Patients with schizophrenia have higher mortality and shortened life expectancy than the general population, and cardiovascular disease (CVD) accounts for up to 50% cases of early mortality in schizophrenia. We determined risk factors, particularly pathophysiological changes, for early circulatory mortality in schizophrenia. In this multi-institutional, nested, case–control study, we enrolled consecutive inpatients with schizophrenia admitted to three psychiatric hospitals in the northern Taiwan. Seventy-nine patients who died of CVD before 65 years of age were identified as cases through record linkage, and 158 controls were randomly selected in a 2:1 ratio through risk-set density sampling, after matching for age ( ± ۲ years), sex, and index admission ( ± ۳ years). Data were obtained through medical record reviews. At the time of death, the mean age of the patients was 47.5 years (standard deviation = 10.3). Conditional logistic regression revealed that the duration of antipsychotic treatment was significantly associated with a lower risk of early circulatory mortality, and leukocyte counts at index hospitalization were significantly associated with a higher risk. Systemic inflammation may be a risk factor for early circulatory mortality in schizophrenia, but antipsychotic treatment, in particular typical antipsychotic treatment, could be a protective factor.

Introduction

Schizophrenia typically has a debilitating course and is associated with 2–۴ times higher mortality and 10–۲۵ years of shortened life expectancy in early adults than in the general population worldwide (Crump et al., 2013; Laursen et al., 2012; McGrath et al., 2008; Saha et al., 2007; Wildgust and Beary, 2010). Cardiovascular disease (CVD) is the principal cause of death among natural and unnatural deaths, accounting for up to 50% cases of early mortality in schizophrenia (Hennekens et al., 2005; Laursen et al., 2014; Lemogne et al., 2013; Sweeting et al., 2013), with a 10-fold higher risk than that of suicide (Kisely et al., 2013). Studies have identified many risk factors for circulatory mortality, including smoking, hypertension, physical inactivity, unhealthy lifestyle, obesity, dyslipidemia, hyperglycemia, psychotropic agents, suboptimal medical treatment, and social disadvantages (Brown and Mitchell, 2012; Correll et al., 2015; Laursen et al., 2012). However, it remains unclear whether the increased mortality is mediated by traditional risk factors for CVD or is associated with an unidentified and inherent mental illness pathophysiology. Growing evidence shows that systemic inflammation may play an important role in the pathophysiology of schizophrenia (Muller et al., 2015). Neuroinflammation-related immune alterations may influence dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission (Muller et al., 2015), resulting in an increased risk of CVD and early death in schizophrenia. Systemic inflammation may involve the cardiovascular and cerebrovascular systems, which should be considered while investigating the association between schizophrenia and early mortality due to circulatory system diseases (Hsu et al., 2016; Wang et al., 2006). The effects of psychotropic agents on the risk of CVD are controversial. Some studies have suggested that antipsychotics increase the risk of cardiovascular mortality because of the tendency of metabolic syndrome, orthostatic hypotension, corrected QT segment (QTc) changes, sudden death, and myocarditis (Acharya et al., 2013; Hsieh et al., 2013; Shulman et al., 2014), whereas other studies have highlighted the benefits of reduced cardiovascular risk because of adequate treatment responses with improved self-care ability (Crump et al., 2013; Suvisaari et al., 2013; Tiihonen et al., 2009) and the anti-inflammatory properties of antipsychotics (Al-Amin et al., 2013; Kato et al., 2011).