-
Human Psychopharmacology Jun 2024In this cross-sectional study, we compared fasting serum asprosin levels and metabolic parameters between patients receiving one of three atypical antipsychotics...
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/m, women >25 kg/m) 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.
PubMed: 38940745
DOI: 10.1002/hup.2907 -
Biomolecules Jun 2024Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular...
BACKGROUND
Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs).
METHODS
Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone).
RESULTS
Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment.
CONCLUSIONS
Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action.
Topics: Humans; Olanzapine; Risperidone; Neurogenesis; Hippocampus; Haloperidol; Antipsychotic Agents; Induced Pluripotent Stem Cells; Neural Stem Cells; Cell Differentiation; Cell Proliferation; Cells, Cultured; Neuronal Outgrowth
PubMed: 38927091
DOI: 10.3390/biom14060688 -
British Journal of Clinical Pharmacology Jun 2024Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the... (Review)
Review
Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.
PubMed: 38926083
DOI: 10.1111/bcp.16152 -
JAMA Psychiatry Jun 2024Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use...
IMPORTANCE
Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia.
OBJECTIVE
To estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023.
EXPOSURES
Use of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high.
MAIN OUTCOMES AND MEASURES
The primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference.
RESULTS
The study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk.
CONCLUSIONS AND RELEVANCE
Results of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.
PubMed: 38922592
DOI: 10.1001/jamapsychiatry.2024.1441 -
Expert Opinion on Drug Metabolism &... Jun 2024The literature associates clozapine with pneumonia/aspiration pneumonia.
Investigating in VigiBase® over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.
BACKGROUND
The literature associates clozapine with pneumonia/aspiration pneumonia.
RESEARCH DESIGN AND METHODS
The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023.
RESULTS
There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with: 1) very high titration doses, 2) very small doses in Parkinson's disease and 3) Japan vs other countries.
CONCLUSIONS
In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients in long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.
PubMed: 38920369
DOI: 10.1080/17425255.2024.2373111 -
Hospital Pharmacy Aug 2024Olanzapine (OLZ) containing regimens are approved in adults for chemotherapy-induced nausea and vomiting (CINV) receiving highly emetogenic chemotherapy (HEC) or... (Review)
Review
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. 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. 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; = .0004); and (RR = 1.23; 95% CI = 0.92-1.63; = .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; = .66) and (RR = 1.12; 95% CI = 0.79-1.61; = .52) respectively. The use of rescue medication was significantly less in the OLZ group (RR = 0.62; 95% CI = 0.42-0.91; = .01). More patients experienced reduced CNS arousal in the OLZ group (RR = 2.97; 95% CI = 2.02-4.38; < .0001). 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.
PubMed: 38919763
DOI: 10.1177/00185787241231739 -
Naunyn-Schmiedeberg's Archives of... Jun 2024Clozapine has been considered the "gold standard" in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of...
Clozapine has been considered the "gold standard" in the treatment of schizophrenia for many years. Clozapine has a superior effect, particularly in the treatment of negative symptoms and suicidal behaviour. However, due to its numerous adverse reactions, clozapine is mainly used for treatment-resistant schizophrenia. The aim of this paper is to analyze the results of clinical studies on clozapine from 2012-2022. PubMed was used as the database. Sixty-four studies were included and categorised by topic. The pharmacokinetic properties of clozapine tablets and a clozapine suspension solution did not differ markedly. Clozapine was superior to olanzapine and risperidone in reducing aggression and depression. A long-term study showed that metabolic parameters changed comparably with olanzapine and clozapine after 8 years. Risperidone and ziprasidone can be used as an alternative to clozapine. Scopolamine, atropine drops, and metoclopramide are effective in the treatment of clozapine-induced hypersalivation. Eight drugs, including liraglutide, exenatide, metformin, and orlistat, are potentially effective in the treatment of clozapine-induced weight gain. Ziprasidone, haloperidol, and aripiprazole showed a positive effect on symptoms when added to clozapine. No investigated drug was superior to clozapine for the treatment of schizophrenia. Ziprasidone and risperidone can also be used well for the treatment of schizophrenia. In the treatment of clozapine-induced hypersalivation and weight gain, some drugs proved to be effective.
PubMed: 38918233
DOI: 10.1007/s00210-024-03209-1 -
Drugs - Real World Outcomes Jun 2024Reducing falls and fractures remains an important clinical goal in managing older residents with Parkinson's disease psychosis (PDP) in long-term care/nursing home...
