UNASSIGNED: Antipsychotics are widely used in the elderly due to the high prevalence of neuropsychiatric associated with dementia.
UNASSIGNED: To analyze potential disparities in antipsychotic use in the general population of Gipuzkoa by socioeconomic status (SES) and diagnosis of Alzheimer\'s disease and related dementia (ADRD) adjusting for somatic and psychiatric comorbidities, age, and sex.
UNASSIGNED: A retrospective observational study was carried out in all the 221,777 individuals over 60 years of age (Gipuzkoa, Spain) to collect diagnosis of ADRD, the Charlson Comorbidity Index, and psychiatric comorbidities considering all primary, outpatient, emergency and inpatient care episodes and first- and second-generation antipsychotics, and sociodemographic variables, namely, age, sex, SES and living in a nursing home. Logistic regression was used for multivariate statisticalanalysis.
UNASSIGNED: Use of any antipsychotic was greater in women, individuals over 80 years old, living in a nursing home, with a diagnosis of dementia, somatic and psychiatric comorbidities, and low SES. Quetiapine was the most used drug. The likelihood of any antipsychotic use was significantly associated with low SES (odds ratio [OR]: 1.60; confidence interval [CI]: 1.52-1.68), age over 80 years (OR: 1.56; CI: 1.47-1.65), institutionalization (OR: 12.61; CI: 11.64-13.65), diagnosis of dementia (OR: 10.18; CI: 9.55-10.85) and the comorbidities of depression (OR: 3.79; CI: 3.58-4.01) and psychosis (OR: 4.96; CI: 4.64-5.30).
UNASSIGNED: The greater levels of antipsychotic use and institutionalization in people of low SES indicate inequity in the management of neuropsychiatric symptoms. Increasing the offer of non-pharmacological treatments in the health system might help reduce inequity.

Antipsychotic drugs often lead to adverse effects, including those related to the cardiovascular system. Of these, quetiapine is known to cause significant changes in the QT interval although the underlying mechanism remains mysterious, prompting us to examine its effects on cardiac electrophysiological properties. Therefore, we investigated the effect of quetiapine on contraction, action potential (AP), and the associated membrane currents such as L-type Ca2+ and K+ using the whole-cell patch clamp method to examine its impacts on isolated rat ventricular myocytes. Our results showed that (1) quetiapine reduces cell contractility in a concentration-dependent manner and (2) leads to a significant prolongation in the duration of AP in isolated ventricular myocytes. This effect was both concentration and frequency-dependent; (3) quetiapine significantly decreased the Ca2+, transient outward K+, and steady-state K+ currents. However, only high concentration of quetiapine (100 μM) could significantly change the activation and reactivation kinetics of L-type Ca2+ channels. This study demonstrates that QT extension induced by quetiapine is mainly associated with the prolongation of AP. Moreover, quetiapine caused a significant decrease in contractile force and excitability of ventricular myocytes by suppressing Ca2+ and K+ currents.

OBJECTIVE: Accumulating studies have assessed mortality risk associated with mood-stabilizers, the mainstay treatment for bipolar disorder (BD). However, existing data were mostly restricted to suicide risk, focused on lithium and valproate and rarely adequately adjusted for potential confounders. This study aimed to assess comparative mortality risk with all, natural and unnatural causes between lithium, valproate and three frequently prescribed second-generation antipsychotics (SGA), with adjustment for important confounders.
METHODS: This population-based cohort study identified 8137 patients with first-diagnosed BD, who had exposed to lithium (n = 1028), valproate (n = 3580), olanzapine (n = 797), quetiapine (n = 1975) or risperidone (n = 757) between 2002 and 2018. Data were retrieved from territory-wide medical-record database of public healthcare services in Hong Kong. Propensity-score (PS)-weighting method was applied to optimize control for potential confounders including pre-existing chronic physical diseases, substance/alcohol use disorders and other psychotropic medications. PS-weighted Cox proportional-hazards regression was conducted to assess risk of all-, natural- and unnatural-cause mortality related to each mood-stabilizer, compared to lithium. Three sets of sensitivity analyses were conducted by restricting to patients with (i) length of cumulative exposure to specified mood-stabilizer ≥90 days and its medication possession ratio (MPR) ≥90%, (ii) MPR of specified mood-stabilizer ≥80% and MPR of other studied mood-stabilizers <20% and (iii) monotherapy.
RESULTS: Incidence rates of all-cause mortality per 1000 person-years were 5.9 (95% confidence interval [CI]: 4.5-7.6), 8.4 (7.4-9.5), 11.1 (8.3-14.9), 7.4 (6.0-9.2) and 12.0 (9.3-15.6) for lithium-, valproate-, olanzapine-, quetiapine- and risperidone-treated groups, respectively. BD patients treated with olanzapine (PS-weighted hazard ratio = 2.07 [95% CI: 1.33-3.22]) and risperidone (1.66 [1.08-2.55]) had significantly higher all-cause mortality rate than lithium-treated group. Olanzapine was associated with increased risk of natural-cause mortality (3.04 [1.54-6.00]) and risperidone was related to elevated risk of unnatural-cause mortality (3.33 [1.62-6.86]), relative to lithium. The association between olanzapine and increased natural-cause mortality rate was consistently affirmed in sensitivity analyses. Relationship between risperidone and elevated unnatural-cause mortality became non-significant in sensitivity analyses restricted to low MPR in other mood-stabilizers and monotherapy. Valproate- and lithium-treated groups did not show significant differences in all-, natural- or unnatural-cause mortality risk.
CONCLUSIONS: Our data showed that olanzapine and risperidone were associated with higher mortality risk than lithium, and further supported the clinical guidelines recommending lithium as the first-line mood-stabilizer for BD. Future research is required to further clarify comparative mortality risk associated with individual SGA agents to facilitate risk-benefit evaluation of alternative mood-stabilizers to minimize avoidable premature mortality in BD.

