2008; medical Thomas and Ellingrod,

2009], and can interact with other medications by inhibiting various isoenzymes of the cytochrome P450 (CYP) enzyme system [Greenblatt et al. 1998; Kelly et al. 2010; Spina et al. 2003]. Depression is especially common in patients with cardiovascular disease [Schleifer et al. 1989], and metoprolol is commonly prescribed to patients with ischemic heart disease. Since the initial finding that depression is associated with increased mortality after acute myocardial infarction [Frasure-Smith et al. 1995], the association between depression and cardiovascular disease has also assumed a high profile [Bush et al. 2005], and has been the subject of a large, randomized controlled trial showing Inhibitors,research,lifescience,medical the safety of sertraline in patients with cardiovascular disease [Glassman et al. 2002]. Inhibitors,research,lifescience,medical Indeed, increased awareness of the implications of depression in cardiovascular illness has likely increased the rate of antidepressant prescriptions in patients with coronary disease. Metoprolol toxicity manifests primarily as conduction disturbances, Inhibitors,research,lifescience,medical generally including bradycardia. Metoprolol is metabolized primarily by CYP2D6, a highly polymorphic enzyme inactive in roughly 7% of white people. People exhibiting this ‘poor metabolizer’ phenotype display more metoprolol-related adverse events [Wuttke et al.

2002]. This is relevant because fluoxetine and paroxetine are potent inhibitors of CYP2D6 [Alfaro et al. 2000; Lam et al. 2002]. Indeed, the initiation of paroxetine in patients receiving Inhibitors,research,lifescience,medical metoprolol could provoke metoprolol-related bradycardia, as has been described in case reports [Goryachkina et al. 2008; Onalan et al. 2008]. Metoprolol is frequently prescribed with fluoxetine or paroxetine [Molden et al. 2005] and in vitro evidence suggests that fluoxetine and paroxetine are more likely than other antidepressants to interact with metoprolol to cause bradycardia [Alfaro et al. 2000; Belpaire et al. 1998; Inhibitors,research,lifescience,medical Hemeryck et al. 2001; Walley et al. 1993; Yoon et al. 2000]. We speculated that, among older patients

receiving metoprolol, the initiation of antidepressants that inhibit CYP2D6 would be associated with an increased risk of bradycardia-related hospital visits. To test this of hypothesis, we conducted a nested case–control study examining the risk of bradycardia in older patients taking metoprolol who recently commenced an antidepressant. Methods Setting and design We conducted a nested case–control analysis of multiple linked healthcare databases spanning 13 years (1 April 1997 to 31 March 2009) in Ontario, Canada. Ontario is Canada’s most populous province with a registered population of 13,069,200 in 2009, of whom 1,787,900 were 65 years of age or older. Ontario’s older residents have universal access to hospital care, physician services, and prescription drug coverage.