Falls and Fractures among Nursing Home Residents Treated with Pimavanserin versus Other Atypical Antipsychotics: Analysis of Medicare Beneficiaries with Parkinson's Disease Psychosis.
BACKGROUND
Reducing falls and fractures remains an important clinical goal in managing older residents with Parkinson's disease psychosis (PDP) in long-term care/nursing home (LTC/NH) settings.
OBJECTIVES
This analysis examined risk of all-cause falls or fractures among PDP residents on continuous monotherapy with pimavanserin (PIM) versus (i) other atypical antipsychotics (AAPs) [quetiapine (QUE), risperidone (RIS), olanzapine (OLA), aripiprazole (ARI)] and (ii) QUE.
METHODS
A retrospective analysis of parts A, B, and D claims from a 100% Medicare sample (2013-2019) in LTC/NH settings was conducted. LTC/NH residents in the USA initiating continuous monotherapy (PIM versus other AAPs; PIM versus QUE) for ≥ 6 months between 01 January 2014 and 31 December 2018 were 1:1 propensity score matched (PSM) on 31 variables (age, sex, race, region, and 27 Elixhauser comorbidities). Outcomes included three measures: risks of falls only, fractures only, and falls/fractures during 6-months follow-up. Demographic characteristics were described using chi-square and t-tests. Generalized linear models were used to assess difference in risks of falls/fractures.
RESULTS
Of 7187 residents, 47.59% (n = 3420) were female and mean age was 78.8 (± 7.75) years. In total, 14% (n = 1005) were on PIM and 86% (n = 6182) were on other AAPs. After PSM, falls only among PIM residents (n = 1005) was 4.58% (n = 46) versus 7.66% (n = 77) for other AAPs (n = 1005) [relative risk (RR) = 0.63 (0.46, 0.86), p < 0.05] and 8.26% (n = 83) for QUE (n = 1005) residents (p < 0.05). Fractures only among PIM residents was 1.39% (n = 14) compared with 2.09% (n = 21) for other AAPs (p = 0.31) and 1.89% (n = 19) for QUE (p = 0.49), respectively. Taken together, falls/fractures among PIM residents were 5.67% (n = 57) versus 9.05% (n = 91) for other AAPs [RR = 0.63 (0.46, 0.86), p < 0.05] and 9.55% (n = 96) for QUE (p < 0.05), respectively.
CONCLUSIONS
In this analysis of LTC/NH residents with PDP, PIM had a 37% and 41% lower risk of all-cause falls/fractures versus other AAPs and versus QUE, respectively.
PubMed: 38914856
DOI: 10.1007/s40801-024-00433-2 -
International Journal of General... 2024Dementia is a common neurogenerative disease among older adults. Therefore, they are more prone to potentially inappropriate medication (PIM), which is medication that...
BACKGROUND
Dementia is a common neurogenerative disease among older adults. Therefore, they are more prone to potentially inappropriate medication (PIM), which is medication that causes more harm rather than protecting the health of an individual. Hence, the American Geriatrics Society (AGS) has recognized the risk of certain medication classes on this population and released PIM according to Beers criteria, which is a helpful guide for clinicians to ensure the safety of medication before it is prescribed. The aim of this study is to assess the prevalence of PIM use among older adults with dementia as a risk factor in comparison to other older adults without dementia.
METHODS
A retrospective study was conducted in an outpatient setting in a tertiary hospital targeting elderly patients aged 65 years old or over from January 2020 to September 2022. A total of 598 patients were screened, and 270 patients met the inclusion criteria. The eligible patients were then divided into two groups: 168 were in a non-dementia group and 102 were in a dementia group.
RESULTS
PIM use was reported in patients with and without dementia. The most inappropriate medication that was prescribed comprised atypical antipsychotics PIM for both patients with and without dementia. However, the prevalence was higher in the dementia group for quetiapine (75% vs 24% respectively), olanzapine (82% vs 17% respectively) or risperidone (92% vs 7%, respectively). Anticholinergics were highly prescribed in older adult without dementia as compared to dementia patient and was statistically significant for solifenacin (96% vs.3.6% respectively) and amitriptyline (88% vs 11% respectively).
CONCLUSION
Among elderly patients in outpatient care settings, the prevalence of PIM use is considered high in dementia patients for antipsychotics, while a higher use of benzodiazepine and anticholinergics was found in non-dementia patients.
PubMed: 38912331
DOI: 10.2147/IJGM.S456091 -
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