Risk of Cardiovascular Events in Schizophrenic Patients Treated with Paliperidone Palmitate Once-Monthly Injection (PP1M): A Population-Based Retrospective Cohort Study in Taiwan.

BACKGROUND: Schizophrenia is one of the leading causes of disability. Paliperidone palmitate once-monthly injection (PP1M) was developed to provide consistent drug delivery and improve medication adherence for maintenance treatment. It is well known that patients with schizophrenia have higher cardiovascular risks, however little is known about the cardiovascular risks of patients with schizophrenia treated with PP1M in Asia. OBJECTIVE: This study aimed to estimate the incidence of cardiovascular events after initiating PP1M treatment and evaluate the cardiovascular risk associations compared with oral second-generation antipsychotics (SGAs). METHODS: Data from Taiwan's National Health Insurance Research Database were used to identify a cohort of adult patients with schizophrenia who received any SGAs from 1 March 2012 to 31 December 2018. Patients who initiated PP1M treatment were enrolled for descriptive analysis of incidence rates. PP1M patients were propensity matched 1:1 to patients initiating a new oral SGA, for comparative analysis based on demographics, clinical characteristics and treatment history at baseline, in three-step matching procedures, following the prevalent new-user design to enhance comparability. Follow-up ended at the end of the treatment episode of index drug, death, last record available, or end of the study (31 December 2019). Study endpoints included serious cardiovascular events (including severe ventricular arrhythmia and sudden death), expanded serious cardiovascular events (which further included acute myocardial infarction and ischemic stroke), and cardiovascular hospitalizations. Risks of study endpoints between matched cohorts were compared using Cox regression. RESULTS: Overall, 11,023 patients initiating PP1M treatment were identified (49.5% were females; mean age of 43.2 [12.2] years). Overall incidences for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 3.92, 7.88 and 51.96 per 1000 person-years, respectively. In matched cohort analysis (N = 10,115), the hazard ratios (HRs) between initiating PP1M and a new oral SGA for serious cardiovascular events, expanded serious cardiovascular events, and cardiovascular hospitalizations were 0.86 (95% confidence interval [CI] 0.55-1.36), 0.88 (95% CI 0.63-1.21), and 0.78 (95% CI 0.69-0.89), respectively. CONCLUSION: This study reported the population-based incidence of cardiovascular events in schizophrenic patients initiating PP1M treatment. PP1M was not associated with increased risks of serious cardiovascular events but was potentially associated with lower risks of cardiovascular hospitalizations compared with oral SGAs.

Healthcare resource utilization and costs associated with generalized myasthenia gravis: a retrospective matched cohort study using the National Health Insurance Research Database in Taiwan.

Background: We estimated healthcare resource utilization (HRU) and costs in patients with generalized myasthenia gravis (gMG) in Taiwan. Methods: This retrospective population-based, matched cohort study used the National Health Insurance Research Database to identify prevalent patients with gMG (cases) in 2019. In total, 2537 cases were matched (1:4) by age, sex, and urbanization level to 10148 randomly selected patients without gMG (comparators). A generalized linear regression model predicted the frequency of HRU and costs among service users. Costs attributable to gMG were obtained by subtracting all-cause HRU costs incurred by comparators from cases. Results: The mean age of all patients was 54.99 years and 55.97% were female. Compared with comparators, cases had significantly higher rates of hypertension (33.03%/24.26%), diabetes mellitus (18.92%/11.37%), malignancies (16.00%/4.08%), cardiovascular disease (11.35%/8.12%), thyroid-related conditions (5.99%/1.16%), respiratory illness/disorders (4.38%/1.22%), and neurotic disorders (4.65%/2.6%). Amongst users of healthcare resources, cases had a mean 10 additional outpatient visits, 0.62 inpatient stays, and 0.49 emergency room visits in 2019 compared with comparators (p < 0.0001 for all). The mean (standard deviation) difference in all-cause healthcare costs between cases and comparators was NT$ 94997 (76431) [US$ 3133 (2521)], and was significantly higher for all categories (outpatient, inpatient, emergency room, drugs; p < 0.0001 for all). Among employed persons, 13.18%/7.59% of cases/comparators changed employment status during the study (p < 0.0001). Conclusion: gMG presents a substantial burden on HRU and healthcare costs in Taiwan. A high attrition rate from full-time employment suggests additional societal costs. Improved treatments are needed to alleviate the burden of disease on individuals, healthcare systems, and economies.

