-
International Immunopharmacology Jun 2024The accumulation of amyloid-β (Aβ) in the brain is the first pathological mechanism to initiate Alzheimer's disease (AD) pathogenesis. However, the precise role of Aβ...
The accumulation of amyloid-β (Aβ) in the brain is the first pathological mechanism to initiate Alzheimer's disease (AD) pathogenesis. However, the precise role of Aβ in the disease progression remains unclear. Through decades of research, prolonged inflammation has emerged as an important core pathology in AD. Previously, a study has demonstrated the neurotoxic effect of Aβ-induced neuroinflammation in neuron-glia co-culture at 72 h. Here, we hypothesise that initial stage Aβ may trigger microglial inflammation, synergistically contributing to the progression of neurite lesions relevant to AD progression. In the present study, we aimed to determine whether olanzapine, an antipsychotic drug possessing anti-inflammatory properties, can ameliorate Aβ-induced progressive neurite lesions. Our study reports that Aβ induces neurite lesions with or without inflammatory microglial cells in vitro. More intriguingly, the present study revealed that Aβ exacerbates neurite lesions in synergy with microglia. Moreover, the time course study revealed that Aβ promotes microglia-mediated neurite lesions by eliciting the secretion of pro-inflammatory cytokines. Furthermore, our study shows that olanzapine at lower doses prevents Aβ-induced microglia-mediated progressive neurite lesions. The increase in pro-inflammatory cytokines induced by Aβ is attenuated by olanzapine administration, associated with a reduction in microglial inflammation. Finally, this study reports that microglial senescence induced by Aβ was rescued by olanzapine. Thus, our study provides the first evidence that 1 µM to 5 µM of olanzapine can effectively prevent Aβ-induced microglia-mediated progressive neurite lesions by modulating microglial inflammation. These observations reinforce the potential of targeting microglial remodelling to slow disease progression in AD.
PubMed: 38908083
DOI: 10.1016/j.intimp.2024.112469 -
Journal of Huntington's Disease Jun 2024Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI)...
Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI) is a rare psychotic manifestation of the disease. This report presents two cases of HD patients with DI, both middle-aged females. The first patient achieved remission of DI with olanzapine, later cross-tapered to risperidone, but had spontaneous relapses. The second experienced gradual resolution of DI with risperidone in the setting of iron repletion and amantadine discontinuation, although her other psychotic symptoms remained. These cases shed light on an uncommon condition and may help guide understanding of the most effective treatment for it.
PubMed: 38905053
DOI: 10.3233/JHD-240013 -
Indian Journal of Anaesthesia Jun 2024Post-discharge nausea and vomiting (PDNV) is a pertinent problem in patients undergoing ambulatory surgery. The objective of this study was to assess the efficacy of the...
Olanzapine versus standard antiemetic prophylaxis for the prevention of post-discharge nausea and vomiting after propofol-based general anaesthesia: A randomised controlled trial.
BACKGROUND AND AIMS
Post-discharge nausea and vomiting (PDNV) is a pertinent problem in patients undergoing ambulatory surgery. The objective of this study was to assess the efficacy of the novel drug olanzapine, which has proved its efficiency in patients undergoing highly emetogenic chemotherapy for PDNV prevention.
METHODS
This randomised controlled trial recruited 106 adult patients (18-65 years) undergoing highly emetogenic daycare surgeries with propofol-based general anaesthesia (GA). Group O received preoperative oral olanzapine 10 mg, and Group C, acting as a control, received 8 mg of intravenous dexamethasone and 4 mg of ondansetron intraoperatively. The primary outcome was nausea (numeric rating scale >3) and/or vomiting 24 h after discharge. Secondary outcomes included nausea and vomiting in the post-anaesthesia care unit (PACU), severe nausea, vomiting and side effects. Normality was assessed using the Shapiro-Wilk test, and the independent samples -test or the Mann-Whitney test was used to compare continuous variables. Fisher's exact test was used to assess any non-random associations between the categorical variables.
