Contents lists available at ScienceDirect Asian Journal of Psychiatry journal homepage: www.elsevier.com/locate/ajp Association of antipsychotics adherence and cardiovascular disease among newly diagnosed schizophrenia patients: A national cohort among Koreans Jooyoung Chang a , Jihoon Andrew Kim b , Kyuwoong Kim a , Seulggie Choi a , Sung Min Kim a , Yoon-Young Nam c , Subin Park d , Ae Jin Goo e, **, Sang Min Park a,f, * a Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea b Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA c Department of Psychiatry, National Center for Mental Health, Seoul, South Korea d Department of Research Planning, National Center for Mental Health, Seoul, South Korea e Department of Family Medicine, National Center for Mental Health, Seoul, South Korea f Department of Family Medicine, Seoul National University Hospital, 127, Yongmasan-ro, Gwangjin-gu, Seoul, South Korea ARTICLE INFO Keywords: Adherence Antipsychotics Schizophrenia Cardiovascular disease All-cause mortality Cohort ABSTRACT Background: The effect of antipsychotics adherence on the risk of cardiovascular disease (CVD) among schizo- phrenia patients has not been studied. While antipsychotic adherence is favorable for all-cause mortality, its association with CVD incidence is unclear due to the potential risk of CVD caused by antipsychotics. Methods: Using the Korean National Health Insurance Service Database, we constructed a case-cohort of 80,581 newly-diagnosed schizophrenia patients between 2004 and 2013 from a cohort of all Koreans 20–40 years old. Patients were divided into quartiles by adherence determined by their two-year medication possession ratio. Patients were followed from two years following the diagnosis of schizophrenia until Dec. 31st, 2017 for the primary outcome of incident CVD and secondary outcomes of stroke, myocardial infarction, and all-cause mortality. Cox proportional hazards analysis was performed adjusting for conventional risk factors. Outcomes: Newly diagnosed schizophrenia patients were followed for a median of 7.0 years resulting in 1396 incident CVD cases over 5.73 × 10 5 person-years. When adjusted for potential confounders, the best adherence quartile group had significantly lower risk of CVD (HR, 95%CI; 0.78, 0.66-0.92; p-trend, 0.003), stroke (HR, 95%CI; 0.79, 0.66-0.94; p-trend, 0.015), and all-cause mortality (HR, 95%CI; 0.86, 0.78-0.95; p-trend, 0.003) compared to the worst adherent quartile group. Subgroup analysis by antipsychotics generation, concurrent medication, and comorbidities did not significantly alter results. Interpretation: Among newly diagnosed schizophrenia patients, better adherence to antipsychotics lowered the risk CVD incidence despite previously suggested antipsychotic-associated CVD risk. Thus, efforts to improve antipsychotics adherence may improve CVD outcomes in schizophrenia patients. 1. Introduction Schizophrenia is a severe mental illness which has a lifetime pre- valence of 0.48%, (Simeone et al., 2015) and schizophrenia patients have higher prevalence and incidence of cardiovascular disease (CVD) than non-schizophrenia patients.(Correll et al., 2017) Thus, preventing CVD of schizophrenia patients is of clinical importance. Antipsychotic medication leads to less frequent relapse, control of symptoms, better functional outcomes, and survival rates,(Baandrup et al., 2010; Tiihonen et al., 2011, 2006) but have been suggested to increase the risk of cardiovascular disease (Correll et al., 2015a,b; De Hert et al., 2011) In a Finnish claims-based cohort study, levomepro- mazine increased cardiovascular deaths.(Kiviniemi et al., 2013) In Swedish claims-based cohort study, low-dose antipsychotics use was associated with decreased cardiovascular mortality compared to non- users, but the dose-response u-shaped curve suggested greater risk at higher doses.(Tiihonen et al., 2015) However, such studies do not account for the adherence of anti- psychotic medication, and the analysis of CVD risk without the con- sideration for adherence may not properly reflect the real-world. Up to https://doi.org/10.1016/j.ajp.2020.102161 Received 1 March 2020; Received in revised form 17 April 2020; Accepted 4 May 2020 ⁎ Corresponding authors at: Department of Family Medicine and Biomedical Sciences, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, South Korea. ⁎⁎ Corresponding author at: Department of Family Medicine, National Center for Mental Health, Seoul, South Korea. E-mail addresses: chokyul211@gmail.com (A.J. Goo), smpark.snuh@gmail.com (S.M. Park). Asian Journal of Psychiatry 52 (2020) 102161 1876-2018/ © 2020 Elsevier B.V. All rights reserved. T