The growing burden of generalized myasthenia gravis: a population-based retrospective cohort study in Taiwan.

Background: The prevalence of myasthenia gravis is increasing in many countries, including Asia. As treatment options expand, population-based information about the disease burden can inform health technology assessments. Methods: We conducted a population-based retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to describe the epidemiology, disease burden and treatment patterns of generalized myasthenia gravis (gMG) from 2009 to 2019. Episodes of hepatitis B virus (HBV) infection or reactivation were explored. Results: The number of patients with gMG increased from 1,576 in 2009 to 2,638 in 2019 and the mean (standard deviation) age from 51.63 (17.32) to 55.38 (16.29) years. The female:male ratio was 1.3:1. Frequently reported co-morbidities were hypertension (32-34% of patients), diabetes mellitus (16-21%) and malignancies (12-17%). The prevalence of patients with gMG increased annually from 6.83/100,000 population in 2009 to 11.18/100,000 population in 2019 (p < 0.0001). There was no temporal trend in all-cause fatality rates (range 2.76-3.79/100 patients annually) or gMG incidence rates (2.4-3.17/100,000 population annually). First-line treatment was with pyridostigmine (82%), steroids (58%), and azathioprine (11%). There was minimal change in treatment patterns over time. Among 147 new HBV infections, 32 (22%) received ≥4 weeks of antiviral therapy suggesting chronic infection. The HBV reactivation rate was 7.2%. Conclusion: The epidemiology of gMG in Taiwan is evolving rapidly, with higher prevalence rates and increasing involvement of older age-groups suggesting a growing burden of disease and associated healthcare costs. HBV infection or reactivation may pose a previously unrecognized recognized risk for patients with gMG receiving immunosuppressants.

A population-based cohort study of the epidemiology of light-chain amyloidosis in Taiwan.

The incidence rate of AL (light-chain) amyloidosis is not known in Asia. We conducted a retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Death Registry to estimate incidence and all-cause case fatality rates, and characteristics of patients with AL amyloidosis in Taiwan. All patients with confirmed, newly diagnosed AL amyloidosis from 01-Jan-2016 until 31-Dec-2019 were enrolled and followed up until dis-enrolment, death or study end (31-Dec-2019). There were 841 patients with newly diagnosed AL amyloidosis with median age of 61.4 years and 58.7% were men. At diagnosis, cardiac, renal and liver-related diseases were present in 28.54%, 23.19% and 2.14% of patients, respectively. AL amyloidosis age-adjusted annual incidence was 5.73 per million population in 2016 and 5.26 per million population in 2019. All-cause case fatality ranged from 1.7 to 2.9% over the study period and was highest (~10%) in patients ≥ 80 years. Survival was significantly lower in patients with co-morbid cardiac, renal, or liver-related diseases which could indicate organ involvement. The incidence of AL amyloidosis in Taiwan appears to be similar to Western countries. The poor prognosis in patients with co-morbid diseases highlights the need for earlier diagnosis.

Risks of all-cause death and completed suicide in patients with schizophrenia/schizoaffective disorder treated with long-acting injectable or oral antipsychotics: A population-based retrospective cohort study in Taiwan.

