Association of atypical antipsychotic use with mortality risk in patients with behavioural and psychological symptoms of dementia

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The mortality risk posed by AAP treatment remains unclear. This global, population-based, retrospective cohort study compared all-cause mortality risk between patients with dementia prescribed AAPs and those prescribed nonpharmacological interventions instead of AAPs. Propensity score matching was performed to optimize comparability. Participants were enrolled between 2015 and 2024 by using the Global Collaborative Network of the TriNetX platform. The primary outcome was the rate of all-cause mortality from initial AAP use until death or June 30, 2025, using the Intent-to-Treat principle to define exposure status and Kaplan–Meier analyses. 72 805 patients with dementia prescribed AAPs were included in an AAP group, and 3645 patients treated with concomitant nonpharmacological interventions instead of AAPs were included in a control group. After propensity score matching, AAP use was associated with a 59.0% increased risk of all-cause mortality compared with nonpharmacological interventions (HR = 1.590, 95% CI 1.422–1.777). Regarding the risk of specific AAPs, all-cause mortality HRs, in descending order, were as follows: 1.926 (95% CI 1.728–2.147) for risperidone, 1.787 (95% CI 1.598–2.000) for olanzapine, 1.520 (95% CI 1.363–1.694) for quetiapine, 1.230 (95% CI 1.067–1.418) for aripiprazole, and 1.157 (95% CI 0.705–1.900) for brexpiprazole. This study showed that AAP use is associated with a significantly increased risk of mortality in patients with dementia. These findings highlight the importance of cautious AAP use for BPSD and suggest that brexpiprazole has a more favorable safety profile. Health sciences/Diseases/Psychiatric disorders/Schizophrenia Health sciences/Diseases/Psychiatric disorders/Depression Figures Figure 1 Figure 2 INTRODUCTION Dementia is one of the leading causes of death and disability, affecting an estimated 57 million people worldwide in 2021, with nearly 10 million new cases reported each year [ 1 ]. During the course of the illness, approximately 60% to 80% of patients with dementia develop behavioral and psychological symptoms of dementia (BPSD), which include agitation, aggression, depression, apathy, psychosis, sleep disturbances, repetitive questioning, wandering, and other inappropriate behaviors [ 2 – 4 ]. BPSD may accelerate disease progression, reduce the quality of life of patients and their caregivers, lead to institutionalization, impose a substantial burden, and even result in death in the older population [ 2 , 3 ]. Although the majority of best practice guidelines for BPSD recommend nonpharmacological interventions as the preferred first-line management and only judicious, short-term use of antipsychotics [ 4 – 6 ], implementing these approaches in clinical practice remains a major challenge. Several factors hinder the use of nonpharmacological interventions in real-world settings: severe disease presentations such as dementia with delirium and dementia with severe psychotic symptoms; the perceived lack of immediate efficacy compared with pharmacological treatments; the greater time and effort required, often without reimbursement for nonpharmacological treatments; the absence of clear guidelines on the timing and dosing of such interventions; and inadequate provider training in their application [ 4 , 7 ]. Regarding pharmacological treatments for BPSD, antipsychotics have been widely prescribed off-label in patients with dementia because of their immediate effectiveness, ease of use, and strong evidence base [ 4 , 8 ]. Atypical antipsychotics (AAPs) are preferred over conventional antipsychotics for the treatment of BPSD [ 9 ]. No antipsychotics, including AAPs, have been approved by the US Food and Drug Administration (FDA) for the treatment of BPSD. In 2005 and 2008, the FDA issued warnings that patients with dementia prescribed antipsychotics had an increased risk of mortality. This warning was based on the results of 17 placebo-controlled trials [ 4 , 10 – 12 ]. The FDA granted supplemental approval for brexpiprazole, an AAP, for the treatment of agitation in patients with Alzheimer’s dementia in May 2023. Nevertheless, the FDA maintains that brexpiprazole increases mortality risk when used for this indication [ 13 , 14 ]. Evidence remains insufficient to support antipsychotics as an efficacy or safe alternative to nonpharmacological interventions for BPSD, especially in dementia with delirium or severe psychotic symptoms; physicians, patients, and their families are left with ambiguous choices for managing BPSD [ 15 ]. The decision to initiate any intervention in clinical practice requires balancing benefits and harms with potential quality-of-life improvements for patients and caregivers. Physicians often encounter difficulty in clarifying the clinical importance of absolute changes in benefits or harms [ 15 , 16 ]. Therefore, a clear understanding of the efficacy and safety profile of individual antipsychotics is critical to guide prescribing decisions, including the evaluation of mortality risks associated with AAP use in dementia and potential differences in mortality risk among specific AAPs [ 17 ]. The importance of shared decision-making and caution in antipsychotic use for BPSD is emphasized. This retrospective cohort study evaluated the risk of all-cause death in patients with dementia prescribed AAPs by using the TriNetX global network. The mortality risk posed by different AAPs was compared. METHODS Study Design and Ethics Statement We conducted a global, population-based, retrospective cohort study to evaluate the risk of all-cause death in patients with dementia who were prescribed AAPs. Data were obtained from the TriNetX Global Collaborative Network, a computerized database containing more than 275 million patient records from 151 health-care organizations that provide de-identified electronic medical records to a central repository [ 18 , 19 ]. The AAPs included in the present study were clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, paliperidone, iloperidone, lurasidone, and brexpiprazole [ 20 ]. To account for the limited number of patients prescribed newly-developed AAPs, we categorized AAPs by their pharmacological targets into 2 subgroups: second-generation antipsychotics (SGAs), namely clozapine, risperidone, olanzapine, quetiapine, ziprasidone, asenapine, and paliperidone, and third-generation antipsychotics (TGAs), namely aripiprazole, iloperidone, lurasidone, and brexpiprazole [ 21 , 22 ] . This study adhered to Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Because the data were de-identified, the need for informed consent was waived. The Institutional Review Board of Dalin Tzu Chi Hospital approved this study. Study Patients We enrolled patients aged 65 years or older who received a new diagnosis of dementia, identified using International Classification of Diseases, Tenth Revision codes (F01, F02, F03, and G30) and the prescription of dementia medications (eg, donepezil [RXNORM:135447], rivastigmine [183379], galantamine [4637], or memantine [617]). Patients registered in the database between January 1, 2015, and December 31, 2024, with at least 3 clinical visits were enrolled [ 23 , 24 ]. Patients were excluded if they had received dementia medications or antipsychotics (ATC NA05A*) before the date of dementia diagnosis. In this study, we apply the Intent-to-Treat (ITT) principle to define exposure status. The AAP group comprised patients with dementia who had at least one exposure to an AAP after the date of dementia diagnosis. The control group consisted of patients with dementia who were antipsychotic-naïve and had received nonpharmacological interventions after the date of dementia diagnosis [ 25 – 28 ]. Detailed definitions of study medications, diagnoses, and nonpharmacological interventions for BPSD are provided in e-Table 1 of the Supplement Materials. ITT ensures that all patients, regardless of subsequent medication changes or discontinuations, are analyzed in the group to which they were initially assigned. Matching Process Participants in both the AAP and control groups underwent 1:1 propensity score matching (PSM) to minimize confounding effects [ 29 ]. The propensity score model was adjusted for potential confounders examined before the date of dementia diagnosis, including demographic variables (eg, age, sex, and race), nicotine dependence (smoking), alcohol abuse (drinking), obesity, hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, atrial fibrillation and flutter, heart failure, peripheral vascular disease, angina pectoris, cerebral infarction, transient cerebral ischemic attacks, chronic kidney disease, chronic obstructive pulmonary disease, sleep apnea, chronic liver disease, and malignant neoplasm (e-Table 2) [ 30 – 32 ]. The index date was defined as the date of AAP prescription for the AAP group and the date of the initiation of a recommended nonpharmacological intervention for the control group. Participants were followed from the index date until death or June 30, 2025. Data analysis was conducted on August 11, 2025. Study Outcomes The primary outcome was all-cause mortality. Secondary outcomes were the effects of specific AAPs, AAP class, and various health factors on mortality risk. Statistical Analysis All statistical analyses were performed using the TriNetX platform. Baseline characteristics are presented as numbers and percentages for categorical variables and as means with standard deviations (SDs) for continuous variables. Group comparisons were conducted using Pearson’s chi-square test, for categorical variables and Student’s t test for continuous variables. After PSM, the balance of potential confounding variables between the AAP and control groups was determined using standardized mean differences (SMDs), with a predefined threshold of 0.10 indicating adequate balance. A SMD was preferred over a P value to quantify group differences because SMDs are less sensitive to sample size [ 33 ]. Survival analyses were conducted using the Kaplan-Meier method, and differences in the distribution of survival between the groups were evaluated using the log-rank test. Hazard ratios (HRs) and 95% CIs for the risk of death were estimated using a Cox proportional hazards regression model. A 2-tailed P -value of ≦ .05 was considered statically significant. RESULTS A total of 311 488 patients who had received a new diagnosis of senile dementia between 2015 and 2024 were identified. After the exclusion of patients who had received antipsychotic treatment before the date of dementia diagnosis, the remaining patients were divided into 2 groups on the basis of their antipsychotic treatment status: 173 814 (57.4%) patients with dementia received no antipsychotic treatment, and 129 131 (42.6%) patients received antipsychotic treatment, including 72 805 (24.0%) who were prescribed AAPs. Furthermore, 3645 (1.2%) patients were not prescribed any antipsychotics but were treated with a concomitant nonpharmacological intervention. Thus, 