Electrolyte and magnesium levels, thyroid function, and liver function tests were normal. Potassium was 3.9 mEq/L, indicating possible deficiency. Toxicity screen was negative, ruling out substance abuse or medication overdose. Baseline ECG—ordered because of Mr. B’s bradycardia—showed a QTc interval of 519 msec (almost 80 msec above high-normal for men) and a heart rate of 50 bpm.
The cardiology team found that 1 year before, while being examined for suspected syncope, Mr. B had a prolonged QTc interval that resolved after olanzapine was stopped. Acting on cardiology’s advice, the psychiatrist stopped olanzapine and clonazepam, continued gabapentin, 300 mg/d, and added lorazepam, 1 mg as needed for agitation.
Within 48 hours, Mr. B’s QTc interval decreased to 400 msec. Gabapentin and lorazepam were continued. He received potassium chloride, 40 mEq qid for 4 days, and within 2 days potassium was normal (4.4 to 4.8 mEq/L). Magnesium also was monitored.
Over the next few days, Mr. B decompensated. He exposed himself, requested sexual favors from staff, and became agitated. Staff reported that he was responding to internal stimuli and had pressured speech and flight of ideas.
After consulting cardiology, the psychiatrist restarted olanzapine, 10 mg/d, and lorazepam, 1 mg bid. Daily ECGs were ordered. After two olanzapine doses, Mr. B’s QTc interval rose to 550 msec. The psychiatrist stopped all psychotropics except lorazepam, which was increased to 2 mg bid. When Mr. B became more agitated, throwing himself to the floor and hitting himself, he was isolated for his safety.
The authors’ observations
For years, olanzapine abated Mr. B’s mood and psychotic symptoms, and until the previous year significant QTc prolongation had not been detected. Other risk factors—such as electrolyte imbalance and change in olanzapine metabolism—were ruled out.
Mr. B’s chart indicated that he had responded well to haloperidol during a prior hospitalization. Divalproex, which has little effect on QTc interval, was also considered to control his mood.
CASE 2 CONTINUED: DRUG TRIALS
Eight days after Mr. B was hospitalized, the psychiatrist added divalproex, 250 mg tid titrated over 4 days to 1,000 mg/d. Mr. B became less manic but remained psychotic and disorganized. Lorazepam was increased to 2 mg tid and 3 mg at bedtime. His QTc interval now averaged 400 msec.
Loxapine, 10 mg tid, was added but then quickly discontinued after Mr. B’s QTc interval approached 500 msec.
Table 2
QTc interval ranges in men and women
| Range | Men (msec) | Women (msec) |
|---|---|---|
| Normal | <430 | <450 |
| Borderline | 431-450 | 451-470 |
| Source: reference 8. | ||
The following week, after consulting cardiology, the psychiatrist started haloperidol, 2 mg tid, and added benztropine, 1 mg for dystonia as needed. The next day, Mr. B’s QTc interval was 402 msec.
Medications were readjusted gradually. Gabapentin was restarted and increased to 600 mg tid, lorazepam was decreased to 1 mg tid, and divalproex was increased to 500 mg tid with no major QTc change.
Haloperidol was titrated to 5 mg bid, but the interval increased to 549 msec, then fell below 500 msec after haloperidol was readjusted to 2 mg bid.
Over the next 2 weeks, Mr. B’s mood and psychotic symptoms gradually improved. He was discharged after 27 days, at which point his QTc interval ranged between 360 and 409 msec. He was told to continue his medications.
The authors’ observations
Many factors other than antipsychotic use can lengthen QTc interval. Patients with major psychiatric disorders tend to have more risk factors compared with the general population.4
Serial or signal-averaged ECGs are the most accurate ways to monitor QTc intervals.5 Obtain a baseline ECG before starting an antipsychotic for patients with one or more risk factors:
Age >65. Older persons without coronary artery disease (CAD) have longer QTc intervals than do younger patients in similar health.6
Drug-drug interactions—common among the elderly—can further prolong the interval. Decreased drug metabolism also raises drug plasma levels and increases QTc prolongation risk.
Cardiac diseases. CAD, cardiac arrhythmias, and congestive heart failure are serious risk factors, particularly for older patients. Watch for pre-existing heart disease—which heightens risk of conduction defects—and family history of cardiac disease, syncope, or sudden death.
CNS diseases. Stroke, tumors, and brain infections can cause autonomic dysfunction and electrolyte imbalances.
Electrolyte imbalance. Hypokalemia and hypomagnesemia can prolong the interval.7 Take complaints of diarrhea or frequent vomiting seriously, and refer patients with renal disease or who are using diuretics for an ECG. Regularly test for electrolytes, especially potassium and magnesium.
Endocrine diseases. Diabetes, hypothyroidism, and pituitary insufficiency can cause electrolyte abnormalities.
Female sex. QTc intervals are on average 20 msec longer in women <age>Table 2)8 and are prolonged during the first half of the menstrual cycle. Androgen may shorten intervals in men. Women account for about 70% of drug-induced torsade de pointes cases.9
</age>