BACKGROUND: Long-acting injectable (LAI) antipsychotics improve medication adherence in patients with schizophrenia and extend the duration of therapeutic drug levels but with administration of an increased dose. Real-world mortality data in patients prescribed LAIs are lacking. We conducted a population-based cohort study to estimate and compare the incidence rates of all-cause death and completed suicide in patients with schizophrenia/schizoaffective disorder exposed to LAIs and oral antipsychotics. METHODS: Patients with a diagnosis of schizophrenia/schizoaffective disorder between January 1, 2015 and November 30, 2019 were enrolled from the Taiwan National Health Insurance Research Database and linked to Death Registry records. Eligible patients were new antipsychotic users. Relative risks of death for each antipsychotic compared with oral paliperidone were evaluated using a Cox proportional hazard model adjusted for age, sex, Charlson Comorbidity Index, index year, bipolar or major depressive or other mood disorders, mental disorders due to drug use, and baseline hospitalization frequency. RESULTS: There were 228,791.08 person-years of follow-up (mean 2.48 years). The incidence rates of all-cause death in users of LAI paliperidone administered monthly (PP1M) and every 3 months (PP3M) were 7.40/1,000 person-years (95% confidence interval 5.94-9.11) and 9.93 (5.88-15.79), respectively. The incidences of completed suicide were 2.03/1,000 person-years (1.32-2.99) and 3.10 (1.14-6.88), respectively. No significant associations were observed between PP1M and PP3M compared to oral paliperidone in incidences of all-cause death or for completed suicide. DISCUSSION: No increased risk of all-cause death or completed suicide was observed in users of antipsychotic LAIs, including PP1M and PP3M.

The risk of bone fracture after long-term risperidone exposure is not increased compared to other atypical antipsychotics: A retrospective cohort study.

OBJECTIVE: Antipsychotic agents can increase circulating serum prolactin levels, potentially leading to osteoporosis and increased risk of bone fracture. The risk appears to be lower for atypical antipsychotics. We investigated whether risperidone was associated with an increased fracture risk by estimating the incidence of hip/femur and non-hip/femur fractures in users of risperidone, other atypical, and typical antipsychotics. METHODS: This retrospective cohort study with a nested case-control study used claims data from the Taiwan National Healthcare Insurance database. All new users of antipsychotics between 2000-2012 were included. Incident fractures were identified using ICD-9 codes from inpatient records. Cox proportional hazards models compared fracture incidence among exposure groups. Conditional logistic regression models compared antipsychotic exposure among fracture cases versus matched controls. RESULTS: 340,948 patients were included in the analysis. There were 2832 hip/femur fractures and 2693 non-hip/femur fractures: Hip/femur fracture incidence 636.8/100,000 person-years (Risperidone), 885.7/100,000 person-years (Other Atypical), 519.4/100,000 person-years (Typical). The adjusted hazard ratio of hip/femur fracture was 0.92 (95%CI 0.84-1.01) comparing Other Atypical with Risperidone, and 1.00 (95%CI 0.89-1.11) comparing Typical with Risperidone. The adjusted hazard ratio of non-hip/femur fracture was 1.08 (95%CI 0.98-1.20) for Other Atypical versus Risperidone, and 1.10 (95%CI 0.99-1.22) for Typical versus Risperidone. The adjusted odds ratio for hip/femur fractures was 0.92 (95% CI 0.83-1.01) in cases and controls exposed to other atypical antipsychotics compared with risperidone for 1 year prior to fracture date, 0.97 (95% CI 0.87-1.07) during 1-3 years, and 0.92 (95% CI 0.81-1.06) during 3-5 years prior to fracture date. The adjusted odds ratio for non-hip/femur fractures were 1.11 (95% CI 0.99-1.24), 1.02 (95% CI 0.0.91-1.14), and 0.95 (95% CI 0.82-1.09), respectively. CONCLUSION: There was no increased risk of bone fracture in long-term users of risperidone compared to users of other atypical antipsychotics.

A comparison of hospital and community stay in patients who underwent compulsory admission before and after the 2007 Amendment to the Mental Health Act in Taiwan.

