Certain psychotropic medications and somatic medications can increase the

risk of lethal torsade de pointes through a mechanism of blocking cardiac

conduction channels (e.g., Na⁺, K⁺ and/or Ca⁺⁺). The best available parameter

for assessing risk of torsade de pointes is measuring the rate-corrected QT

interval (QT_C) on electrocardiogram (Labellarte et al., 2003a; Tisdale et al.,

2001).

While it is necessary to identify whether or not a psychotropic medication

can prolong QT_C alone or in combination with other medications, the list of

marketed medications that are known to prolong QT_C is incomplete (Labellarte et

al., 2003a). Available QT_C safety data are a hodgepodge of post-marketing

clinician case reports, animal and human myocyte conduction studies using

proprietary technology, and treatment studies screening for QT_C prolongation. Of

the medications known to prolong QT_C, some are more dangerous than others at

clinical doses, in overdose or in combination with other medications.

Few of the studies reporting cardiac safety of psychotropic medications have

involved children and adolescents. Three practical guidelines discuss

conservative screening and monitoring of children and adolescents who require

treatment with psychotropics known or suspected to cause QT_C prolongation

(Labellarte et al., 2003a) (Table) .

Medications That Prolong QT_C

The most comprehensive and easily accessed reference source for somatic and

psychotropic medications known or suspected to cause QT_C prolongation is at

<www.Qtdrugs.org>. This Web site is maintained by the University of Arizona Center

for Education and Research on Therapeutics in Tucson, Ariz. It lists cautious

medication combinations by identifying which medications could cause additive

pharmacodynamic risk when combined with psychotropics that prolong QT_C.

A more concise list of psychotropics that can contribute to QT_C prolongation

is inspired by earlier recommendations from the American Heart Association

(Gutgesell et al., 1999). The list contains no surprises: older medications

(e.g., tricyclic antidepressants, phenothiazines, butyrophenones and pimozide

[Orap]) that have been known for decades to cause QT_C prolongation/torsade de

pointes. The only newer medication on the list is ziprasidone (Geodon), which

has caused a mild but measurable QT_C prolongation in a comparison study (~21

msec) (Harrigan et al., 2004) but has not caused cardiac events in clinical or

research settings (Daniel, 2003). In contrast to the old-school medications,

ziprasidone's potential impact on ion channels has not been studied.

The older medications have not compared well in QT_C monitoring studies of

adults. Droperidol (Inapsine) caused the highest documented QT_C prolongation

(~59 msec) (Lischke et al., 1994) and also has the highest relative risk of

causing QT_C duration >450 msec (Reilly et al., 2000). Thioridazine

(Mellaril) had the next highest relative risk (Reilly et al., 2000), and also

caused noteworthy QT_C prolongation (~30 msec to 36 msec) compared to

haloperidol's (Haldol) minimal QT_C prolongation (8 msec) in the comparison study

by Harrigan and colleagues (2004). The impact of haloperidol on QT_C

duration/torsade de pointes has debatable clinical relevance (Di Salvo and

O'Gara, 1995; Hatta et al., 2001), but haloperidol merits ECG monitoring in

light of emerging data that its active metabolites may have different patterns

of toxicity (Kalgutkar et al., 2003).

Important Drug Interactions

The most comprehensive and easily accessed reference source for

pharmacokinetic interactions is maintained at <www.drug-interactions.com> by the

Indiana University Department of Medicine.

While the Web site does not focus specifically on interactions that

contribute to QT_C prolongation, it is easy to extrapolate a working list of

important medications that could cause worrisome metabolic inhibition and

potentially increased risk of QT_C prolongation.

In addition, protein-binding competition can potentially cause increased

serum levels of medications that prolong QT_C when combined with seemingly benign

medications that are highly protein-bound (e.g., aspirin, valproic acid

[Depakene], herbal preparations). Unclear pharmacokinetic mechanisms also result

in increased exposure to psychotropics that prolong QT_C with a few identified

medication combinations, e.g., pimozide plus sertraline (Zoloft) (Zoloft package

insert).

Pretreatment Risk Factors

Pretreatment risk factors of QT_C prolongation are rare but can be easily

screened. Screening includes pertinent medical history for signs/symptoms of

cardiac events, including syncope-like events and pertinent family history for

cardiac events such as syncope-like events, sudden death or congenital deafness

(which can be associated with an inherited variant of long QT syndrome) (Ocal

et al., 1997). Pretreatment laboratory test screening, when appropriate, would

test serum for hyponatremia, hypokalemia or hypermagnesemia.