Association of Antipsychotic and Antidepressant Drugs With Q-T interval Prolongation

Wesley R. Zemrak, Pharm.D.; George A. Kenna, Ph.D., B.S.Pharm.

Disclosures

Am J Health Syst Pharm. 2008;65(11):1029-1038. 

In This Article

Evidence of Q-T Interval Prolongation

Relative to Q-Tc interval prolongation, the primary difference between tricyclic antidepressants and SSRIs is due to effects of the drugs on hERG potassium ion channels in cardiomyocytes. The SSRIs are more likely to cause bradycardia than tachycardia; the latter often leads to arrhythmias with tricyclic antidepressants.[63,64] Overall, the SSRIs are not typically linked to an increased risk of Q-Tc interval prolongation. Though tricyclic antidepressants have been associated with Class I antiarrhythmic properties, one study showed that imipramine (whose antiarrhythmic properties are similar to quinidine’s) was only marginally effective in preventing premature ventricular contractions.[65]

Vieweg and Wood[66] highlighted several case reports of Q-Tc interval prolongation associated with the use of tricyclic antidepressants. Amitriptyline and maprotiline were the drugs most commonly implicated in these cases.

Ray et al.[26] conducted a retrospective cohort study to establish the risk of SCD in Tennessee Medicaid recipients receiving therapy with a tricyclic antidepressant or an SSRI. Approximately 480,000 patient records were screened. Deaths were attributed to the antidepressant if the patient did not have a coexisting cardiac condition. The patient group not taking any antidepressant served as the control. The use of SSRIs did not increase the risk of SCD (incidence rate ratio [IRR], 0.95; 95% confidence interval [CI], 0.42-2.15). Compared with patients not taking antidepressants, patients receiving a tricyclic antidepressant had a slightly higher but dose-dependent risk of SCD (IRR, 1.12; 95% CI, 0.89-1.40). Though the risk of SCD was not increased in patients who were taking less than 100 mg of amitriptyline equivalents (IRR, 0.97; 95% CI, 0.72-1.29), the risk was about 2.5 times greater in patients taking at least 300 mg of amitriptyline equivalents (IRR, 2.53; 95% CI, 1.04-6.12). Table 1 highlights case reports of antidepressant-induced Q-Tc interval prolongation.

Typical antipsychotics are recognized as having a greater risk of Q-Tc interval prolongation than are atypical antipsychotics. As the years of experience with atypical antipsychotics increase and their use becomes more widespread, case reports of Q-Tc interval prolongation in patients receiving these drugs are surfacing. Table 2 highlights several case reports of Q-Tc interval prolongation with typical and atypical antipsychotics.

Thioridazine has been associated with Q-Tc interval prolongation and SCD since it was introduced in 1959.[24] Reilly et al.[67] examined the rates of Q-Tc interval prolongation in patients taking antipsychotics and found that thioridazine use was more than five times more likely to prolong the Q-Tc interval compared with the use of other antipsychotics (odds ratio, 5.4; 95% CI, 2.0-13.7; p = 0.03).

Pimozide, another typical anti-psychotic, is indicated for the treatment of Tourette’s syndrome in the United States. Pimozide has been extensively linked to Q-Tc interval prolongation.[24]

Haloperidol is used quite frequently in a wide variety of clinical situations, but many of the cases of Q-Tc interval prolongation have occurred with off-label i.v. administration of haloperidol in the intensive care setting. In a retrospective case-control study, 8 (3.6%) of 223 patients treated with i.v. haloperidol developed torsades de pointes.[68] The risk was significantly greater in patients receiving at least 35 mg within 24 hours, in patients with a Q-Tc interval of >500 msec, or in patients who had both risk factors compared with controls. Most cases of Q-Tc interval prolongation typically involve higher doses of haloperidol used to control agitation after intubation or psychosis, though prolongation has occurred with lower doses as well.[53,54]

While the majority of cases of Q-Tc interval prolongation have been associated with the use of typical antipsychotics, atypical agents have also been found to cause some degree of prolongation.[69] Sertindole was the first atypical antipsychotic to be associated with prolongation of the Q-Tc interval. The manufacturers of sertindole first applied for labeling approval in the United States in the late 1990s, only to see the drug fail to progress through initial marketing trials due to adverse events.[69] In these initial trials, sertin-dole was associated with a marked increase (approximately 22 msec) in the Q-Tc interval and 12 cases of SCD. For these reasons, the Food and Drug Administration (FDA) did not approve the drug’s marketing, but sertindole was approved for use in Europe in 1997.[69] After reports of increased rates of SCD, sertindole was voluntarily withdrawn from the European market.

Among the atypical antipsychotics currently marketed in the United States, the agent most frequently linked to Q-Tc interval prolongation is ziprasidone, which received marketing approval from FDA in 2001. Preclinical research demonstrated that the drug prolonged the Q-Tc interval in a non-dose-dependent manner.[69] In small-sample premarketing trials, few cases of Q-Tc interval prolongation, torsades de pointes, and SCD were reported.

In 2004, Harrigan et al.[70] conducted a study of six antipsychotic drugs to determine their effects on the Q-Tc interval both in the absence and presence of other drugs metabolized by the cytochrome P-450 (CYP) isoenzyme system. The investigators randomized 183 patients (of which 164 completed the study) to receive maximum daily doses of ziprasidone hydrochloride 160 mg (n = 31), quetiapine 750 mg (as the fumarate) (n = 27), olanzapine 20 mg (n = 24), or risperidone 6-8 mg or 16 mg (n = 25) or typical daily doses of haloperidol 15 mg (n = 27) or thioridazine hydrochloride 300 mg (n = 30).

All treatment groups in the study had a mean increase in Q-Tc interval from baseline; however, no intervals were greater than 500 msec. Thioridazine was associated with a mean increase of 30.1 msec; ziprasidone, 15.9 msec; haloperidol, 7.1 msec; quetiapine, 5.7 msec; risperidone, 3.6 msec; and olanzapine, 1.7 msec.

Case reports of Q-Tc interval prolongation associated with risperidone have been published;[71] however, a meta-analysis of trials with risperidone failed to establish a relationship between its use and either Q-Tc interval prolongation or torsades de pointes.[71]

Quetiapine has been linked to Q-Tc interval prolongation, particularly in overdose situations. In one case report, the patient’s Q-Tc interval peaked at 710 msec, 14 hours after ingesting 9.6 g of quetiapine.[57] Harrigan and colleagues[70] found that quetiapine was associated with a modest increase of 5.7 msec in Q-Tc interval, much less than that of thioridazine and ziprasidone. Of all the atypical antipsychotic drugs studied, olanzapine was associated with the shortest prolongation of the Q-Tc interval;[70] however, several published case reports have described greater increases in the Q-Tc interval with olanzapine,[56,61] including one describing a possible interaction between olanzapine and ciprofloxacin that resulted in a Q-Tc interval of 610 msec.[72]

Clozapine may prolong the Q-Tc interval, but clinical trials have failed to consistently report this effect.[73]

Antipsychotics have also been linked to SCD.[74] For example, Ray et al.[75] evaluated the risk of SCD in 481,744 Tennessee Medicaid recipients who were taking antipsychotics. SCD was confirmed in 1,487 of these patients. These results demonstrated that patients receiving moderate doses of antipsychotics had an increased risk of SCD, thought to be associated with an increased risk of serious ventricular arrhythmias. Antipsychotics should therefore be used with caution, particularly in patients with cardiovascular disease.

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