OBJECTIVE: The main purpose of this study was to assess the empirical findings of compulsory admission for psychiatric disorders before and after the 2007 amendment to the Mental Health Act in Taiwan. METHODS: A matched case-control study design was applied. Participants were selected using the National Health Insurance Research Database (NHIRD) in Taiwan. The control and case data were collected in 2006 and 2011, and the number of compulsory admission cases was recorded with a case-control ratio of 1:4, along with information on age (±3 years) and gender. In 2006, the number of patients recruited was 9265, including 1853 compulsorily admitted patients and 7412 voluntarily admitted patients. In 2011, the number of patients recruited was 4505, including 901 compulsorily admitted patients and 3604 voluntarily admitted patients. RESULTS: The data collected for the patients who underwent compulsory admission before and after the amended Mental Health Act included gender, diagnosis, Charlson Comorbidity Index Score (CCIS), length of stay in an acute hospital ward (days), hospital accreditation level, ownership, teaching hospital status, psychiatrist gender and age, and hospital location. Although the number of compulsory admission cases (1853 vs. 901) markedly decreased and the length of stay in an acute hospital ward (30.7 ±â€¯25.0 days vs. 39.0 ±â€¯22.6 days) increased from 2006 to 2011, the readmission rate was reduced from 52.6% in 2006 to 42.5% in 2011. CONCLUSIONS: The average lengths of hospital stay and community survival time were greater for compulsorily admitted patients than those for voluntarily admitted patients. This result might be attributed to a number of changes implemented since the 2007 amendment of the Mental Health Act, including a strict review process for compulsory admissions and a new discharge planning process, which require further research for approval.

Myst2/Kat7 histone acetyltransferase interaction proteomics reveals tumour-suppressor Niam as a novel binding partner in embryonic stem cells.

MYST histone acetyltransferases have crucial functions in transcription, replication and DNA repair and are hence implicated in development and cancer. Here we characterise Myst2/Kat7/Hbo1 protein interactions in mouse embryonic stem cells by affinity purification coupled to mass spectrometry. This study confirms that in embryonic stem cells Myst2 is part of H3 and H4 histone acetylation complexes similar to those described in somatic cells. We identify a novel Myst2-associated protein, the tumour suppressor protein Niam (Nuclear Interactor of ARF and Mdm2). Human NIAM is involved in chromosome segregation, p53 regulation and cell proliferation in somatic cells, but its role in embryonic stem cells is unknown. We describe the first Niam embryonic stem cell interactome, which includes proteins with roles in DNA replication and repair, transcription, splicing and ribosome biogenesis. Many of Myst2 and Niam binding partners are required for correct embryonic development, implicating Myst2 and Niam in the cooperative regulation of this process and suggesting a novel role for Niam in embryonic biology. The data provides a useful resource for exploring Myst2 and Niam essential cellular functions and should contribute to deeper understanding of organism early development and survival as well as cancer. Data are available via ProteomeXchange with identifier PXD005987.

Cancer in patients with schizophrenia: What is the next step?

People with schizophrenia, who constitute approximately 0.3-1% of the general population, have a nearly 20% shorter life expectancy than the general population. The incidence of varied types of cancers in patients with schizophrenia is controversial. The majority of previous research has demonstrated that patients who have schizophrenia and cancer have early mortality compared to the general population with cancer. The causes of early mortality in patients with schizophrenia and cancer might be attributed to a lower cancer screening rate and lack of effective treatment, including: (i) patient factors, such as poor lifestyle, passive attitude toward treatment, or comorbidity; (ii) physician factors, such as physician bias, which may decrease the delivery of care for individuals with mental disorders; and (iii) hospital administration factors, such as stigma and discrimination. Additional studies on patients with schizophrenia and cancer are warranted and should include the following: a comprehensive review of previous studies; a focus on differentiating the specific types of cancer; and methods for improvement. To decrease the early mortality of patients with schizophrenia, the following measures are proposed: (i) enhance early detection and early treatment, such as increasing the cancer screening rate for patients with schizophrenia; (ii) provide effective, timely treatment and rehabilitation; (iii) improve patients' psychiatric symptoms and cognitive impairment; (iv) promote healthy behavior in the general population and emphasize healthy lifestyles in vulnerable populations; and (v) remove the stigma of schizophrenia. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this group of patients.

