(Circulation. 1999;99:979-982.)
© 1999 American Heart Association, Inc.
AHA Scientific Statement |
Cardiovascular Monitoring of Children and Adolescents Receiving Psychotropic Drugs
A Statement for Healthcare Professionals From the Committee on Congenital Cardiac Defects, Council on Cardiovascular Disease in the Young, American Heart Association
Key Words: AHA Scientific Statements • psychotropic drugs • death, sudden
Overview
Reports of sudden deaths of children and adolescents treated with psychotropic medications have raised concerns regarding the appropriateness of this therapy, as well as the advisability of baseline and periodic electrocardiographic (ECG) monitoring of such patients.1 2 3 4 What follows is a review of the drug effects on the ECG, cardiovascular effects of the commonly used psychotropic medications in children and adolescents, a summary of potentially dangerous drug interactions, and recommendations for cardiovascular monitoring.
Potential Mechanisms for Sudden Death
Although medications can potentially cause sudden, unexpected death by a variety of mechanisms (eg, seizures, central nervous system depression, or coronary artery spasm), cardiac arrhythmias are the most frequent cause. In particular, a unique form of ventricular tachycardia termed torsade de pointes has been recognized as the arrhythmia responsible for the so-called proarrhythmic effect of several antiarrhythmia drugs, and recent evidence has pointed to a similar mechanism in syncope and deaths related to other medications5 and in the familial long-QT syndromes.6 The common feature of these conditions is delayed repolarization of the myocardium (related to abnormal sodium or potassium currents) with resultant prolongation of the QT interval of the ECG. This appears to leave the myocardium vulnerable to ventricular tachycardia, primarily in the setting of bradycardia but occasionally in association with exercise.
Other ECG abnormalities, such as sinus node depression, second- or third-degree heart block, and supraventricular tachycardia, seem unlikely causes of sudden death in patients receiving psychotropic medications. Additionally, the rSR' pattern in lead V1, sometimes referred to as incomplete right bundle-branch block or right ventricular conduction delay, is a normal childhood variant and is not a risk factor for sudden death.
Specific Drugs
The major cardiovascular and
electrophysiological effects of the
commonly used psychotropic drugs are listed in Table 1
. Stimulants such as the
amphetamines and methylphenidate (Ritalin) cause slight but
clinically insignificant increases in heart rate and blood pressure.
The tricyclic antidepressants (TCA) imipramine and desipramine have
been associated with at least 7 reported deaths in young
patients.1 7 The precise mechanism of death has not been
documented. Some of the patients have had toxic levels of drugs, and at
least 2 had risk factors for sudden death (a coronary anomaly
in 1 and a family history of sudden death in another). The ECG effects
of TCA administration include an increase in heart rate (by 20% to
25%), prolongation of the PR interval (by 5% to 10%), increase in
QRS duration (by 7% to 25%), and prolongation of the QT interval
(by 3% to 10%). Although 8% of patients have a corrected QT
interval (QTc) of >460 ms, the mean value of the QTc remained within
normal limits for pediatric patients.4 8 9 10 11 Malignant
arrhythmias, in particular torsade de pointes, have not been
documented except for the ventricular fibrillation observed
in the emergency room in the patient with a family history of sudden
death.
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The selective serotonin reuptake inhibitors have minimal cardiovascular effects; deaths have been rare, even with massive overdose. Clonidine, a widely used antihypertensive medication, has been associated with 2 deaths in patients who also received methylphenidate, but the mechanism for these deaths is unknown and may have been sudden cessation of treatment.
Drug Interactions
Many psychotropic medications are metabolized by the
cytochrome P450 system, an enzyme system that may be inhibited by a
multitude of medications12 (Table 2). Adverse effects have occurred when
the P450 system is inhibited, which leads to elevated levels of
medications that prolong the QT interval and produce
ventricular tachycardia (torsade de pointes).
Most notable have been deaths related to torsade de pointes from
nonsedating histamine-blocking agents such as terfenadine (Seldane) and
astemizole (Hismanal).13 Many of these episodes were
associated with coadministration of other medications such as macrolide
antibiotics or imidazole antifungal agents (Table 2). Other
classes of medications that inhibit or are metabolized by the P450
cytochrome system include antidepressants, calcium channel blockers,
histamine blockers, gastrointestinal motility agents, and steroids.