72 805 patients were included in the AAP group, and 3645 patients were included in the control group. PSM resulted in 3347 patients per 1:1 matched cohort. A flowchart of the patient selection process is illustrated in Fig. 1 . Characteristics of the Study Cohort Before PSM, the AAP group was younger (mean [SD] age, 77.6 [6.0] vs 78.8 [5.6] years) and had a greater proportion of men (42.7% vs 39.6%). The AAP group was less likely to have hypertension (61.3% vs 65.8%), diabetes mellitus (27.7% vs 33.9%), hyperlipidemia (45.3% vs 52.2%), ischemic heart disease (27.1% vs 32.4%), atrial fibrillation and flutter (16.3% vs 18.6%), heart failure (14.0% vs 17.4%), cerebral infarction (11.4% vs 15.3%), transient cerebral ischemic attack (6.5% vs 8.5%), chronic kidney disease (20.0% vs 24.6%), chronic obstructive pulmonary disease (11.9% vs 14.5%), and hepatic fibrosis (0.4% vs 0.9%). After PSM, the groups were well-balanced (SMD < 0.1), with only minor residual imbalances. A full comparison of baseline characteristics before and after PSM is presented in Table 1 , and propensity score density curves before and after matching are depicted in eFig. 1 in Supplement 1. Table 1 Baseline Characteristics of Patients with Dementia Prescribed AAP Treatment and Controls Patients, No. (%) Patient count before matching Patient count after matching Characteristic ICD-10 code Case (n = 71 718) Control (n = 3347) P value SMD Case (n = 3347) Control (n = 3347) P value SMD Age, mean (SD), y NA 77.6 (6.0) 78.8 (5.6) < 0.001 0.260 79.0 (5.6) 78.8 (5.6) 0.101 0.040 Sex NA Female NA 41065 (57.3) 2021 (60.4) < 0.001 0.063 2070 (61.8) 2021 (60.4) 0.219 0.030 Male NA 30613 (42.7) 1326 (39.6) < 0.001 0.062 1274 (38.1) 1326 (39.6) 0.192 0.032 Race White 2106-3 50252 (70.1) 2206 (65.9) < 0.001 0.089 2243 (67.0) 2206 (65.9) 0.338 0.023 Black or African American 2054-5 6948 (9.1) 259 (7.7) 0.009 0.048 238 (7.1) 259 (7.7) 0.328 0.024 Asian 2028-9 3184 (4.4) 570 (17.0) < 0.001 0.415 563 (16.8) 570 (17.0) 0.820 0.006 Other racea 2131-1 1653 (2.3) 54 (1.6) 0.009 0.050 50 (1.5) 54 (1.6) 0.693 0.010 Unknown race NA 9817 (13.7) 235 (7.0) < 0.001 0.220 232 (6.9) 235 (7.0) 0.886 0.004 Comorbidity Nicotine dependence F17 5526 (7.7) 254 (7.6) 0.805 0.004 237(7.1) 254 (7.6) 0.425 0.019 Alcohol abuse F10.1 1818 (2.5) 77 (2.3) 0.398 0.015 70 (2.1) 77 (2.3) 0.559 0.014 Obesity E66.9 6918 (9.6) 346 (10.3) 0.186 0.023 339 (10.1) 346 (10.3) 0.778 0.007 Hypertension I10 43937 (61.3) 2202 (65.8) < 0.001 0.094 2243 (67.0) 2202 (65.8) 0.289 0.026 Diabetes mellitus E11 19852 (27.7) 1134 (33.9) < 0.001 0.135 1080 (32.3) 1134 (33.9) 0.161 0.034 Hyperlipidemia E78.2 32456 (45.3) 1747 (52.2) < 0.001 0.139 1734 (51.8) 1747 (52.2) 0.750 0.008 Ischemic heart diseases I20-I25 19471 (27.1) 1084 (32.4) < 0.001 0.115 1040 (31.1) 1084 (32.4) 0.248 0.028 Atrial fibrillation and flutter I48 11693 (16.3) 623 (18.6) < 0.001 0.061 603 (18.0) 623 (18.6) 0.527 0.015 Heart failure I50 10019 (14.0) 583 (17.4) < 0.001 0.095 533 (15.9) 583 (17.4) 0.101 0.040 Peripheral vascular diseases I73 5569 (7.8) 248 (7.4) 0.452 0.013 236 (7.1) 248 (7.4) 0.571 0.014 Angina pectoris I20 3308 (4.6) 189 (5.6) 0.006 0.047 161 (4.8) 189 (5.6) 0.124 0.038 Cerebral infarction I63 8175 (11.4) 458 (15.3) < 0.001 0.069 420 (12.5) 458 (13.7) 0.169 0.034 Transient cerebral ischemic attacks G45 4657 (6.5) 286 (8.5) < 0.001 0.078 281 (8.4) 286 (8.5) 0.826 0.005 Chronic kidney disease N18 14353 (20.0) 822 (24.6) < 0.001 0.109 784 (23.4) 822 (24.6) 0.277 0.027 Chronic obstructive pulmonary disease J44 8523 (11.9) 484 (14.5) < 0.001 0.076 455 (13.6) 484 (14.5) 0.307 0.025 Sleep apnea G47.3 9019 (12.6) 432 (12.9) 0.572 0.010 399 (11.9) 432 (12.9) 0.221 0.030 Hepatic fibrosis K74.0 254 (0.4) 29 (0.9) < 0.001 0.066 27 (0.8) 29 (0.9) 0.788 0.007 Malignant neoplasm C80.1 755 (1.1) 43 (1.3) 0.201 0.022 38 (1.1) 43 (1.3) 0.576 0.014 Abbreviation: AAP, atypical antipsychotic; SMD, standard mean difference; SD, standard deviate; NA, not available. a Other race is defined internally by TriNetX. All-Cause Mortality The mean follow-up duration was 1736 days for the AAP group and 2666 days for the control group. After adjustment for covariates, the mortality rate was significantly higher in the AAP Group than in the control group (HR = 1.590, 95% CI 1.422–1.777; Table 2 and Fig. 2 ). Table 2 Risk of All-Cause Mortality in Patients with Dementia Prescribed AAPs. No. (%) HR (95% CI) Median survival (days) Overall analysis AAP treatment 71 805 1.590 (1.422–1.777) 1736/2666 Control* 3645 Reference (2666) Subgroup analysis Age categories (y) Very advanced old (≥ 85) 26 355 (36.2) 1.926 (1.814–2.045) 1533/3326 Advanced old (75–84) 36 257 (49.8) 1.467 (1.381–1.559) 2162/3205 Young old (65–74) 10 120 (13.9) Reference - Sex Male 31 105 (42.7) 1.458 (1.411–1.505) 1538/2167 Female 41 668 (57.2) Reference (2167) Subtype of dementia Alzheimer's disease 35 055 (48.1) 1.021 (0.976–1.068) 1582/1688 Vascular dementia 12 889 (17.7) Reference (1688) AAP classes SGA 65 584 (90.1) 1.678 (1.508–1.867) 1609/2666 TGA 3715 (5.1) 1.366 (1.200-1.554) 2162/3090 Control* 3645 Reference - Specific AAPs** Quetiapine 34 929 (48.0) 1.520 (1.363–1.694) 1971/2666 Olanzapine 9283 (12.8) 1.787 (1.598-2.000) 1577/2556 Risperidone 7735 (10.6) 1.926 (1.728–2.147) 1445/2666 Aripiprazole 2814 (3.9) 1.230 (1.067–1.418) 2404/2556 Brexpiprazole 684 (0.9) 1.157 (0.705-1.900) -/- Control* 3645 Reference - Haloperidol*** 13 338 2.587 (2.322–2.882) 1296/2564 Abbreviations: AAP, atypical antipsychotic; SGA, second-generation antipsychotic; TGA, third-generation antipsychotic; HR, hazard ratio. * Patients with dementia who were antipsychotic-naïve and had received a documentation nonpharmacological intervention for behavioral and psychological symptoms of dementia after the date of dementia diagnosis. ** clozapine (n = 268), ziprasidone (n = 563), asenapine (n = 13), paliperidone (n = 50), iloperidone (n = 10), lurasidone (n = 116). *** belonging to typical antipsychotics Effects of Demographic Factors on Mortality Risk We examined mortality risk in subgroups stratified by age, sex, and dementia subtypes (Table 2 ). For age, patients were classified into 3 categories: very advanced old (≥ 85 years), advanced old (75–84 years), and young old (65–74 years). Patients in the very advanced old group (HR = 1.926, 95% CI 1.814–2.045) and the advanced old group (HR = 1.467, 95% CI 1.381–1.559) had a significantly higher risk of all-cause mortality than did those in the young old group. Male patients with dementia who were prescribed AAPs had a higher risk of all-cause mortality than did female patients who were prescribed AAPs (HR = 1.458, 95% CI 1.411–1.505). When dementia subtypes were examined, patients with Alzheimer disease had a slightly higher but not statistically significant risk of all-cause mortality than did those with vascular dementia (HR = 1.021, 95% CI 0.976–1.068). Effects of AAP Class and Specific AAPS on Mortality Risk AAPs were categorized into 2 classes on the basis of their pharmacological target: SGAs and TGAs. Patients with dementia prescribed SGAs had a significantly higher risk of all-cause mortality than did controls (HR = 1.678, 95% CI 1.508–1.867). Patients prescribed TGAs also had a significantly higher risk of all-cause mortality than did controls, but their risk was lower than that associated with SGAs (HR = 1.366, 95% CI 1.200–1.554). Among 129 131 antipsychotic-exposed patients, 72 805 (56.4%) were prescribed an AAP. The 4 most commonly prescribed medications were quetiapine (34 929 [48.0%]), olanzapine (9283 [12.8%]), risperidone (7735 [10.6%]), and aripiprazole (2814 [3.9%]). Additionally, 684 (0.9%) patients were prescribed brexpiprazole, and 13 338 received haloperidol (a conventional antipsychotics; Table 2 ). Relative to nonpharmacological interventions, AAP use was associated with an increase of all-cause mortality. Mortality risk was highest for risperidone (HR = 1.926, 95% CI 1.728–2.147), followed by olanzapine (HR = 1.787, 95% CI 1.598–2.000), quetiapine (HR = 1.520, 95% CI 1.363–1.694), aripiprazole (HR = 1.230, 95% CI, 1.067–1.418), and brexpiprazole (HR = 1.157, 95% CI 0.705–1.900). Additionally, the HR for all-cause mortality associated with haloperidol use was 2.587 (95% CI 2.322–2.882; Table 2 ). DISCUSSION According to a review of the literature, this is the first study to examine the difference in mortality risks among patients with dementia prescribed different AAP classes and specific AAPs by using the TriNetX global dataset. Data from 311 488 patients who received a new diagnosis of senile dementia between 2015 and 2024 were analyzed, including 72 805 patients prescribed AAPs and 3645 controls treated with nonpharmacological interventions instead of antipsychotics. After adjustment for covariates, patients with dementia prescribed AAPs had an approximately 1.6-fold higher risk of all-cause mortality than did controls. Notably, the risk of all-cause mortality varied by AAP types, with risperidone, olanzapine, quetiapine, aripiprazole, and brexpiprazole posing the greatest risks (in descending order). The rate of antipsychotic prescriptions in patients with dementia was 42.6%. This rate is higher than that reported in other studies-antipsychotic prescription rates in older patients with dementia range from 10% to 15% [ 25 , 34 , 35 ]. One possible explanation for this finding is the difference in assessment methods. Antipsychotic prescription in the present study was defined as having at least one exposure to antipsychotics after the date of dementia diagnosis. Consequently, 24% of patients with dementia were prescribed AAPs, and 1.2% of patients received no antipsychotics and were treated solely with concomitant nonpharmacological interventions. This finding suggests that nonpharmacological interventions for the treatment of BPSD are challenging to implement in clinical practice. AAP prescriptions are more common and are easier to apply in real-world settings [ 4 – 8 ]. Before PSM, patients with dementia who were prescribed AAPs were younger and had a lower prevalence of physical comorbidities than did those treated with nonpharmacological interventions. This finding indicates that physicians generally prefer AAP treatment for younger and healthier patients with dementia and prefer nonpharmacological interventions for older and less healthy patients. Our primary finding revealed that AAP treatment was associated with an increased mortality risk in patients with dementia, consistent with the findings of preliminary studies (17 double-blind, randomized, placebo-controlled trials in older patients with dementia) that reported an approximately 1.5-fold higher mortality risk with AAP use compared with placebo [ 11 , 36 ]. Although AAP treatment for BPSD substantially reduces mortality risk compared with conventional antipsychotics (from approximately 2.5-fold to 1.5-fold) [ 36 , 37 ], patients with dementia prescribed AAPs still have an increased risk of death. Therefore, strategies to minimize this risk are crucial when the clinical use of AAPs is indicated in patients with dementia. We identified potential risk factors for mortality