EphA2 is a biomarker of hMSCs derived from human placenta and umbilical cord.

OBJECTIVE: The heterogeneous nature of mesenchymal stem cells (MSCs) and the absence of known MSC-specific biomarkers make it challenging to define MSC phenotypes and characteristics. In this study, we compared the phenotypic and functional features of human placenta-derived MSCs with those of human dermal fibroblasts in vitro in order to identify a biomarker that can be used to increase the purity of MSCs in a primary culture of placenta-derived cells. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry analysis was used to analyze and compare the proteome of human placenta-derived MSCs with that of fibroblasts. Quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to determine expression levels of EphA2 in placenta-derived MSCs. EphA2-positive cells were enriched by magnetic-activated cell sorting or with a cell sorter. An shRNA-mediated EphA2 knockdown was used to assess the role of EphA2 in MSC response to Tumor necrosis factor (TNF)-α stimulation. RESULTS: Analysis of proteomics data from MSCs and fibroblasts resulted in the identification of the EphA2 surface protein biomarker, which could reliably distinguish MSCs from fibroblasts. EphA2 was significantly upregulated in placenta-derived MSCs when compared to fibroblasts. EphA2 played an important role in MSC migration in response to inflammatory stimuli, such as TNF-α. EphA2-enriched MSCs were also more responsive to inflammatory stimuli in vitro when compared to unsorted MSCs, indicating a role for EphA2 in the immunomodulatory functionality of MSCs. CONCLUSION: EphA2 can be used to distinguish and isolate MSCs from a primary culture of placenta-derived cells. EphA2-sorted MSCs exhibited superior responsiveness to TNF-α signaling in an inflammatory environment compared with unsorted MSCs or MSC-like cells.

The risks of major osteoporotic fractures in patients with schizophrenia: a population-based 10-year follow-up study.

OBJECTIVE: The aim of the study is to explore the incidence and the risks associated with major osteoporotic fractures, all-cause mortality with osteoporotic fractures and the effect of the psychiatric drug exposure in patients with schizophrenia during a 10-year follow-up period. METHODS: Two nationwide cohorts were selected from the Taiwan National Health Insurance Research Database (NHIRD) consisting of 30,335 patients with schizophrenia (age ≥ 40 years) and 121,340 age- and sex-matched control participants without schizophrenia. The psychiatric proportion of days covered (PDC) is an indicator of the intensity of drug exposure in patients with schizophrenia. The incidence and risk factors of major osteoporotic fractures were calculated for both cohorts. Additionally, the patient survival rate after major osteoporotic fractures was also calculated. RESULTS: During a 10-year follow-up period, 1677 (5.53%) schizophrenia and 4257 (3.51%) control subjects had major osteoporotic fractures (P < 0.001). The schizophrenia patients with a PDC > 0.1 showed a significantly higher incidence of major osteoporotic fractures than did the non-schizophrenia controls; however, those with a psychiatric PDC ≤ 0.1 did not. After adjustment, the psychiatric PDC was significantly and independently associated with the risk of major osteoporotic fractures except some medical morbidities but the schizophrenia diagnosis was not. In addition, among all 5934 patients with major osteoporotic fracture, the adjusted mortality hazard ratio for psychiatric PDC was 1.92 (95% CI = 1.63-2.26). CONCLUSIONS: Patients with schizophrenia are at a higher risk for major osteoporotic fractures than the general population and also have a higher mortality rate due to major osteoporotic fractures. These findings may be caused by psychiatric drug use rather than schizophrenia, which suggests that directions can be taken in future studies.

Is low individual socioeconomic status (SES) in high-SES areas the same as low individual SES in low-SES areas: a 10-year follow-up schizophrenia study.

