mcg/kg/min over the 0 to 24 hours period, was reduced by 19.4% compared to baseline to a rate of 25 mcg/kg/min during the greater than 24 to 48 hours period, and finally a percent reduction of 54.2% seen during the greater than 48 to 72 hours period to a rate of 14 mcg/kg/min. Conclusions: Patients who received an adjunctive antipsychotic saw resulting propofol rate reductions of 8.6% at 24 hours, 19.4% at 48 hours, and 54.2% at 72 hours. However, research on this topic should not end here, as further investigation with higher-level study design is needed to determine the true impact of these agents for this indication.