Strategies to prevent fatal arrhythmias in patients taking antipsychotics

Menstrual cycle QTc interval measurements are stable throughout the menstrual cycle if quinidine-like drugs are not given.

Variations were seen, however, when Rodriguez et al studied the effect of IV low-dose ibutilide (an antiarrhythmic agent known to prolong the QT interval) on the QTc intervals of 58 healthy subjects (38 men and 20 women, ages 21 to 40). During 1 month, men were studied once and women studied three times, coincident with the three phases of the menstrual cycle. The greatest increase in QTc intervals measurements occurred in women during the first half of their menstrual cycles.¹⁹

Age and cardiovascular disease Two congenital long QT syndromes may be associated with sudden death, mostly in children and young adults:

• The Jervell and Lange-Nielsen syndrome is marked by severe congenital deafness and autosomal recessive inheritance.
• The Romano-Ward syndrome has normal hearing and autosomal dominant inheritance.²⁰

Congenital long QT syndrome (LQTS) occurs in about one in 5,000 births and accounts for about 3,000 to 4,000 deaths per year in the United States. Nine percent of pediatric LQTS subjects present with sudden cardiac death. More than 71% of patients will die before age 15 if not treated.

Elderly persons tend to have longer QTc intervals than do younger subjects, even when both groups are free of cardiovascular disease.²¹ Also, age-matched subjects with cardiovascular disease tend to have longer QTc intervals than do those free of cardiovascular disease.

Electrolytes Electrolyte disturbances, particularly hypokalemia and hypomagnesemia, may contribute to or even cause QT interval prolongation.²²

Hypokalemia prolongs the cardiac action potential and may cause early afterdepolarization, leading to torsade.²³ Low potassium levels reduce the net outward potassium current during phase 3 of the cardiac action potential. Hypomagnesemia may contribute to gross U wave alternans, lengthening the cardiac action potential and setting the stage for torsade.²⁴ Various factors may contribute to electrolyte disturbances, including use of diuretics and excessive vomiting and diarrhea. Even postprandial states may induce hypokalemia.

Intensive exercise and agitation may be associated with hypokalemia.²⁵ Serum potassium may be lower in severely agitated patients (3.59 mmol/L) than in mildly agitated patients (3.79 mmol/L). The mean QTc interval of psychiatric emergency patients may be prolonged (453±40 msec),⁵ with QTc intervals of psychiatric inpatients longer than those of psychiatric outpatients. Altered potassium states probably explain these observations. Mechanisms that link exercise and agitation with hypokalemia remain to be elucidated.

Metabolic factors Drugs may alter phase 3 potassium flow, thereby disrupting the synchrony of action of individual cardiac cells during repolarization. This change may induce early afterdepolarizations and torsade.²³

Five percent to 10% of Americans of European descent have genetic profiles that make them poor metabolizers of drugs that are metabolized by the cytochrome P-450 isoenzyme 2D6. The Pfizer Inc. 054 study assessed the potential for metabolic inhibitors such as paroxetine to raise antipsychotic drug levels in these patients and induce QTc interval prolongation.²⁶

In response to FDA concerns about QTc interval prolongation associated with the use of ziprasidone, Pfizer studied the potential for QTc interval prolongation when antipsychotics are given with and without metabolic inhibitors of cytochrome P-450 isoenzymes 2D6 (paroxetine), 3A4 (ketoconazole), and 1A2 (fluvoxamine). The study population of 183 subjects (mean age:men, 37.1 years, women 38.8 years) was three-quarters young men with schizophrenia, in good health otherwise and possessing normal ECGs—i.e., patients with a low risk of developing cardiac arrhythmias.

Figure 3 Antipsychotic drugs and QTc interval changes

Six antipsychotic drugs and QTc interval changes from baseline when given with and without metabolic inhibitors. QTc interval changes (in msec) when given without a metabolic inhibitor were ziprasidone, 20.3; risperidone, 11.6; olanzapine, 6.8; quetiapine, 14.5; thioridazine, 35.6; and haloperidol 4.7.

Reprinted from: “FDA Psychopharmacological Drugs Advisory Committee. 19 July 2000. Briefing Documents for Zeldox Capsules (Ziprasidone HCL). Pfizer.” Available from Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, (860) 441-4100.Over the course of about 1 week, daily doses were escalated to ziprasidone, 160 mg; risperidone, 8 mg and 16 mg; olanzapine, 20 mg; quetiapine, 750 mg; thioridazine, 300 mg; and haloperidol, 15 mg. Thioridazine (35.6 msec) and ziprasidone (20.3 msec) showed the greatest QTc interval increase following drug administration (Figure 3). Co-administration of a metabolic inhibitor did not further prolong the QTc interval for these two drugs.

Of the six drugs studied, only thioridazine and ziprasidone showed QTc interval increases 5% compared with baseline measurements.

Co-administration of a metabolic inhibitor caused the greatest increase in QTc intervals for quetiapine (from 14.5 to 19.7 msec). This value closely approached the steady-state ziprasidone measurement (20.3 msec). Because quetiapine is more likely than the other antipsychotic drugs studied to increase heart rate, it may be argued that the Bazett formula’s limitations in estimating the QTc interval at higher heart rates contributed to the quetiapine study findings.