OBJECTIVE: This study investigates the relationship between individual and neighborhood socioeconomic status (SES) and mortality among patients with schizophrenia. METHODS: A study population was identified from the National Health Insurance Research Database (NHIRD) prior to the end of 1999 that included 60,402 patients with schizophrenia. Each patient was tracked until death or to the end of 2009. Individual SESs were defined by enrollee category. Neighborhood SES was defined by enrollee category (as a proxy for occupation) and education, which were classified according to the conventions of Hollingshead. Neighborhoods were also grouped into advantaged and disadvantaged areas. The Cox proportional hazards model was used to compare the death-free survival rate between the different SES groups after adjusting for possible confounding factors and risk factors. RESULTS: During the 10-year follow-up period, the mortality rates among high, moderate, and low individual SES groups were 12.22, 14.75, and 18.48%, respectively (P < 0.001). Schizophrenia patients with low individual SESs in disadvantaged neighborhoods had a risk of death that was 18-22% higher than that of those with high individual SES in advantaged neighborhoods. The analysis of the combined effect of individual SES and neighborhood SES revealed that the death rates were highest among those with low individual SES and low neighborhood SES (P < 0.001). CONCLUSIONS: Schizophrenia patients with low individual SES in disadvantaged neighborhoods have the highest risk of mortality despite a universal health-care system. Public health strategies and welfare policies must continue to focus on this vulnerable group.

The incidence and relative risk of stroke among patients with bipolar disorder: a seven-year follow-up study.

OBJECTIVE: This study aimed to estimate the incidence and relative risk of stroke and post-stroke all-cause mortality among patients with bipolar disorder. METHODS: This study identified a study population from the National Health Insurance Research Database (NHIRD) between 1999 and 2003 that included 16,821 patients with bipolar disorder and 67,284 age- and sex-matched control participants without bipolar disorder. The participants who had experienced a stroke between 1999 and 2003 were excluded and were randomly selected from the NHIRD. The incidence of stroke (ICD-9-CM code 430-438) and patient survival after stroke were calculated for both groups using data from the NIHRD between 2004 and 2010. A Cox proportional-hazards model was used to compare the seven-year stroke-free survival rate and all-cause mortality rate across the two cohorts after adjusting for confounding risk factors. RESULTS: A total of 472 (2.81%) patients with bipolar disorder and 1,443 (2.14%) controls had strokes over seven years. Patients with bipolar disorder were 1.24 times more likely to have a stroke (95% CI = 1.12-1.38; p<0.0001) after adjusting for demographic characteristics and comorbid medical conditions. In addition, 513 (26.8%) patients who had a stroke died during the follow-up period. The all-cause mortality hazard ratio for patients with bipolar disorder was 1.28 (95% CI = 1.06-1.55; p = 0.012) after adjusting for patient, physician and hospital variables. CONCLUSIONS: The likelihood of developing a stroke was greater among patients with bipolar disorder than controls, and the all-cause mortality rate was higher among patients with bipolar disorder than controls during a seven-year follow-up period.

A comparison of quality of life and depression between female married immigrants and native married women in Taiwan.

BACKGROUNDS: Immigration to Taiwan is often connected with marriage, resulting in the presence of so-called married immigrants or foreign brides. AIMS: To compare the quality of life (QOL) and prevalence of depression between female married immigrants and native married women. METHODS: Trained assistants used the Medical Outcomes Study Short Form-36 (MOS SF-36) and the disaster-related psychological screening test (DRPST) to interview 1,602 married women who were 16-50 years of age. Half (801) of the participants were female immigrants, whilst the remainder comprised the age-matched control group that consisted of 801 native married women. Participants who scored C2 (probable major depressive episode) on the DRPST were assessed according to DSM-IV criteria by a senior psychiatrist. The MOS SF-36 measures QOL and has two dimensions: the physical component summary (PCS) and the mental component summary (MCS). RESULTS: Married immigrants had a lower prevalence (3.5%) of major depressive episodes than native women (8.9%) in Taiwan. Variables such as an increased severity of psychosocial impact were the best predictors of a lower PCS and MCS. CONCLUSION: Compared to Taiwanese native married women, fewer married immigrants had stressful life events or depression, and they reported higher QOL. After controlling for putative confounding factors, the married immigrants still had better mental QOL and a lower prevalence rate of depression