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.

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.

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health.

OBJECTIVE: Pharmacological treatment strategies for insomnia seem to vary, and there is lack of knowledge about how sedative drugs are used in a real-world setting. We investigated changes in sedative drug prescription patterns in Danish adults who initiated treatment between 2002 and 2016.
METHODS: All adults with a first-time purchase of a sedative drug registered in the Danish National Prescription Register from 2002 through 2016 were followed for five years between 2002 and 2021 for subsequent prescriptions of sedative drugs, death, or emigration. Sedative drugs were classified into anxiolytic benzodiazepines (N05BA), hypnotic benzodiazepines (N05CD), Z-drugs (N05CF), melatonin (N05CH01), promethazine (R06AD), and low-dose quetiapine (N05AH04). Analyses were stratified on time: 2002-2006, 2007-2011, and 2012-2016.
RESULTS: A total of 842,880 individuals purchased their first sedative drug between 2002 and 2016. Most of them (40.0%) initiated treatment between 2002 and 2006, whereas 29.2% initiated treatment in 2012-2016. In 2002-2006, anxiolytic benzodiazepines (46.4%), Z-drugs (42.8%), and hypnotic benzodiazepines (5.4%) were the most common first treatment. This pattern changed over time with a gradual increase in the use of melatonin, promethazine, and low-dose quetiapine, which in 2011-2016 accounted for 27% of all first treatments. During the five years from first prescription, around 27% shifted to a different sedative drug. This percentage increased slightly over time, but over time the first shift to another drug class was most often to a Z-drug or anxiolytic benzodiazepine. Few individuals (5.8%) had more than one shift and the third choice seemed randomly distributed across all other drug classes.
CONCLUSIONS: Sedative drug prescriptions are distributed on different drug classes, with Z-drugs and anxiolytic benzodiazepines as the most frequent first treatment, and second choice in case of shift.

This study aimed to estimate all-cause mortality in patients after a first-episode mania (FEM) and examine whether six guideline-recommended medications can reduce mortality.
The cohort included population-based FEM samples and matched controls from Taiwan, spanning 2007 to 2018. The primary outcomes assessed were all-cause/suicide-related mortality, while the secondary outcome focused on mortality associated with pharmacological treatments. We compared mortality in post-FEM patients and age-/sex-matched controls without any diagnosed bipolar disorders and patients with and without psychopharmacological treatment using Cox regression analysis, respectively. Statistics were presented with time-to-event adjusted hazard ratios (AHRs) and 95% confidence intervals (CIs).
The study included 54,092 post-FEM patients and 270,460 controls, totaling 2,467,417 person-years of follow-up. Post-FEM patients had higher risks of all-cause mortality (AHR 2.38, 95% CI: 2.31-2.45) and suicide death (10.80, 5.88-19.84) than controls. Lithium (0.62, 0.55-0.70), divalproex (0.89, 0.83-0.95), and aripiprazole (0.81, 0.66-1.00) were associated with reduced all-cause mortality compared to non-users. There were no significant all-cause mortality differences for quetiapine (0.95, 0.89-1.01), risperidone (0.92, 0.82-1.02), and paliperidone (1.24, 0.88-1.76) users. When accounting for drug action onset times in sensitivity analyses, only lithium significantly reduced all-cause mortality (AHR range 0.65-0.72). There were 35 and 16 suicide deaths in post-FEM patients and controls, respectively. No drug had a significant effect on suicide deaths (lithium: 6; divalproex: 7; aripiprazole: 0; quetiapine: 10; risperidone: 4; paliperidone: 1).
Post-FEM patients had a higher risk of all-cause/suicide-related mortality, and lithium treatment might reduce all-cause mortality.

BACKGROUND: Neuropsychiatric symptoms (NPS) are distressing for patients with dementia, often accelerating functional decline and nursing home placement. Medications such as quetiapine are used to alleviate NPS, but their side effects require cautious use. Liquid formulations such as quetiapine oral suspension suit specific populations; however, real-world data on their use in patients with dementia are limited.
OBJECTIVE: The purpose of this retrospective, naturalistic study was to provide preliminary data on the effects of treatment with quetiapine oral suspension on behavioral and psychiatric disturbances in Alzheimer\'s disease (AD) outpatients in Taiwan.
METHODS: Between January 2022 and June 2023, data were collected from outpatients with a diagnosis of probable AD who received treatment with Qting® (quetiapine oral solution 25 mg/ml). Primary outcome measures were changes in Neuropsychiatric Inventory (NPI) total score and its sub-items from baseline to the endpoint.
RESULTS: We recruited 66 AD patients with a mean age of 72.1±7.6 years, most of whom were female (69.7%). Twenty-three patients had data on neuropsychological test and NPI scores before and after quetiapine treatment. There was no significant change in global cognitive function from baseline to the endpoint. A significant reduction in NPI total score after quetiapine treatment was noted, while the effect on NPI sub-items was limited. The average maintenance dose was 1.5±0.6 ml.
CONCLUSIONS: We demonstrated our clinical experience of the use of quetiapine oral solution in AD patients with NPS. Our results showed that quetiapine oral solution treatment significantly improved these symptoms at a relatively low dose.