RESULTS
The incidence and severity of postoperative nausea and vomiting were similar in both groups within PACU (four patients experienced nausea and vomiting, three had severe symptoms in Group O, = 0.057) and in the post-discharge period (three patients in Group O had nausea and vomiting compared to five patients in Group C, of which four were severe, = 0.484). The side effects (sedation, dizziness, and light-headedness) were comparable between the two groups.
CONCLUSION
A single preoperative oral olanzapine can be an effective alternative to standard antiemetic prophylaxis involving dexamethasone and ondansetron for preventing PDNV in highly emetogenic daycare surgeries with propofol-based GA.
PubMed: 38903258
DOI: 10.4103/ija.ija_1162_23 -
Psychiatry Research Jun 2024The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related...
The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.
PubMed: 38901365
DOI: 10.1016/j.psychres.2024.116012 -
Journal of Nippon Medical School =... Jun 2024Schizophrenia develops during adolescence. Maternal infections during the fetal period increase the incidence of schizophrenia in children, which suggests that the...
Schizophrenia develops during adolescence. Maternal infections during the fetal period increase the incidence of schizophrenia in children, which suggests that the pathogenesis involves neuroinflammation. Here, we report a case of new-onset schizophrenia in a 16-year-old boy after COVID-19. After developing COVID-19, he entered a catatonic state 4 days later and was hospitalized. Benzodiazepines alleviated his catatonia, but hallucinations and delusions persisted. Encephalitis and epilepsy were excluded by magnetic resonance imaging (MRI), encephalography, and cerebrospinal fluid examination. Psychosis persisted after the virus titer declined and the inflammatory response subsided. Moreover, the patient exhibited delusions of control-a Schneider's first-rank symptom. Schizophrenia was diagnosed, and olanzapine improved his symptoms. He had a brief history of insomnia before COVID-19 but his symptoms did not satisfy the ultra-high-risk criteria. However, COVID-19 may have facilitated development of schizophrenia through neuroinflammation and volume reduction in the gray matter of the right medial temporal lobe. This case demonstrates that infectious diseases in adolescents should be carefully managed, to prevent schizophrenia.
PubMed: 38897947
DOI: 10.1272/jnms.JNMS.2025_92-301 -
The Lancet. Child & Adolescent Health Jul 2024The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the... (Meta-Analysis)
Meta-Analysis Comparative Study
BACKGROUND
The degree of physiological responses to individual antipsychotic drugs is unclear in children and adolescents. With network meta-analysis, we aimed to investigate the effects of various antipsychotic medications on physiological variables in children and adolescents with neuropsychiatric and neurodevelopmental conditions.
METHODS
For this network meta-analysis, we searched Medline, EMBASE, PsycINFO, Web of Science, and Scopus from database inception until Dec 22, 2023, and included randomised controlled trials comparing antipsychotics with placebo in children or adolescents younger than 18 years with any neuropsychiatric and neurodevelopmental condition. Primary outcomes were mean change from baseline to end of acute treatment in bodyweight, BMI, fasting glucose, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, prolactin, heart rate, systolic blood pressure (SBP), and QT interval corrected for heart rate (QTc) for patients receiving either active treatment or placebo. For multigroup trials reporting several doses, we calculated a summary value for each physiological variable for all doses. After transitivity assessment, we fitted frequentist random-effects network meta-analyses for all comparisons in the network. A Kilim plot was used to summarise the results for all treatments and outcomes, providing information regarding the strength of the statistical evidence of treatment effects, using p values. Network heterogeneity was assessed with τ, risk of bias of individual trials was assessed with the Cochrane Collaboration's Tool for Assessing Risk of Bias, and the credibility of findings from each network meta-analysis was assessed with the Confidence in Network Meta-Analysis (CINEMA) app. This study is registered on PROSPERO (CRD42021274393).