in patients with dementia treated with AAPs. Alzheimer’s disease is recognized as a risk factor for mortality associated with long-term antipsychotic use (38).Our findings exhibited a similar trend with AAP treatment, although the association between AAP use and an increased mortality risk was not significant for vascular dementia. Male sex and older age were identified as risk factors for all-cause mortality in patients with dementia prescribed AAPs in the present study. We further analyzed differences in mortality risk associated with specific AAPs. First, we confirmed evidence that the risk of mortality is highest in patients with dementia prescribed haloperidol, followed by risperidone, olanzapine, and quetiapine [ 39 , 40 ]. Second, we categorized AAPs into SGAs and TGAs on the basis of their pharmacological targets, considering the number of patients prescribed newer AAPs. Our findings indicated a higher mortality risk in patients with dementia treated with SGAs than in those treated with TGAs. This finding suggests that TGAs have more favorable cardiac and metabolic outcomes than do SGAs, potentially reducing the risk of mortality [ 41 ]. Finally, when evaluating mortality risk across all AAPs, including brexpiprazole, we observed that the risk of all-cause mortality in patients with dementia varied by specific AAPs, in descending order: risperidone, olanzapine, quetiapine, aripiprazole, and brexpiprazole. Additional evidence is required to confirm whether brexpiprazole is the safest of the currently available antipsychotics for treating BPSD. The growing body of evidence regarding the mortality risk of antipsychotic treatment for BPSD has led to considerable pressure to limit their use in real-world settings. Although the causes of death among patients with dementia receiving antipsychotics varied, most deaths were attributable to cardiovascular disease (eg, sudden cardiac death and heart failure) or infection (eg, pneumonia and urinary tract infection) [ 11 , 42 ]. The findings of the present and other studies provide insights into the pathways that may lead to death. Notably, providing better care for patients with dementia treated with AAPs, particularly for male and older patients, may help prevent adverse effects. For example, infection-related mortality could be reduced by monitoring for antipsychotic-induced dysphagia, improving oral hygiene, adhering to routine vaccination recommendations, and maintaining vigilance for the early detection and treatment of chest infections. Additionally, electrocardiogram monitoring for prolonged QTc intervals should be considered in routine clinical practice [ 40 ]. The findings of the present study provide critical information that can help physicians minimize potential harms at multiple decision points. Regarding the choice of AAPs, the current study provides further evidence supporting the use of brexpiprazole for managing BPSD when an antipsychotic is deemed necessary. Such use should be integrated within a framework to improve the overall management of BPSD, including the appropriate implementation of nonpharmacological interventions, effective relief of pain and discomfort, and judicious, short-term use of AAPs when clinically indicated [ 40 , 43 ]. Strengths and Limitations The primary strength of this study is the use of a large-scale cohort design that enabled us to determine the difference in mortality risk among patients with dementia posed by specific AAPs. These findings provide a valuable reference for clinicians in determining whether their patients are likely to benefit from treatment for BPSD. Although this study was retrospective, the cohort approach within a global database reduced the likelihood of selection and recall biases. Another strength is the incorporation of a time lag between medication exposure and outcome measurement, which helps address concerns related to reverse causality and disease latency as well as prevents immortal time bias. Finally, the use of PSM allowed for control of clinically and prognostically relevant factors, thereby minimizing the risk of bias from confounding. This study has some limitations that should be considered. First, adherence to prescribed drugs and information on dementia severity and BPSD could not be evaluated because the study was based on an administrative claims database. Second, the prevalence of dementia and comorbidities, such as obesity, hypertension, diabetes, and cardiovascular disease, may have been underestimated because patients with no or mild symptoms might not seek medical care. Third, we could not account for dietary and other potential confounders of death, including disease severity, biochemical and electrocardiographic results, and unhealthy lifestyle factors such as sweetened beverage consumption and inadequate exercise. Finally, changes to prescribed drugs that occurred outside of health-care organizations would not have been captured in the TriNetX health research network. CONCLUSIONS This large-scale, real-world cohort study demonstrates that AAP treatment is associated with a significantly increased mortality risk in patients with dementia, with varying risks among AAP classes and specific AAPs. Clinicians treating patients with BPSD should be aware of the relatively favorable safety profile of brexpiprazole. Future research should focus on developing new pharmacotherapy for BPSD that do not increase mortality risk in patients with dementia. Declarations Author Contributions: Drs C.-S. Hung, Y.-P. Chang and J.-H. Tsai had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization: C.-S. Hung, Y.-P. Chang and J.-H. Tsai. Data curation: C.-S. Hung, C.-H.R. Lin and J.-H. Tsai Formal analysis: C.-H.R. Lin and P.-S. Ho Investigation: Y.-P. Chang, C.-L. Tung, Y.-L. Chu and J.-H. Tsai. Methodology: C.-H.R. Lin, Y.-H. Yang and P.-S. Ho. Project administration: J.-H. Tsai. Resources: C.-L. Tung, J.-H. Tsai and Y.-L. Chu. Supervision: C.-H.R. Lin, Y.-H. Yang and P.-S. Ho. Validation: C.-H.R. Lin, Y.-H. Yang and P.-S. Ho. Writing-original draft: C.-S. Hung, Y.-P. Chang and J.-H. Tsai. Writing-review & editing: Y.-P. Chang and J.-H. Tsai. Critical manuscript for key intellectual content: All authors. DATA AVAILABILITY The data used in this study was collected on August 16, 2024 from the TriNetX Network. The platform aggregates de-identified electronic medical record data from numerous healthcare organizations. Due to data privacy regulations, patient-level data cannot be shared publicly. AUTHOR CONTRIBUTIONS: CSH, YPC and JHT had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization: CSH, YPC and JHT; Data curation: CSH, CHRL and JHT; Formal analysis: CHRL and PSH; Investigation: YPC, CLT, YLC and JHT; Methodology: CHRL, YHY and PSH; Project administration: JHT; Resources: CLT, JHT and YLC; Supervision: CHRL, YHY and PSH; Validation: CHRL, YHY and PSH; Writing-original draft: CSH, YPC and JHT; Writing-review & editing: YPC and JHT; Critical manuscript for key intellectual content: All authors. CONFLICTS OF INTEREST: The authors declare no potential conflicts of interest regarding the research, authorship, or publication of this article. FUNDING: None. References World Health Organization. Dementia. 2025. http://www.who.int/news-room/fact-shhets/detail/dementia Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry. 2000; 157:708–14. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. 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Mucci F, Arone A, Gurrieri R, Weiss F, Russomanno G, Marazziti D. Third-generation antipsychotics: the quest for the key to neurotrophism. Life (Basel). 2025; 15:391. Pai YW, Chen IC, Lin JF, Chen XH, Chen HH, Chang MH , et al: Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks. Diabetes Obes Metab. 2024; 26:5420–30. Sagris D, Ntaios G, Buckley BJR, Harrison SL, Underhill P, Lane DA, et al: Direct oral anticoagulants are associated with lower risk of dementia in patients with atrial fibrillation. Eur J Intern Med. 2024; 121:114–20. de Oliveira AM, Radanovic M, de Mello PC, Buchain PC, Vizzotto AD, Celestino DL, et al: Nonpharmacological interventions to reduce behavioral and psychological symptoms of dementia: a systematic review. Biomed Res Int. 2015; 2015:218980. Dyer SM, Harrison SL, Laver K, Whitehead C, Crotty M. An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. Int Psychogeriatr. 2018; 30:295–309. Abraha I, Rimland JM, Trotta FM, Dell'Aquila G, Cruz-Jentoft A, Petrovic M, et al: Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series. BMJ Open. 2017; 7:e012759. Douglas S, James I, Ballard C. Non-pharmacological interventions in dementia.Adv Psychiatr Treat. 2004; 10:171–77. Austin PC. An Introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011; 46:399–424. Beeri MS, Goldbourt U. Late-life dementia predicts mortality beyond established midlife risk factors. Am J Geriatr Psychiatry. 2011; 19:79–87 Chung SC, Providencia R, Sofat R, Pujades-Rodriguez M, Torralbo A, Fatemifar G, et al. Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals. Alzheimers Dement. 2023; 19:123–135 Golüke NMS, van de Vorst IE, Vaartjes IH, Geerlings MI, de Jonghe A, et al: Risk factors for in-hospital mortality in patients with dementia. Maturitas. 2019; 129:57–61. Sullivan GM, Feinn R. Using effect size-or why the p value is not enough. J Grad Med Educ. 2012; 4:279–82. Saito Y, Oishi S, Takizawa T, Muraoka H, Yoshimura Y, Hashimoto I, et al. Analysis of concomitant medications prescribed with antipsychotics to patients with dementia. Dement Geriatr Cogn Disord. 2023; 52:222–31 Kuroda N, Hamada S, Sakata N, Jeon B, Iijima K, Yoshie S, et al. Antipsychotic use and related factors among people with dementia aged 75 years or older in Japan: a comprehensive population-based estimation using medical and long-term care data. Int J Geriatr Psychiatry. 2019; 34:472–79. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005; 294:1934–43. Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, et al: Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005; 353:2335–41. Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, et al: The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009; 8:151–57. Phiri P, Engelthaler T, Carr H, Delanerolle G, Holmes C, Rathod S. Associated mortality risk of atypical antipsychotic medication in individuals with dementia. World J Psychiatry. 2022; 12:298–307. Kales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C, et al.Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry. 2012; 169:71–9. Li XQ, Tang XR, Li LL.Antipsychotics cardiotoxicity: What's known and what's next. World J Psychiatry. 2021; 11:736–53. Jeste DV, Blazer D, Casey D, Meeks T, Salzman C, Schneider L, et al: ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008; 33:957–70. Husebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ. 