Spotting a silent killer

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

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

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>

Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

The other authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

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

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>

Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

The other authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

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

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
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Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

The other authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.