FINDINGS
Of 6676 studies screened, 47 randomised controlled trials were included, which included 6500 children (mean age 13·29 years, SD 2·14) who received treatment for a median of 7 weeks (IQR 6-8) with either placebo (n=2134) or one of aripiprazole, asenapine, blonanserin, clozapine, haloperidol, lurasidone, molindone, olanzapine, paliperidone, pimozide, quetiapine, risperidone, or ziprasidone (n=4366). Mean differences for bodyweight change gain compared with placebo ranged from -2·00 kg (95% CI -3·61 to -0·39) with molindone to 5·60 kg (0·27 to 10·94) with haloperidol; BMI -0·70 kg/m (-1·21 to -0·19) with molindone to 2·03 kg/m (0·51 to 3·55) with quetiapine; total cholesterol -0·04 mmol/L (-0·39 to 0·31) with blonanserin to 0·35 mmol/L (0·17 to 0·53) with quetiapine; LDL cholesterol -0·12 mmol/L (-0·31 to 0·07) with risperidone or paliperidone to 0·17 mmol/L (-0·06 to 0·40) with olanzapine; HDL cholesterol 0·05 mmol/L (-0·19 to 0·30) with quetiapine to 0·48 mmol/L (0·18 to 0·78) with risperidone or paliperidone; triglycerides -0·03 mmol/L (-0·12 to 0·06) with lurasidone to 0·29 mmol/L (0·14 to 0·44) with olanzapine; fasting glucose from -0·09 mmol/L (-1·45 to 1·28) with blonanserin to 0·74 mmol/L (0·04 to 1·43) with quetiapine; prolactin from -2·83 ng/mL (-8·42 to 2·75) with aripiprazole to 26·40 ng/mL (21·13 to 31·67) with risperidone or paliperidone; heart rate from -0·20 bpm (-8·11 to 7·71) with ziprasidone to 12·42 bpm (3·83 to 21·01) with quetiapine; SBP from -3·40 mm Hg (-6·25 to -0·55) with ziprasidone to 10·04 mm Hg (5·56 to 14·51) with quetiapine; QTc from -0·61 ms (-1·47 to 0·26) with pimozide to 0·30 ms (-0·05 to 0·65) with ziprasidone.
INTERPRETATION
Children and adolescents show varied but clinically significant physiological responses to individual antipsychotic drugs. Treatment guidelines for children and adolescents with a range of neuropsychiatric and neurodevelopmental conditions should be updated to reflect each antipsychotic drug's distinct profile for associated metabolic changes, alterations in prolactin, and haemodynamic alterations.
FUNDING
UK Academy of Medical Sciences, Brain and Behaviour Research Foundation, UK National Institute of Health Research, Maudsley Charity, the Wellcome Trust, Medical Research Council, National Institute of Health and Care Research Biomedical Centre at King's College London and South London and Maudsley NHS Foundation Trust, the Italian Ministry of University and Research, the Italian National Recovery and Resilience Plan, and Swiss National Science Foundation.
Topics: Humans; Antipsychotic Agents; Child; Adolescent; Network Meta-Analysis; Randomized Controlled Trials as Topic; Mental Disorders; Heart Rate; Blood Pressure
PubMed: 38897716
DOI: 10.1016/S2352-4642(24)00098-1 -
Cureus May 2024Introduction Cancer chemotherapy regimens include multiple classes of adjuvant drugs as supportive therapy. Because of the concurrent intake of other drugs (like...
Prevalence, Attributes, and Risk Factors of QT-Interval-Prolonging Drugs and Potential Drug-Drug Interactions in Cancer Patients: A Prospective Study in a Tertiary Care Hospital.