2011; 343:d4065 Additional Declarations The authors have declared there is NO conflict of interest to disclose Supplementary Files SupplementalOnlineContenteTable20250925.docx Supplemental Online Content eTable Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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16:36:52","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":134877,"visible":true,"origin":"","legend":"","description":"","filename":"2025MP0025110structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/c768e4221b41477ef8cc0e34.xml"},{"id":98248631,"identity":"08bd096e-095b-462b-9991-0a01df05fb1b","added_by":"auto","created_at":"2025-12-15 16:36:52","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":145095,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/8551f68c7e933ce0296aaee9.html"},{"id":98248617,"identity":"a114d8c9-1ca4-4084-a791-2eb949068f6b","added_by":"auto","created_at":"2025-12-15 16:36:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":160329,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of Patient Selection for Study and Control Cohorts.\u003c/strong\u003eAbbreviations: TAP, typical antipsychotic; AAP, atypical antipsychotic.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/a5e84c9dfba2f9c45942df24.png"},{"id":98434567,"identity":"70f91288-1558-4756-a880-0c640378d896","added_by":"auto","created_at":"2025-12-17 16:52:21","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66792,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier Survival Curves for the Composite Outcome of All-Cause Mortality in Patients with Senile Dementia Prescribed AAP Treatment Versus Controls. \u003c/strong\u003eAbbreviations: AAP, atypical antipsychotic. The log-rank test was significant (hazard ratio [HR], 1.590; 95% CI, 1.422-1.777) that survival was comparable between both groups.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/c96eb3c9a96e3ae9473a4403.png"},{"id":100358205,"identity":"c9c19363-5e14-475b-8952-11fc2bf6b1cd","added_by":"auto","created_at":"2026-01-16 07:20:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1222455,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/e0e67f18-ad44-42d3-bcfc-b698a2012dc8.pdf"},{"id":98248618,"identity":"b10a4fa9-1006-4439-9931-d0f82ba2e30f","added_by":"auto","created_at":"2025-12-15 16:36:52","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":69070,"visible":true,"origin":"","legend":"Supplemental Online Content eTable","description":"","filename":"SupplementalOnlineContenteTable20250925.docx","url":"https://assets-eu.researchsquare.com/files/rs-7795097/v1/d238b88ab61d5a590b448af4.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose","formattedTitle":"Association of atypical antipsychotic use with mortality risk in patients with behavioural and psychological symptoms of dementia","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eDementia is one of the leading causes of death and disability, affecting an estimated 57\u0026nbsp;million people worldwide in 2021, with nearly 10\u0026nbsp;million new cases reported each year [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. During the course of the illness, approximately 60% to 80% of patients with dementia develop behavioral and psychological symptoms of dementia (BPSD), which include agitation, aggression, depression, apathy, psychosis, sleep disturbances, repetitive questioning, wandering, and other inappropriate behaviors [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. BPSD may accelerate disease progression, reduce the quality of life of patients and their caregivers, lead to institutionalization, impose a substantial burden, and even result in death in the older population [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough the majority of best practice guidelines for BPSD recommend nonpharmacological interventions as the preferred first-line management and only judicious, short-term use of antipsychotics [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], implementing these approaches in clinical practice remains a major challenge. Several factors hinder the use of nonpharmacological interventions in real-world settings: severe disease presentations such as dementia with delirium and dementia with severe psychotic symptoms; the perceived lack of immediate efficacy compared with pharmacological treatments; the greater time and effort required, often without reimbursement for nonpharmacological treatments; the absence of clear guidelines on the timing and dosing of such interventions; and inadequate provider training in their application [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Regarding pharmacological treatments for BPSD, antipsychotics have been widely prescribed off-label in patients with dementia because of their immediate effectiveness, ease of use, and strong evidence base [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Atypical antipsychotics (AAPs) are preferred over conventional antipsychotics for the treatment of BPSD [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. No antipsychotics, including AAPs, have been approved by the US Food and Drug Administration (FDA) for the treatment of BPSD. In 2005 and 2008, the FDA issued warnings that patients with dementia prescribed antipsychotics had an increased risk of mortality. This warning was based on the results of 17 placebo-controlled trials [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The FDA granted supplemental approval for brexpiprazole, an AAP, for the treatment of agitation in patients with Alzheimer\u0026rsquo;s dementia in May 2023. Nevertheless, the FDA maintains that brexpiprazole increases mortality risk when used for this indication [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEvidence remains insufficient to support antipsychotics as an efficacy or safe alternative to nonpharmacological interventions for BPSD, especially in dementia with delirium or severe psychotic symptoms; physicians, patients, and their families are left with ambiguous choices for managing BPSD [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The decision to initiate any intervention in clinical practice requires balancing benefits and harms with potential quality-of-life improvements for patients and caregivers. Physicians often encounter difficulty in clarifying the clinical importance of absolute changes in benefits or harms [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, a clear understanding of the efficacy and safety profile of individual antipsychotics is critical to guide prescribing decisions, including the evaluation of mortality risks associated with AAP use in dementia and potential differences in mortality risk among specific AAPs [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The importance of shared decision-making and caution in antipsychotic use for BPSD is emphasized.\u003c/p\u003e\u003cp\u003eThis retrospective cohort study evaluated the risk of all-cause death in patients with dementia prescribed AAPs by using the TriNetX global network. The mortality risk posed by different AAPs was compared.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Ethics Statement\u003c/h2\u003e\u003cp\u003eWe conducted a global, population-based, retrospective cohort study to evaluate the risk of all-cause death in patients with dementia who were prescribed AAPs. Data were obtained from the TriNetX Global Collaborative Network, a computerized database containing more than 275\u0026nbsp;million patient records from 151 health-care organizations that provide de-identified electronic medical records to a central repository [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The AAPs included in the present study were clozapine, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, paliperidone, iloperidone, lurasidone, and brexpiprazole [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. To account for the limited number of patients prescribed newly-developed AAPs, we categorized AAPs by their pharmacological targets into 2 subgroups: second-generation antipsychotics (SGAs), namely clozapine, risperidone, olanzapine, quetiapine, ziprasidone, asenapine, and paliperidone, and third-generation antipsychotics (TGAs), namely aripiprazole, iloperidone, lurasidone, and brexpiprazole [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003e This study adhered to Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Because the data were de-identified, the need for informed consent was waived. The Institutional Review Board of Dalin Tzu Chi Hospital approved this study.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Patients\u003c/h3\u003e\n\u003cp\u003eWe enrolled patients aged 65 years or older who received a new diagnosis of dementia, identified using \u003cem\u003eInternational Classification of Diseases, Tenth Revision\u003c/em\u003e codes (F01, F02, F03, and G30) and the prescription of dementia medications (eg, donepezil [RXNORM:135447], rivastigmine [183379], galantamine [4637], or memantine [617]). Patients registered in the database between January 1, 2015, and December 31, 2024, with at least 3 clinical visits were enrolled [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Patients were excluded if they had received dementia medications or antipsychotics (ATC NA05A*) before the date of dementia diagnosis.\u003c/p\u003e\u003cp\u003eIn this study, we apply the Intent-to-Treat (ITT) principle to define exposure status. The AAP group comprised patients with dementia who had at least one exposure to an AAP after the date of dementia diagnosis. The control group consisted of patients with dementia who were antipsychotic-na\u0026iuml;ve and had received nonpharmacological interventions after the date of dementia diagnosis [\u003cspan additionalcitationids=\"CR26 CR27\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Detailed definitions of study medications, diagnoses, and nonpharmacological interventions for BPSD are provided in e-Table\u0026nbsp;1 of the Supplement Materials. ITT ensures that all patients, regardless of subsequent medication changes or discontinuations, are analyzed in the group to which they were initially assigned.\u003c/p\u003e\n\u003ch3\u003eMatching Process\u003c/h3\u003e\n\u003cp\u003eParticipants in both the AAP and control groups underwent 1:1 propensity score matching (PSM) to minimize confounding effects [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The propensity score model was adjusted for potential confounders examined before the date of dementia diagnosis, including demographic variables (eg, age, sex, and race), nicotine dependence (smoking), alcohol abuse (drinking), obesity, hypertension, diabetes mellitus, hyperlipidemia, ischemic heart disease, atrial fibrillation and flutter, heart failure, peripheral vascular disease, angina pectoris, cerebral infarction, transient cerebral ischemic attacks, chronic kidney disease, chronic obstructive pulmonary disease, sleep apnea, chronic liver disease, and malignant neoplasm (e-Table\u0026nbsp;2) [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe index date was defined as the date of AAP prescription for the AAP group and the date of the initiation of a recommended nonpharmacological intervention for the control group. Participants were followed from the index date until death or June 30, 2025. Data analysis was conducted on August 11, 2025.