A rapid, highly specific and sensitive UPLC-MS/MS method was developed for the determination of Quetiapine Fumarate, a therapeutic drug for various psychiatric disorders, in human plasma. The samples were pretreated using a protein precipitation method, followed by chromatographic separation using a column (Kinetex C18, 2.6µm 50*2.1mm) equipped with an ESI source and MRM mode mass spectrometer. In the validation results of the method, the analyte quetiapine showed a peak at approximately 1.0 minute and exhibited good linearity within the concentration from 2.5 to 2000ng/mL. The intra- and inter-batch precision CV% were within the range of -1.3% to 7.7% and precision of intra- and inter-batch were below 15.0%. Furthermore, this method demonstrated low matrix effects and high recovery rates. The quetiapine plasma sample solution remained stable at room temperature for 25 hours and following 4 freeze-thaw cycles. The prepared samples remained stable in the autosampler (The temperature control of the autosampler was 5oC) for 185 hours and after four freeze-thaw cycles at -20oC and -70oC for 40 days. The present work effectively employed this approach to investigate the pharmacokinetics of orally administered quetiapine fumarate tablets in a cohort of healthy Chinese individuals, both in a fasting state and after a meal.

BACKGROUND: Constipation is a common adverse effect of antipsychotics, but little investigation has been conducted. We aimed to address the factors associated with the initiation of laxative use in the same patients with schizophrenia over a 20-year period.
METHODS: We enrolled patients with schizophrenia attending each hospital (n = 14) from April 1, 2021, and retrospectively examined all prescriptions as of April 1, 2016, 2011, 2006, and 2001, every 5 years starting in 2021, for this population. 716 participants with complete data were included in the analysis. The Cochran Q test followed by Bonferroni correction and the Cochran-Armitage trend test were used to determine the differences and trends of the frequency of each laxative. Multivariate logistic regression analysis was performed to assess the factors on the initiation of laxative use over a 20-year period.
RESULTS: Of the patients, 25.1% were treated with laxatives in 2001, and 34.1% were treated in 2021. The numbers of patients treated with any laxatives significantly differed over the 20-year period, with a significant increasing trend. In all laxatives, the numbers of patients treated with magnesium oxide, lubiprostone and elobixibat differed with a significant increasing trend. Female sex, age, the total DZP equivalent dose, and the doses of levomepromazine maleate, olanzapine, quetiapine, zotepine, lithium, and carbamazepine in 2021 were significant factors associated with the initiation of laxative use over the 20-year period.
CONCLUSIONS: Careful monitoring is needed for patients treated with levomepromazine maleate, olanzapine, quetiapine and zotepine. Optimizing prescriptions according to treatment guidelines could reduce antipsychotic-induced constipation.

Antipsychotics are commonly used to manage postoperative delirium. Recent studies reported that haloperidol use has declined, and atypical antipsychotic use has increased over time.
To compare the risk for in-hospital adverse events associated with oral haloperidol, olanzapine, quetiapine, and risperidone in older patients after major surgery.
Retrospective cohort study.
U.S. hospitals in the Premier Healthcare Database.
17 115 patients aged 65 years and older without psychiatric disorders who were prescribed an oral antipsychotic drug after major surgery from 2009 to 2018.
Haloperidol (≤4 mg on the day of initiation), olanzapine (≤10 mg), quetiapine (≤150 mg), and risperidone (≤4 mg).
The risk ratios (RRs) for in-hospital death, cardiac arrhythmia events, pneumonia, and stroke or transient ischemic attack (TIA) were estimated after propensity score overlap weighting.
The weighted population had a mean age of 79.6 years, was 60.5% female, and had in-hospital death of 3.1%. Among the 4 antipsychotics, quetiapine was the most prescribed (53.0% of total exposure). There was no statistically significant difference in the risk for in-hospital death among patients treated with haloperidol (3.7%, reference group), olanzapine (2.8%; RR, 0.74 [95% CI, 0.42 to 1.27]), quetiapine (2.6%; RR, 0.70 [CI, 0.47 to 1.04]), and risperidone (3.3%; RR, 0.90 [CI, 0.53 to 1.41]). The risk for nonfatal clinical events ranged from 2.0% to 2.6% for a cardiac arrhythmia event, 4.2% to 4.6% for pneumonia, and 0.6% to 1.2% for stroke or TIA, with no statistically significant differences by treatment group.
Residual confounding by delirium severity; lack of untreated group; restriction to oral low-to-moderate dose treatment.
These results suggest that atypical antipsychotics and haloperidol have similar rates of in-hospital adverse clinical events in older patients with postoperative delirium who receive an oral low-to-moderate dose antipsychotic drug.
National Institute on Aging.

Low-dose lithium (LD-Li) has been shown to rescue cognitive impairment in mouse models of short-term mild cognitive impairment, dementia, and schizophrenia. However, few studies have characterized the effects of LD-Li, alone or in conjunction with anti-psychotics, in the mouse model of MK801-induced long term cognitive impairment.
The present study used in vivo Ca2+ imaging and a battery of cognitive function assessments to investigate the long-term effects of LD-Li on cognition in mice exposed to repeated injections of MK801. Prefrontal Ca2+ activity was visualized to estimate alterations in neural activity in the model mice. Pre-pulse inhibition (PPI), novel object recognition (NOR), Morris water maze (MWM), and fear conditioning (FC) tasks were used to characterize cognitive performance; open field activity (OFA) testing was used to observe psychotic symptoms. Two treatment strategies were tested: LD-Li [250 mg/d human equivalent dose (HED)] adjunct to quetiapine (QTP; 600 mg/d HED); and QTP-monotherapy (mt; 600 mg/d HED).
Compared to the QTP-mt group, the LD-Li + QTP group showed greatly improved cognitive performance on all measures between experimental days 29 and 85. QTP-mt improved behavioral measures compared to untreated controls, but the effects persisted only from day 29 to day 43. These data suggest that LD-Li + QTP is superior to QTP-mt for improving long-term cognitive impairments in the MK801 mouse model.
There is no medical consensus regarding lithium use in patients with schizophrenia.
More pre-clinical and clinical studies are needed to further investigate effective treatment strategies for patients with long-term cognitive impairments, such as chronic schizophrenia.