Association of antipsychotic formulations with sudden cardiac death in patients with schizophrenia: A nationwide population-based case-control study

“Among the leading causes of this premature mortality are suicide, accidents, and sudden cardiac death (SCD) (Crump et al., 2013; Saha et al., 2007; Sweeting et al., 2013).”

“However, over half of patients with schizophrenia exhibit poor or no adherence to medication (Byerly et al., 2007; Chan et al., 2017; Lacro et al., 2002; Velligan et al., 2006).”

“Antipsychotic medications may increase the risk of serious ventricular arrhythmias such as TdP, probably QT interval prolongation through blockade of potassium ion channels (Ray et al., 2009; Straus et al., 2004).”

“The standardized mean difference (SMD) was used to evaluate the balance of covariates, with an absolute SMD below 0.1 indicating a balanced distribution (Zhang et al., 2019).”

“Weights were calculated as 1/propensity score for cases and 1/ (1 (cid:0) propensity score) for controls (Chesnaye et al., 2012).”

“Comedications included digoxin and drugs known to increase the risk of torsade de pointes (TdP) (Glassman and Bigger, 2001; Suvi-saari et al., 2010) (see Table S3).”

“It often leads to premature death, shortening life expectancy by 10 to 25 years (Crump et al., 2013).”

“Antipsychotic medications form the cornerstone of treatment for schizophrenia (Lally and MacCabe, 2015; Zhu et al., 2019).”

“We excluded patients with missing data on sex or age, those younger than 20 years, and older than 60 years, considering the rarity of SCD in younger individuals (Liberthson, 1996) and differing aetiologies in older individuals.”

“This omission is notable because smoking is a potential SCD risk factor and the prevalence of smoking is high among patients with schizophrenia (Kannel et al., 1975; Ray et al., 2001).”

“…hypertension, epilepsy, depression or other mood disorders, ischemic cerebrovascular disease, diabetes mellitus, heart failure, alcohol abuse or alcoholism, cardiovascular disease, and obesity (Adabag et al., 2010; Hou et al., 2015; Nemeroff et al., 2002; Straus et al., 2004) (see Table S2).”

“(Jones et al., 2013; Ray et al., 2001, 2009; R. Girardin et al., 2013; Straus et al., 2004; Wu et al., 2015).”

“However, over half of patients with schizophrenia exhibit poor or no adherence to medication (Byerly et al., 2007; Chan et al., 2017; Lacro et al., 2002; Velligan et al., 2006).”

“…are associated with an increased risk of premature death from SCD. Patients on either first-or second-generation antipsychotics typically face a similar, dose-related increased risk of SCD (Jones et al., 2013; Ray et al., 2001, 2009; R. Girardin et al., 2013; Straus et al., 2004; Wu et al., 2015).”

“…predisposition, autonomic effects, other acute cardiotoxicity, inhibition of other ion channels, and pharmacokinetic and pharmacodynamic interactions (Abdelmawla and Mitchell, 2006; Buckley et al., 2000; Ray et al., 2009; Sheehan et al., 2012; Sicouri and Antzelevitch, 2018; Straus et al., 2004).”

“Compared with the general population, patients with schizophrenia face a threefold higher risk of sudden unexpected death (Appleby et al., 2000; Ruschena et al., 1998).”

“(Jones et al., 2013; Ray et al., 2001, 2009; R. Girardin et al., 2013; Straus et al., 2004; Wu et al., 2015).”

“However, over half of patients with schizophrenia exhibit poor or no adherence to medication (Byerly et al., 2007; Chan et al., 2017; Lacro et al., 2002; Velligan et al., 2006).”

“(Jones et al., 2013; Ray et al., 2001, 2009; R. Girardin et al., 2013; Straus et al., 2004; Wu et al., 2015).”

“Compared with the general population, patients with schizophrenia face a threefold higher risk of sudden unexpected death (Appleby et al., 2000; Ruschena et al., 1998).”

“Furthermore, a genetic mechanism by which antipsychotics might induce SCD relates to the gene mutations encoding potassium ion channel proteins (i.e., SCN5A, KCNQ1, and KCNH2 ) (Sicouri and Antzelevitch, 2018).”

“Although the occurrence of antipsychotic-induced SCD is rare, the potential for fatal adverse effects may lead to restrictions on prescribing certain antipsychotics, particularly LAIs, to patients with schizophrenia (Zhu et al., 2019).”

“SCD was defined as immediate death with an underlying cardiac disease cause, identified using cardiac death codes ( ICD-9-CM and ICD-10-CM codes) from the NHIRD and MCOD data (Chung et al., 2010) (see Table S2).”

“Among the leading causes of this premature mortality are suicide, accidents, and sudden cardiac death (SCD) (Crump et al., 2013; Saha et al., 2007; Sweeting et al., 2013).”

“The primary strength of this study lies in its large sample size, which represents nearly the entire population of Taiwan.”

“Specifically, polypharmacy and high-dose antipsychotics are widely considered to be an important and the clearest evidence for an elevated SCD risk related to drug-drug interactions in pharmacodynamics and pharmacokinetics (Abdelmawla and Mitchell, 2006).”

“Compared with OAPs, larger fluctuations in peak-to-through concentrations of LAIs may negatively impact clinical response and adverse effects (Correll et al., 2019; Sheehan et al., 2012).”

“We also used propensity score matching and IPW to mitigate biases potentially arising from suboptimal specificity of models for estimating propensity scores or outcome regressions (Chan et al., 2017).”

“Such methods are imperative because patients with severe psychotic symptoms that are not appropriately managed may place themselves at risk of infection and potentially contribute to the spread of COVID-19, which can undermine infection control efforts (MacLaurin et al., 2021).”

“LAIs have emerged as an optimal pharmacotherapeutic regimen to prevent relapse in patients with schizophrenia, particularly young patients who struggle with medication adherence (Miron et al., 2022).”

“While other studies [29–31] did not find specific genetic mutations clearly causing sud - den death in patients with schizophrenia, they did identify shared genetic markers between certain arrhythmic disorders and schizophrenia.”

“Recent nationwide data suggest that antipsychotic formulation may influence sudden cardiac death risk: compared with oral monotherapy, LAI monotherapy, and especially LAI– oral combinations were associated with higher SCD risk, particularly among patients with cardiovascular comorbidities [38].”