\u003c/p\u003e\n\u003ch3\u003eStudy Outcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was all-cause mortality. Secondary outcomes were the effects of specific AAPs, AAP class, and various health factors on mortality risk.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eAll statistical analyses were performed using the TriNetX platform. Baseline characteristics are presented as numbers and percentages for categorical variables and as means with standard deviations (SDs) for continuous variables. Group comparisons were conducted using Pearson\u0026rsquo;s chi-square test, for categorical variables and Student\u0026rsquo;s \u003cem\u003et\u003c/em\u003e test for continuous variables.\u003c/p\u003e\u003cp\u003eAfter PSM, the balance of potential confounding variables between the AAP and control groups was determined using standardized mean differences (SMDs), with a predefined threshold of 0.10 indicating adequate balance. A SMD was preferred over a \u003cem\u003eP\u003c/em\u003e value to quantify group differences because SMDs are less sensitive to sample size [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Survival analyses were conducted using the Kaplan-Meier method, and differences in the distribution of survival between the groups were evaluated using the log-rank test. Hazard ratios (HRs) and 95% CIs for the risk of death were estimated using a Cox proportional hazards regression model. A 2-tailed \u003cem\u003eP\u003c/em\u003e-value of ≦\u0026thinsp;.05 was considered statically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 311 488 patients who had received a new diagnosis of senile dementia between 2015 and 2024 were identified. After the exclusion of patients who had received antipsychotic treatment before the date of dementia diagnosis, the remaining patients were divided into 2 groups on the basis of their antipsychotic treatment status: 173 814 (57.4%) patients with dementia received no antipsychotic treatment, and 129 131 (42.6%) patients received antipsychotic treatment, including 72 805 (24.0%) who were prescribed AAPs. Furthermore, 3645 (1.2%) patients were not prescribed any antipsychotics but were treated with a concomitant nonpharmacological intervention. Thus, 72 805 patients were included in the AAP group, and 3645 patients were included in the control group. PSM resulted in 3347 patients per 1:1 matched cohort. A flowchart of the patient selection process is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eCharacteristics of the Study Cohort\u003c/h3\u003e\n\u003cp\u003eBefore PSM, the AAP group was younger (mean [SD] age, 77.6 [6.0] vs 78.8 [5.6] years) and had a greater proportion of men (42.7% vs 39.6%). The AAP group was less likely to have hypertension (61.3% vs 65.8%), diabetes mellitus (27.7% vs 33.9%), hyperlipidemia (45.3% vs 52.2%), ischemic heart disease (27.1% vs 32.4%), atrial fibrillation and flutter (16.3% vs 18.6%), heart failure (14.0% vs 17.4%), cerebral infarction (11.4% vs 15.3%), transient cerebral ischemic attack (6.5% vs 8.5%), chronic kidney disease (20.0% vs 24.6%), chronic obstructive pulmonary disease (11.9% vs 14.5%), and hepatic fibrosis (0.4% vs 0.9%). After PSM, the groups were well-balanced (SMD\u0026thinsp;\u0026lt;\u0026thinsp;0.1), with only minor residual imbalances. A full comparison of baseline characteristics before and after PSM is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and propensity score density curves before and after matching are depicted in eFig. 1 in Supplement 1.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Characteristics of Patients with Dementia Prescribed AAP Treatment and Controls\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"9\" nameend=\"c12\" namest=\"c4\"\u003e\u003cp\u003ePatients, No. (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c7\" namest=\"c4\"\u003e\u003cp\u003ePatient count before matching\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c12\" namest=\"c9\"\u003e\u003cp\u003ePatient count after matching\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eICD-10\u003c/p\u003e\u003cp\u003ecode\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;71 718)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3347)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSMD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eCase\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3347)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3347)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eSMD\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAge, mean (SD), y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e77.6 (6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e78.8 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.260\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e79.0 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e78.8 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e\u003cp\u003e0.040\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e41065 (57.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2021 (60.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2070 (61.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2021 (60.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.219\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30613 (42.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1326 (39.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.062\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1274 (38.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1326 (39.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.192\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.032\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eRace\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWhite\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2106-3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e50252 (70.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2206 (65.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.089\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2243 (67.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2206 (65.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBlack or African American\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2054-5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6948 (9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e259 (7.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e238 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e259 (7.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.328\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAsian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2028-9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3184 (4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e570 (17.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.415\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e563 (16.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e570 (17.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.820\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOther racea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2131-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1653 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e54 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e50 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e54 (1.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.693\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnknown race\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9817 (13.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e235 (7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e232 (6.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e235 (7.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.886\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eComorbidity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNicotine dependence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5526 (7.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e254 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.805\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e237(7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e254 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.425\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAlcohol abuse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF10.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1818 (2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e77 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.398\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e70 (2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e77 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.559\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.014\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eObesity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE66.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6918 (9.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e346 (10.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e339 (10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e346 (10.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.778\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e43937 (61.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2202 (65.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.094\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2243 (67.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2202 (65.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.289\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19852 (27.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1134 (33.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.135\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1080 (32.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1134 (33.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.034\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHyperlipidemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eE78.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e32456 (45.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1747 (52.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.139\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1734 (51.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1747 (52.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.750\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIschemic heart diseases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI20-I25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e19471 (27.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1084 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.115\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1040 (31.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1084 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.248\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.028\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAtrial fibrillation and flutter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11693 (16.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e623 (18.