79 - Relative cardiotoxicity

Relative cardiotoxicity

412 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 3 Use in at-­risk patients There is clear evidence for the safety of sertraline46 and mirtazapine47 (and to a lesser extent, citalopram,47 fluoxetine48 and bupropion49) in people at risk of arrhythmia due to recent MI. One trial found that SSRIs and trazodone decrease the risk of MI,50 another suggested no effect in either direction for any antidepressant.51 Citalopram seems to be safe to use in patients with coronary artery disease52 (despite its link to a risk of torsades de pointes).53 Escitalopram did not affect mortality in a trial in patients with heart failure,54 and a later systematic review found no adverse effect on mortality for any SSRIs in heart failure.55 Sertraline may help improve cardiovascular risk factors.56 Recent pharmacovigilance database studies report some association between antidepressants and cardiac arrythmias and cardiovascular death.57,58 Meta-­analysis suggests that overall, antidepressants (SSRIs, SNRIs and TCAs) are associated with an increased risk of atrial fibrillation but not ventricular arrythmias or sudden cardiac death.59 Conflicting results are reported in elderly patients, with cohort studies reporting both increased risk of arrythmias60 and no increased risk.61 Relative cardiotoxicity Relative cardiotoxicity of antidepressants is difficult to establish. Surveillance monitoring data suggest that many marketed antidepressants are linked to arrhythmia (ranging from clinically insignificant to life threatening) and sudden cardiac death. For a substantial proportion of drugs, these figures are perhaps more likely to reflect coincidence and/or confounding rather than causation. The Fatal Toxicity Index (FTI) may provide some means for comparison, at least for overdose toxicity. This is a measure of the number of overdose deaths per million (FP10) prescriptions issued. FTI figures suggest high toxicity for all tricyclic drugs (but not lofepramine), medium toxicity for venlafaxine and moclobemide, and low toxicity for SSRIs, mirtazapine and reboxetine.62–66 However, FTI does not necessarily reflect only cardiotoxicity (antidepressants also cause serotonin syndrome, seizures and coma, for example) and is, in any case, open to other influences. This is best evidenced in the change in FTI over time. A good example here is nortriptyline, the FTI of which has been estimated at 0.616 and 39.212 and several values in between.67 This change probably reflects changes in the type of patient prescribed nortriptyline but double counting (nortriptyline is a metabolite of amitriptyline) at post mortem also plays a part. Venlafaxine is relatively more often prescribed to patients with more severe depression and who are relatively more likely to attempt suicide.68–70 This is apt to inflate venlafaxine’s FTI and erroneously suggest greater inherent toxicity. Drugs with consistently low FTIs can probably be assumed to have very low risk of arrhythmias. Citalopram and escitalopram have surprisingly low overdose toxicity, despite QT prolongation occurring in about a third of reported overdoses.71 Standard doses of citalopram may be causally associated with an increased risk of cardiac arrest6 but, as mentioned earlier, other data suggest no increased risk of arrhythmia or death with standard and higher licensed doses of citalopram and escitalopram.34 Citalopram and escitalopram are probably the most cardiotoxic of the SSRIs but their toxicity is modest at worst, and possibly insignificant in respect to risk of adverse outcomes.