In their editorial, Appleby et al (2000) indicated that the mechanism of sudden death among patients taking antipsychotic medications might be ventricular arrhythmias and that QTc prolongation might be a particularly important harbinger of these events.
Another electrocardiographic sign (without prolonged QTc) that may be associated with sudden death from ventricular fibrillation is the Brugada sign (i.e. right bundle branch block and elevation of the ST segment; Reference Brugada and BrugadaBrugada & Brugada, 1992). Buckley & Sanders (Reference Buckley and Sanders2000) have commented that although no specific antipsychotic has been directly associated with the Brugada sign (unlike the tricyclic antidepressants), anti-psychotic medications with the capacity to block sodium channels may precipitate this and possibly lead to sudden death.
In addition to the risk factors mentioned, drug-drug interaction is an important consideration. Drugs like the tricyclic antidepressants and lithium, with their propensity to prolong the QT interval, may have a synergistic additive effect when combined with an antipsychotic medication. Inhibition of the cytochrome P450 enzymes involved in the metabolism of psychotropic drugs leads to increased blood levels, and prolongation of the QT interval in individuals taking antipsychotic medications such as haloperidol, sertindole, risperidone and olanzapine occurs in a concentration-related manner (Reference Drici, Wang and LiuDrici et al, 1998). Certain selective serotonin reuptake inhibitors (fluvoxamine, paroxetine) are potent inhibitors of some of these cytochrome P450 enzymes. Grapefruit juice, although seemingly innocuous, has attained some notoriety from its association with prolonged QT intervals in individuals taking terfenadine and has been implicated in one death (Reference JeffersonJefferson, 1998). Grapefruit juice is a potent inhibitor of the P450 CYP1A2, 2A6 and 3A4 enzymes, which are important in the metabolism of clozapine, amitriptyline, imipramine and clomipramine. Clinicians should therefore be mindful of these interactions and give the appropriate warning to their patients taking these medications.
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