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.061\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e603 (18.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e623 (18.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.527\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHeart failure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10019 (14.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e583 (17.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.095\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e533 (15.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e583 (17.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.040\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePeripheral vascular diseases\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5569 (7.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e248 (7.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.452\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e236 (7.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e248 (7.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.571\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.014\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAngina pectoris\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3308 (4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e189 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e161 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e189 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.124\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.038\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCerebral infarction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eI63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8175 (11.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e458 (15.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e420 (12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e458 (13.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.169\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.034\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTransient cerebral ischemic attacks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4657 (6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e286 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e281 (8.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e286 (8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.826\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChronic kidney disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14353 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e822 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e784 (23.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e822 (24.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eJ44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8523 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e484 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e455 (13.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e484 (14.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.307\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSleep apnea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG47.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e9019 (12.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e432 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.572\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e399 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e432 (12.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.221\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHepatic fibrosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eK74.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e254 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e29 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e27 (0.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e29 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.788\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMalignant neoplasm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC80.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e755 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e43 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.201\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e38 (1.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e43 (1.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e\u003cp\u003e0.576\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e0.014\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"12\"\u003eAbbreviation: AAP, atypical antipsychotic; SMD, standard mean difference; SD, standard deviate; NA, not available.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003ea\u003c/sup\u003e Other race is defined internally by TriNetX.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eAll-Cause Mortality\u003c/h3\u003e\n\u003cp\u003eThe mean follow-up duration was 1736 days for the AAP group and 2666 days for the control group. After adjustment for covariates, the mortality rate was significantly higher in the AAP Group than in the control group (HR\u0026thinsp;=\u0026thinsp;1.590, 95% CI 1.422\u0026ndash;1.777; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk of All-Cause Mortality in Patients with Dementia Prescribed AAPs.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo. (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003cp\u003esurvival (days)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eOverall analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAAP treatment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e71 805\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.590 (1.422\u0026ndash;1.777)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1736/2666\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eControl*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3645\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(2666)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eSubgroup analysis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAge categories (y)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVery advanced old (\u0026ge;\u0026thinsp;85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26 355 (36.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.926 (1.814\u0026ndash;2.045)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1533/3326\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAdvanced old (75\u0026ndash;84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36 257 (49.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.467 (1.381\u0026ndash;1.559)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2162/3205\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eYoung old (65\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 120 (13.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 105 (42.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.458 (1.411\u0026ndash;1.505)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1538/2167\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41 668 (57.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(2167)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSubtype of dementia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAlzheimer's disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 055 (48.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.021 (0.976\u0026ndash;1.068)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1582/1688\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVascular dementia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12 889 (17.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e(1688)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eAAP classes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSGA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65 584 (90.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.678 (1.508\u0026ndash;1.867)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1609/2666\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTGA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3715 (5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.366 (1.200-1.554)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2162/3090\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3645\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eSpecific AAPs**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eQuetiapine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34 929 (48.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.520 (1.363\u0026ndash;1.694)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1971/2666\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOlanzapine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9283 (12.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.787 (1.598-2.000)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1577/2556\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRisperidone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7735 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.926 (1.728\u0026ndash;2.147)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1445/2666\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAripiprazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2814 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.230 (1.067\u0026ndash;1.418)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2404/2556\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBrexpiprazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e684 (0.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.157 (0.705-1.900)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-/-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3645\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHaloperidol***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.587 (2.322\u0026ndash;2.882)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1296/2564\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: AAP, atypical antipsychotic; SGA, second-generation antipsychotic; TGA, third-generation antipsychotic; HR, hazard ratio.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003cb\u003e*\u003c/b\u003e Patients with dementia who were antipsychotic-na\u0026iuml;ve and had received a documentation nonpharmacological intervention for behavioral and psychological symptoms of dementia after the date of dementia diagnosis.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e** clozapine (n\u0026thinsp;=\u0026thinsp;268), ziprasidone (n\u0026thinsp;=\u0026thinsp;563), asenapine (n\u0026thinsp;=\u0026thinsp;13), paliperidone (n\u0026thinsp;=\u0026thinsp;50), iloperidone (n\u0026thinsp;=\u0026thinsp;10), lurasidone (n\u0026thinsp;=\u0026thinsp;116).