BACKGROUND: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied.
METHODS: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg.
RESULTS: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and β-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1β and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels.
CONCLUSIONS: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.

暂无摘要。

OBJECTIVE: In hepatocellular carcinoma (HCC) treatment, radiotherapy (RT) stands as a pivotal approach, yet the emergence of radioresistance poses a formidable challenge. This study aimed to explore the potential synergy between quetiapine and RT for HCC treatment.
METHODS: A Hep3B xenograft mouse model was used, the investigation tracked tumor progression, safety parameters, and molecular mechanisms.
RESULTS: The findings revealed a synergistic anti-HCC effect when quetiapine was coupled with RT that prolonged tumor growth time and a significantly higher growth inhibition rate compared to the control group. Safety assessments indicated minimal pathological changes, suggesting potential of quetiapine in mitigating RT-induced alterations in liver and kidney functions. Mechanistically, the combination suppressed metastasis and angiogenesis-related proteins, while triggering the activation of apoptosis-related proteins via targeting Epidermal growth factor receptor (EGFR)-mediated signaling.
CONCLUSIONS: The potential of the quetiapine and RT combination is emphasized, offering enhanced anti-HCC efficacy, a safety profile, and positioning quetiapine as a radiosensitizer for HCC treatment.

OBJECTIVE: This study aimed to verify the real-world efficacy and safety of quetiapine fumarate extended-release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression.
METHODS: We performed a post-marketing surveillance with an observation period of 12 weeks.
RESULTS: In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and \"longer time since the onset of the first episode\" (p = 0.011) and \"presence of complications\" (p < 0.001) were identified as significant risk factors for the occurrence of ADRs. In the efficacy analysis group (n = 265), the average changes from baseline in the total Montgomery-Åsberg Depression Rating Scale (MADRS) score were -7.3 ± 8.8, -12.2 ± 10.7, -16.8 ± 12.7, and -13.2 ± 12.7 points after 4, 8, and 12 weeks, and at the last evaluation, respectively. The mean MADRS total score decrease had no significant association with maximum daily dose, diagnosis, and presence or absence of prior or concomitant treatment for bipolar disorder with mood stabilizers/antipsychotics/antidepressants.
CONCLUSIONS: The efficacy of quetiapine fumarate extended-release tablets was confirmed in clinical practice, and no new safety concerns or risks were identified.

Quetiapine Fumarate (QF) is an atypical antipsychotic with poor oral bioavailability (9%) due to its low permeability and pH-dependent solubility. Therefore, this study aims to design QF-loaded polyethylene glycol (PEG) functionalized graphene oxide nanosheets (GON) for nasal delivery of QF. In brief, GO was synthesized using a modified Hummers process, followed by ultra-sonication to produce GON. Subsequently, PEG-functionalized GON was prepared using carbodiimide chemistry (PEG-GON). QF was then decorated onto the cage of PEG-GON using the π-π stacking phenomenon (QF@PEG-GON). The QF@PEG-GON nanocomposite underwent several spectral characterizations, in vitro drug release, mucoadhesion study, ex vivo diffusion study, etc. The surface morphology of QF@PEG-GON nanocomposite validates the cracked nature of the nanocomposite, whereas the diffractograms and thermogram of nanocomposite confirm the conversion of QF into an amorphous form with uniform distribution in PEG-GON. Moreover, an ex vivo study of PEG-GON demonstrates superior mucoadhesion capacity due to its surface functional groups and hydrophilicity. The percent drug loading content and percent entrapment efficiency of the nanocomposite were found to be 9.2±0.62% and 92.3±1.02%, respectively. The developed nanocomposite exhibited 43.82±1.65% drug release within 24h, with the Korsemeyer-Peppas model providing the best-fit release kinetics (R2: 0.8614). Here, the interlayer spacing of PEG-GON prevented prompt diffusion of the buffer, leading to a delayed release pattern. In conclusion, the anticipated QF@PEG-GON nanocomposite shows promise as a nanocarrier platform for nasal delivery of QF.

