Antidepressants and the risk of sudden cardiac death and ventricular arrhythmia

Abstract

Purpose To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition Methods A cohort study was conducted within 1999–2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually-eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. Results In 1.3 million person-years of antidepressant exposure, we identified 4,222 SD/VA outcomes for a rate of 3.3/1,000 person-years (95% CI, 3.2 – 3.4). Compared to paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HRs) were 0.80 (0.67 – 0.95) for bupropion, 1.24 (0.93 – 1.65) for doxepin, 0.79 (0.55 – 1.15) for lithium, and 1.26 (1.11 – 1.42) for mirtazapine. HRs for amitriptyline, citalopram, fluoxetine, nefazodone, nortriptyline, sertraline, trazodone, and venlafaxine were near unity. For antidepressants having non-null risks (bupropion and mirtazapine), we observed no relationship with antidepressant dose and some relationships with concomitant cytochrome P-450 inhibition. Conclusions Of antidepressants studied, only mirtazapine had a statistically significantly greater SD/VA risk versus paroxetine. However, baseline differences between these users suggest that this finding may be attributable to residual confounding. Eleven other antidepressants had SD/VA risks no greater than that of paroxetine, thereby providing reassurance regarding the comparative cardiovascular safety of antidepressants.

Evaluation of the FDA Warning Against Prescribing Citalopram at Doses Exceeding 40 mg

“…These findings raise questions regarding the continued merit of the FDA warning and provide support for the question of whether the warning itself will cause more harm than good (18). These findings add to another recent pharmacoepidemiology study that did not find evidence that citalopram is associated with elevations in the risks of QTc prolongation and torsade de pointes (19). The link between citalopram and torsade de pointes is primarily derived from case reports (20).…”

Risk of QT/QTc Prolongation Among Newer Non-SSRI Antidepressants

“…25 The risk for SCD/VA was significantly greater with mirtazapine than paroxetine, with a hazard ratio of 1.26 (1.11-1.42). However, this observation may be confounded by the population using mirtazapine, which consisted of elderly patients with more comorbidities.…”

Management of Depression After Myocardial Infarction

“…Citalopram dose is associated with QTc interval prolongation [40•], and reports of torsades de pointes and sudden cardiac death led the US Food and Drug Administration to require a boxed warning against the use of citalopram doses above 40 mg daily [41]. The increased relative risk is probably low [42,43], and several other studies do not find an association of citalopram with sudden cardiac death [44][45][46].…”