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e*** belonging to typical antipsychotics\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eEffects of Demographic Factors on Mortality Risk\u003c/h2\u003e\u003cp\u003eWe examined mortality risk in subgroups stratified by age, sex, and dementia subtypes (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). For age, patients were classified into 3 categories: very advanced old (\u0026ge;\u0026thinsp;85 years), advanced old (75\u0026ndash;84 years), and young old (65\u0026ndash;74 years). Patients in the very advanced old group (HR\u0026thinsp;=\u0026thinsp;1.926, 95% CI 1.814\u0026ndash;2.045) and the advanced old group (HR\u0026thinsp;=\u0026thinsp;1.467, 95% CI 1.381\u0026ndash;1.559) had a significantly higher risk of all-cause mortality than did those in the young old group. Male patients with dementia who were prescribed AAPs had a higher risk of all-cause mortality than did female patients who were prescribed AAPs (HR\u0026thinsp;=\u0026thinsp;1.458, 95% CI 1.411\u0026ndash;1.505). When dementia subtypes were examined, patients with Alzheimer disease had a slightly higher but not statistically significant risk of all-cause mortality than did those with vascular dementia (HR\u0026thinsp;=\u0026thinsp;1.021, 95% CI 0.976\u0026ndash;1.068).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eEffects of AAP Class and Specific AAPS on Mortality Risk\u003c/h2\u003e\u003cp\u003eAAPs were categorized into 2 classes on the basis of their pharmacological target: SGAs and TGAs. Patients with dementia prescribed SGAs had a significantly higher risk of all-cause mortality than did controls (HR\u0026thinsp;=\u0026thinsp;1.678, 95% CI 1.508\u0026ndash;1.867). Patients prescribed TGAs also had a significantly higher risk of all-cause mortality than did controls, but their risk was lower than that associated with SGAs (HR\u0026thinsp;=\u0026thinsp;1.366, 95% CI 1.200\u0026ndash;1.554).\u003c/p\u003e\u003cp\u003eAmong 129 131 antipsychotic-exposed patients, 72 805 (56.4%) were prescribed an AAP. The 4 most commonly prescribed medications were quetiapine (34 929 [48.0%]), olanzapine (9283 [12.8%]), risperidone (7735 [10.6%]), and aripiprazole (2814 [3.9%]). Additionally, 684 (0.9%) patients were prescribed brexpiprazole, and 13 338 received haloperidol (a conventional antipsychotics; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Relative to nonpharmacological interventions, AAP use was associated with an increase of all-cause mortality. Mortality risk was highest for risperidone (HR\u0026thinsp;=\u0026thinsp;1.926, 95% CI 1.728\u0026ndash;2.147), followed by olanzapine (HR\u0026thinsp;=\u0026thinsp;1.787, 95% CI 1.598\u0026ndash;2.000), quetiapine (HR\u0026thinsp;=\u0026thinsp;1.520, 95% CI 1.363\u0026ndash;1.694), aripiprazole (HR\u0026thinsp;=\u0026thinsp;1.230, 95% CI, 1.067\u0026ndash;1.418), and brexpiprazole (HR\u0026thinsp;=\u0026thinsp;1.157, 95% CI 0.705\u0026ndash;1.900). Additionally, the HR for all-cause mortality associated with haloperidol use was 2.587 (95% CI 2.322\u0026ndash;2.882; Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAccording to a review of the literature, this is the first study to examine the difference in mortality risks among patients with dementia prescribed different AAP classes and specific AAPs by using the TriNetX global dataset. Data from 311 488 patients who received a new diagnosis of senile dementia between 2015 and 2024 were analyzed, including 72 805 patients prescribed AAPs and 3645 controls treated with nonpharmacological interventions instead of antipsychotics. After adjustment for covariates, patients with dementia prescribed AAPs had an approximately 1.6-fold higher risk of all-cause mortality than did controls. Notably, the risk of all-cause mortality varied by AAP types, with risperidone, olanzapine, quetiapine, aripiprazole, and brexpiprazole posing the greatest risks (in descending order).\u003c/p\u003e\u003cp\u003eThe rate of antipsychotic prescriptions in patients with dementia was 42.6%. This rate is higher than that reported in other studies-antipsychotic prescription rates in older patients with dementia range from 10% to 15% [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. One possible explanation for this finding is the difference in assessment methods. Antipsychotic prescription in the present study was defined as having at least one exposure to antipsychotics after the date of dementia diagnosis. Consequently, 24% of patients with dementia were prescribed AAPs, and 1.2% of patients received no antipsychotics and were treated solely with concomitant nonpharmacological interventions. This finding suggests that nonpharmacological interventions for the treatment of BPSD are challenging to implement in clinical practice. AAP prescriptions are more common and are easier to apply in real-world settings [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Before PSM, patients with dementia who were prescribed AAPs were younger and had a lower prevalence of physical comorbidities than did those treated with nonpharmacological interventions. This finding indicates that physicians generally prefer AAP treatment for younger and healthier patients with dementia and prefer nonpharmacological interventions for older and less healthy patients.\u003c/p\u003e\u003cp\u003eOur primary finding revealed that AAP treatment was associated with an increased mortality risk in patients with dementia, consistent with the findings of preliminary studies (17 double-blind, randomized, placebo-controlled trials in older patients with dementia) that reported an approximately 1.5-fold higher mortality risk with AAP use compared with placebo [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Although AAP treatment for BPSD substantially reduces mortality risk compared with conventional antipsychotics (from approximately 2.5-fold to 1.5-fold) [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], patients with dementia prescribed AAPs still have an increased risk of death. Therefore, strategies to minimize this risk are crucial when the clinical use of AAPs is indicated in patients with dementia.\u003c/p\u003e\u003cp\u003eWe identified potential risk factors for mortality in patients with dementia treated with AAPs. Alzheimer\u0026rsquo;s disease is recognized as a risk factor for mortality associated with long-term antipsychotic use (38).Our findings exhibited a similar trend with AAP treatment, although the association between AAP use and an increased mortality risk was not significant for vascular dementia. Male sex and older age were identified as risk factors for all-cause mortality in patients with dementia prescribed AAPs in the present study. We further analyzed differences in mortality risk associated with specific AAPs. First, we confirmed evidence that the risk of mortality is highest in patients with dementia prescribed haloperidol, followed by risperidone, olanzapine, and quetiapine [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Second, we categorized AAPs into SGAs and TGAs on the basis of their pharmacological targets, considering the number of patients prescribed newer AAPs. Our findings indicated a higher mortality risk in patients with dementia treated with SGAs than in those treated with TGAs. This finding suggests that TGAs have more favorable cardiac and metabolic outcomes than do SGAs, potentially reducing the risk of mortality [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Finally, when evaluating mortality risk across all AAPs, including brexpiprazole, we observed that the risk of all-cause mortality in patients with dementia varied by specific AAPs, in descending order: risperidone, olanzapine, quetiapine, aripiprazole, and brexpiprazole. Additional evidence is required to confirm whether brexpiprazole is the safest of the currently available antipsychotics for treating BPSD.\u003c/p\u003e\u003cp\u003eThe growing body of evidence regarding the mortality risk of antipsychotic treatment for BPSD has led to considerable pressure to limit their use in real-world settings. Although the causes of death among patients with dementia receiving antipsychotics varied, most deaths were attributable to cardiovascular disease (eg, sudden cardiac death and heart failure) or infection (eg, pneumonia and urinary tract infection) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The findings of the present and other studies provide insights into the pathways that may lead to death. Notably, providing better care for patients with dementia treated with AAPs, particularly for male and older patients, may help prevent adverse effects. For example, infection-related mortality could be reduced by monitoring for antipsychotic-induced dysphagia, improving oral hygiene, adhering to routine vaccination recommendations, and maintaining vigilance for the early detection and treatment of chest infections. Additionally, electrocardiogram monitoring for prolonged QTc intervals should be considered in routine clinical practice [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The findings of the present study provide critical information that can help physicians minimize potential harms at multiple decision points. Regarding the choice of AAPs, the current study provides further evidence supporting the use of brexpiprazole for managing BPSD when an antipsychotic is deemed necessary. Such use should be integrated within a framework to improve the overall management of BPSD, including the appropriate implementation of nonpharmacological interventions, effective relief of pain and discomfort, and judicious, short-term use of AAPs when clinically indicated [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and Limitations\u003c/h2\u003e\u003cp\u003eThe primary strength of this study is the use of a large-scale cohort design that enabled us to determine the difference in mortality risk among patients with dementia posed by specific AAPs. These findings provide a valuable reference for clinicians in determining whether their patients are likely to benefit from treatment for BPSD. Although this study was retrospective, the cohort approach within a global database reduced the likelihood of selection and recall biases. Another strength is the incorporation of a time lag between medication exposure and outcome measurement, which helps address concerns related to reverse causality and disease latency as well as prevents immortal time bias. Finally, the use of PSM allowed for control of clinically and prognostically relevant factors, thereby minimizing the risk of bias from confounding.\u003c/p\u003e\u003cp\u003eThis study has some limitations that should be considered. First, adherence to prescribed drugs and information on dementia severity and BPSD could not be evaluated because the study was based on an administrative claims database. Second, the prevalence of dementia and comorbidities, such as obesity, hypertension, diabetes, and cardiovascular disease, may have been underestimated because patients with no or mild symptoms might not seek medical care. Third, we could not account for dietary and other potential confounders of death, including disease severity, biochemical and electrocardiographic results, and unhealthy lifestyle factors such as sweetened beverage consumption and inadequate exercise. Finally, changes to prescribed drugs that occurred outside of health-care organizations would not have been captured in the TriNetX health research network.