Parkinson\'s disease is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, including hallucinations. The use of antipsychotic medications is a common strategy to manage hallucinations associated with Parkinson\'s disease psychosis (PDP). However, careful consideration is necessary when selecting the most appropriate drug due to the potential risks associated with the available treatment options. Atypical antipsychotics (AAPs), such as Pimavanserin and Clozapine, have effectively controlled PDP symptoms. On the contrary, the support for utilizing quetiapine is not as substantial as other antipsychotics because research studies specifically investigating its application are still emerging and relatively recent. The broad mechanisms of action of AAPs, involving dopamine and serotonin receptors, provide improved outcomes and fewer side effects than typical antipsychotics. Conversely, other antipsychotics, including risperidone, olanzapine, aripiprazole, ziprasidone, and lurasidone, have been found to worsen motor symptoms and are generally not recommended for PDP. While AAPs offer favorable benefits, they are associated with specific adverse effects. Extrapyramidal symptoms, somnolence, hypotension, constipation, and cognitive impairment are commonly observed with AAP use. Clozapine, in particular, carries a risk of agranulocytosis, necessitating close monitoring of blood counts. Pimavanserin, a selective serotonin inverse agonist, avoids receptor-related side effects but has been linked to corrected QT (QTc) interval prolongation, while quetiapine has been reported to be associated with an increased risk of mortality. This review aims to analyze the benefits, risks, and mechanisms of action of antipsychotic medications to assist clinicians in making informed decisions and enhance patient care.

UNASSIGNED: Antipsychotics, such as quetiapine, are frequently prescribed to people with dementia to address behavioral symptoms but can also cause harm in this population.
UNASSIGNED: To determine whether warning letters to high prescribers of quetiapine can successfully reduce its use among patients with dementia and to investigate the impacts on patients\' health outcomes.
UNASSIGNED: This is a secondary analysis of a randomized clinical trial of overprescribing letters that began in April 2015 and included the highest-volume primary care physician (PCP) prescribers of quetiapine in original Medicare. Outcomes of patients with dementia were analyzed in repeated 90-day cross-sections through December 2018. Analyses were conducted from September 2021 to February 2024.
UNASSIGNED: PCPs were randomized to a placebo letter or 3 overprescribing warning letters stating that their prescribing of quetiapine was high and under review by Medicare.
UNASSIGNED: The primary outcome of this analysis was patients\' total quetiapine use in days per 90-day period (the original trial primary outcome was total quetiapine prescribing by study PCPs). Prespecified secondary outcomes included measures of cognitive function and behavioral symptoms from nursing home assessments, indicators of depression from screening questionnaires in assessments and diagnoses in claims, metabolic diagnoses derived from assessments and claims, indicators of use of the hospital and other health care services, and death. Outcomes were analyzed separately for patients living in nursing homes and in the community.
UNASSIGNED: Of the 5055 study PCPs, 2528 were randomized to the placebo letter, and 2527 were randomized to the 3 warning letters. A total of 84 881 patients with dementia living in nursing homes and 261 288 community-dwelling patients with dementia were attributed to these PCPs. There were 92 874 baseline patients (mean [SD] age, 81.5 [10.5] years; 64 242 female [69.2%]). The intervention reduced quetiapine use among both nursing home patients (adjusted difference, -0.7 days; 95% CI, -1.3 to -0.1 days; P = .02) and community-dwelling patients (adjusted difference, -1.5 days; 95% CI, -1.8 to -1.1 days; P < .001). There were no detected adverse effects on cognitive function (cognitive function scale adjusted difference, 0.01; 95% CI, -0.01 to 0.03; P = .19), behavioral symptoms (agitated or reactive behavior adjusted difference, -0.2%; 95% CI -1.2% to 0.8% percentage points; P = .72), depression, metabolic diagnoses, or more severe outcomes, including hospitalization and death.
UNASSIGNED: This study found that overprescribing warning letters to PCPs safely reduced quetiapine prescribing to their patients with dementia. This intervention and others like it may be useful for future efforts to promote guideline-concordant care.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT05172687.