Introduction Cancer chemotherapy regimens include multiple classes of adjuvant drugs as supportive therapy. Because of the concurrent intake of other drugs (like antiemetics, antidepressants, analgesics, and antimicrobials), there is a heightened risk for possible QT interval prolongation. There is a dearth of evidence in the literature regarding the usage of QT-prolonging anticancer drugs and associated risk factors that have the propensity to prolong QT interval. The purpose was to explore the extent of the use of QT-interval-prolonging drugs and potential QT-prolonging drug-drug interactions (QT-DDIs) in cancer patients attending OPD in a tertiary-care hospital. Methods This was a hospital-based, cross-sectional, observational study. Risk stratification of QT-prolonging drugs for torsades de pointes (TdP) was done by the Arizona Center for Education and Research on Therapeutics (AzCERT)/CredibleMeds-lists, and potential QT-DDIs were determined with four online DDI-checker-software. Results In 1331 cancer patients, the overall prevalence of potential QT-prolonging drug utilization was 97.3%. Ondansetron, pantoprazole, domperidone, and olanzapine were the most frequent QT-prolonging drugs in cancer patients. The top six antineoplastics with potential QT-prolonging and torsadogenic actions were capecitabine, oxaliplatin, imatinib, bortezomib, 5-fluorouracil, and bendamustine. Evidence-based pragmatic QTc interval prolongation risk assessment tools are imperative for cancer patients. Conclusion This study revealed a high prevalence of QT-prolonging drugs and QT-DDIs among cancer patients who are treated with anticancer and non-anticancer drugs. As a result, it's critical to take precautions, stay vigilant, and avoid QT-prolonging in clinical situations. Evidence-based pragmatic QTc interval prolongation risk assessment tools are needed for cancer patients.
PubMed: 38882995
DOI: 10.7759/cureus.60492 -
Expert Opinion on Drug Metabolism &... Jun 2024Dopamine (D)-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). (Review)
Review
INTRODUCTION
Dopamine (D)-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV).
AREAS COVERED
Eight D-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects.
EXPERT OPINION
Since the introduction of D-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)-RAs and neurokinin (NK)-RAs have been developed. The classical D-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT-RA, dexamethasone and a NK-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.
Topics: Humans; Nausea; Vomiting; Antiemetics; Antineoplastic Agents; Dopamine Antagonists; Animals; Dopamine D2 Receptor Antagonists; Receptors, Dopamine D3
PubMed: 38878283
DOI: 10.1080/17425255.2024.2367593 -
Annals of Emergency Medicine Jun 2024United States prescribing information recommends against coadministration of injectable olanzapine with injectable benzodiazepines due to a risk of cardiorespiratory...
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 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.
PubMed: 38878022
DOI: 10.1016/j.annemergmed.2024.05.006 -
EBioMedicine Jun 2024Response to antipsychotic drugs (APD) varies greatly among individuals and is affected by genetic factors. This study aims to demonstrate genome-wide associations...
BACKGROUND
Response to antipsychotic drugs (APD) varies greatly among individuals and is affected by genetic factors. This study aims to demonstrate genome-wide associations between copy number variants (CNVs) and response to APD in patients with schizophrenia.
METHODS
A total of 3030 patients of Han Chinese ethnicity randomly received APD (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, haloperidol and perphenazine) treatment for six weeks. This study is a secondary data analysis. Percentage change on the Positive and Negative Syndrome Scale (PANSS) reduction was used to assess APD efficacy, and more than 50% change was considered as APD response. Associations between CNV burden, gene set, CNV loci and CNV break-point and APD efficacy were analysed.
FINDINGS
Higher CNV losses burden decreased the odds of 6-week APD response (OR = 0.66 [0.44, 0.98]). CNV losses in synaptic pathway involved in neurotransmitters were associated with 2-week PANSS reduction rate. CNV involved in sialylation (1p31.1 losses) and cellular metabolism (19q13.32 gains) associated with 6-week PANSS reduction rate at genome-wide significant level. Additional 36 CNVs associated with PANSS factors improvement. The OR of protective CNVs for 6-week APD response was 3.10 (95% CI: 1.33-7.19) and risk CNVs was 8.47 (95% CI: 1.92-37.43). CNV interacted with genetic risk score on APD efficacy (Beta = -1.53, SE = 0.66, P = 0.021). The area under curve to differ 6-week APD response attained 80.45% (95% CI: 78.07%-82.82%).
INTERPRETATION
Copy number variants contributed to poor APD efficacy and synaptic pathway involved in neurotransmitter was highlighted.
FUNDING
National Natural Science Foundation of China, National Key R&D Program of China, China Postdoctoral Science Foundation.
PubMed: 38870545
DOI: 10.1016/j.ebiom.2024.105195