\u003c/p\u003e\u003c/div\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis large-scale, real-world cohort study demonstrates that AAP treatment\u0026nbsp;is associated with a significantly increased mortality risk in patients with dementia, with varying risks among AAP classes and specific AAPs.\u0026nbsp;Clinicians treating patients with BPSD should be aware of the relatively favorable safety profile of brexpiprazole. Future research should focus on developing new pharmacotherapy for BPSD that do not increase mortality risk in patients with dementia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDrs\u0026nbsp;C.-S. Hung, Y.-P. Chang and J.-H. Tsai had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConceptualization:\u003c/em\u003e C.-S. Hung, Y.-P. Chang and J.-H. Tsai.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData curation:\u003c/em\u003e C.-S. Hung, C.-H.R. Lin and J.-H. Tsai\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFormal analysis:\u003c/em\u003e C.-H.R. Lin and P.-S. Ho\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInvestigation:\u003c/em\u003e Y.-P. Chang, C.-L. Tung, Y.-L. Chu and J.-H. Tsai.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethodology:\u003c/em\u003e C.-H.R. Lin, Y.-H. Yang and P.-S. Ho.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProject administration:\u003c/em\u003e J.-H. Tsai.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eResources:\u003c/em\u003e C.-L. Tung, J.-H. Tsai and Y.-L. Chu.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSupervision:\u003c/em\u003e C.-H.R. Lin, Y.-H. Yang and P.-S. Ho.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eValidation:\u0026nbsp;\u003c/em\u003eC.-H.R. Lin, Y.-H. Yang and P.-S. Ho.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWriting-original draft:\u003c/em\u003e C.-S. Hung, Y.-P. Chang and J.-H. Tsai.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWriting-review \u0026amp; editing:\u003c/em\u003e Y.-P. Chang and J.-H. Tsai.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCritical manuscript for key intellectual content:\u003c/em\u003e All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study was collected on August 16, 2024 from the TriNetX Network. The platform aggregates de-identified electronic medical record data from numerous healthcare organizations. Due to data privacy regulations, patient-level data cannot be shared publicly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCSH,\u0026nbsp;YPC\u0026nbsp;and JHT had full access to all the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003eConceptualization:\u0026nbsp;CSH, YPC and JHT;\u0026nbsp;Data curation:\u0026nbsp;CSH, CHRL and JHT;\u003c/p\u003e\n\u003cp\u003eFormal analysis: CHRL and PSH; Investigation: YPC,\u0026nbsp;CLT, YLC and JHT;\u003c/p\u003e\n\u003cp\u003eMethodology: CHRL, YHY and PSH;\u0026nbsp;Project administration: JHT;\u003c/p\u003e\n\u003cp\u003eResources:\u0026nbsp;CLT, JHT and YLC; Supervision: CHRL, YHY and PSH; Validation: CHRL, YHY and PSH; Writing-original draft: CSH, YPC and JHT; Writing-review \u0026amp; editing: YPC and JHT; Critical manuscript for key intellectual content: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICTS OF INTEREST:\u003c/strong\u003e The authors declare no potential conflicts of interest regarding the research, authorship, or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING:\u003c/strong\u003e None.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eWorld Health Organization. Dementia. 2025. http://www.who.int/news-room/fact-shhets/detail/dementia\u003c/li\u003e\n \u003cli\u003eLyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC.\u0026nbsp;Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry. 2000; 157:708\u0026ndash;14.\u003c/li\u003e\n \u003cli\u003eLyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S.\u0026nbsp;Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002; 288:1475-83.\u003c/li\u003e\n \u003cli\u003eKales HC, Gitlin LN, Lyketsos CG. Assessment and management of behavioral and psychological symptoms of dementia. BMJ. 2015; 350:h369.\u003c/li\u003e\n \u003cli\u003eGuideline Adaptation Committee. Clinical Practice Guidelines and Principles of Care for People with Dementia. 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Psychiatric Times. 2024; 41.\u003c/li\u003e\n \u003cli\u003eJeste DV, Blazer D, Casey D, Meeks T, Salzman C, Schneider L, T\u0026nbsp;et al: ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008; 33:957\u0026ndash;70.\u003c/li\u003e\n \u003cli\u003eMaust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS,\u0026nbsp;et al: Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015; 72:438\u0026ndash;45\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCorbett A, Ballard C.Antipsychotics and mortality in dementia. Am J Psychiatry. 2012; 169:7\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eData Sets. TriNetX. https://trinetx.com/products/real-world-datasets/.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePalchuk MB, London JW, Perez-Rey D, Drebert ZJ, Winer-Jones JP, Thompson CN, et al. A global federated real-world data and analytics platform for research. 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Biomed Res Int. 2015; 2015:218980.\u003c/li\u003e\n \u003cli\u003eDyer SM, Harrison SL, Laver K, Whitehead C, Crotty M.\u0026nbsp;An overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia. Int Psychogeriatr. 2018; 30:295\u0026ndash;309.\u003c/li\u003e\n \u003cli\u003eAbraha I, Rimland JM, Trotta FM, Dell\u0026apos;Aquila G, Cruz-Jentoft A, Petrovic M,\u0026nbsp;et al: Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series. BMJ Open. 2017; 7:e012759.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDouglas S, James I, Ballard C. Non-pharmacological interventions in dementia.Adv Psychiatr Treat. 2004; 10:171\u0026ndash;77.\u003c/li\u003e\n \u003cli\u003eAustin PC. An Introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011; 46:399\u0026ndash;424.\u003c/li\u003e\n \u003cli\u003eBeeri MS, Goldbourt U. Late-life dementia predicts mortality beyond established midlife risk factors. Am J Geriatr Psychiatry. 2011; 19:79\u0026ndash;87\u003c/li\u003e\n \u003cli\u003eChung SC, Providencia R, Sofat R, Pujades-Rodriguez M, Torralbo A, Fatemifar G, et al. Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals. Alzheimers Dement. 2023; 19:123\u0026ndash;135\u003c/li\u003e\n \u003cli\u003eGol\u0026uuml;ke NMS, van de Vorst IE, Vaartjes IH, Geerlings MI, de Jonghe A,\u0026nbsp;\u0026nbsp;et al: Risk factors for in-hospital mortality in patients with dementia. Maturitas. 2019; 129:57\u0026ndash;61.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSullivan GM, Feinn R. Using effect size-or why the p value is not enough. 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JAMA. 2005; 294:1934\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eWang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH, et al: Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005; 353:2335\u0026ndash;41.\u003c/li\u003e\n \u003cli\u003eBallard C, Hanney ML, Theodoulou M, Douglas S, McShane R, et al: The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009; 8:151\u0026ndash;57.\u003c/li\u003e\n \u003cli\u003ePhiri P, Engelthaler T, Carr H, Delanerolle G, Holmes C, Rathod S.\u0026nbsp;Associated mortality risk of atypical antipsychotic medication in individuals with dementia. World J Psychiatry. 2022; 12:298\u0026ndash;307.\u003c/li\u003e\n \u003cli\u003eKales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C,\u0026nbsp;et al.Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry. 2012; 169:71\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eLi XQ, Tang XR, Li LL.Antipsychotics cardiotoxicity: What\u0026apos;s known and what\u0026apos;s next. World J Psychiatry. 2021; 11:736\u0026ndash;53.\u003c/li\u003e\n \u003cli\u003eJeste DV, Blazer D, Casey D, Meeks T, Salzman C, Schneider L, et al: ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology. 2008; 33:957\u0026ndash;70.\u003c/li\u003e\n \u003cli\u003eHusebo BS, Ballard C, Sandvik R, Nilsen OB, Aarsland D. Efficacy of treating pain to reduce behavioural disturbances in residents of nursing homes with dementia: cluster randomised clinical trial. BMJ. 2011; 343:d4065\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7795097/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7795097/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAtypical antipsychotics (AAPs) are widely used to treat behavioral and psychological symptoms of dementia (BPSD). The mortality risk posed by AAP treatment remains unclear. This global, population-based, retrospective cohort study compared all-cause mortality risk between patients with dementia prescribed AAPs and those prescribed nonpharmacological interventions instead of AAPs. Propensity score matching was performed to optimize comparability. Participants were enrolled between 2015 and 2024 by using the Global Collaborative Network of the TriNetX platform. The primary outcome was the rate of all-cause mortality from initial AAP use until death or June 30, 2025, using the Intent-to-Treat principle to define exposure status and Kaplan\u0026ndash;Meier analyses. 72 805 patients with dementia prescribed AAPs were included in an AAP group, and 3645 patients treated with concomitant nonpharmacological interventions instead of AAPs were included in a control group. After propensity score matching, AAP use was associated with a 59.0% increased risk of all-cause mortality compared with nonpharmacological interventions (HR\u0026thinsp;=\u0026thinsp;1.590, 95% CI 1.422\u0026ndash;1.777). Regarding the risk of specific AAPs, all-cause mortality HRs, in descending order, were as follows: 1.926 (95% CI 1.728\u0026ndash;2.147) for risperidone, 1.787 (95% CI 1.598\u0026ndash;2.000) for olanzapine, 1.520 (95% CI 1.363\u0026ndash;1.694) for quetiapine, 1.230 (95% CI 1.067\u0026ndash;1.418) for aripiprazole, and 1.157 (95% CI 0.705\u0026ndash;1.900) for brexpiprazole. This study showed that AAP use is associated with a significantly increased risk of mortality in patients with dementia. These findings highlight the importance of cautious AAP use for BPSD and suggest that brexpiprazole has a more favorable safety profile.\u003c/p\u003e","manuscriptTitle":"Association of atypical antipsychotic use with mortality risk in patients with behavioural and psychological symptoms of dementia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-15 16:36:47","doi":"10.21203/rs.3.rs-7795097/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"787fc16b-1a65-4fd5-b8ee-c41c4c1a393f","owner":[],"postedDate":"December 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59382058,"name":"Health sciences/Diseases/Psychiatric disorders/Schizophrenia"},{"id":59382059,"name":"Health sciences/Diseases/Psychiatric disorders/Depression"}],"tags":[],"updatedAt":"2026-01-09T11:15:59+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-15 16:36:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7795097","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7795097","identity":"rs-7795097","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}