Prolongation of the QT interval and torsade de pointes have been
reported in young children taking cisapride.
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Antiarrhythmic drugs of class Ia (eg, disopyramide, procainamide, and quinidine) and class III (eg, amiodarone and sotalol) likewise prolong the QT interval, and therefore concomitant use of psychotropic medications with these drugs is not recommended.
Family History
In some families, syncope and sudden death have been related to familial prolongation of the QT interval and torsade de pointes. Such individuals are at increased risk for arrhythmias due to medications that prolong the QT interval. Drugs that prolong the QT interval are contraindicated in patients with familial long-QT syndrome.
Recommendations
- Before therapy with psychotherapeutic agents is initiated, a careful history should be obtained, with special attention to symptoms such as palpitations, syncope, or near syncope. Medication use (prescribed and over-the-counter) should be determined. The family history should be reviewed with reference to the long-QT syndrome or other causes of sudden, unexplained death. Detection of these symptoms or risk factors warrants a cardiovascular evaluation by a pediatric cardiologist before initiation of therapy.
- At follow-up visits, patients receiving psychotropic drug therapy should be questioned about the addition of any drugs and the occurrence of any of the above symptoms. The physical examination should include determination of heart rate and blood pressure.
- Despite the lack of understanding of the mechanism of sudden death in young patients taking TCAs or demonstration that ECG monitoring could prevent these deaths, ECG monitoring at baseline and during chronic therapy has been recommended.4 14 15 Until more data are available, it seems prudent to obtain an ECG at baseline before TCA or phenothiazine therapy is begun (primarily to detect unsuspected instances of long-QT syndrome) and another when steady state is achieved. If the sustained resting heart rate is >130 bpm, the PR interval is >200 ms, QRS is >120 ms, or QTc is >460 ms, or if symptoms such as palpitations, near syncope, or syncope develop, alternative therapy may need to be considered along with pediatric cardiology consultation.
- Concomitant use of psychotropic drugs and other drugs that are metabolized by or inhibit the P450 enzyme system should be avoided.
Footnotes
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in November 1998. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Avenue, Dallas, TX 75231-4596. Ask for reprint No. 71-0159. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or
References
1. Popper CW, Zimnitzky B. Sudden death putatively related to desipramine treatment in youth: a fifth case and a review of speculative mechanisms. J Child Adolesc Psychopharmacol. 1995;5:283–300.
2. Werry JS, Biederman J, Thisted R, Greenhill L, Ryan N. Resolved: cardiac arrhythmias make desipramine an unacceptable choice in children. J Am Acad Child Adolesc Psychiatry. 1995;34:1239–1245; discussion 1245–1248.[Medline] [Order article via Infotrieve]
3. Biederman J, Thisted RA, Greenhill LL, Ryan ND. Estimation of the association between desipramine and the risk for sudden death in 5- to 14-year-old children. J Clin Psychiatry. 1995;56:87–93.[Medline] [Order article via Infotrieve]
4. Biederman J, Baldessarini RJ, Wright V, Knee D, Harmatz JS, Goldblatt A. A double-blind placebo controlled study of desipramine in the treatment of ADD, II: serum drug levels and cardiovascular findings. J Am Acad Child Adolesc Psychiatry. 1989;28:903–911.[Medline] [Order article via Infotrieve]
5. Roden DM, Thompson KA, Hoffman BF, Woosley RL. Clinical features and basic mechanisms of quinidine-induced arrhythmias. J Am Coll Cardiol. 1986;8(suppl A):73A–78A.
6. Keating MT, Sanguinetti MC. Molecular genetic insights into cardiovascular disease. Science. 1996;272:681–685. Review.[Abstract]
7. Riddle MA, Nelson JC, Kleinman CS, Rasmusson A, Leckman JF, King RA, Cohen DJ. Sudden death in children receiving Norpramin: a review of three reported cases and commentary. J Am Acad Child Adolesc Psychiatry. 1991;30:104–108.[Medline] [Order article via Infotrieve]
8. Schroeder JS, Mullin AV, Elliott GR, Steiner H, Nichols M, Gordon A, Paulos M. Cardiovascular effects of desipramine in children [see comments in J Am Acad Child Adolesc Psychiatry. 1989;28:964–965]. J Am Acad Child Adolesc Psychiatry. 1989;28:376–379.[Medline] [Order article via Infotrieve]
9. Wilens TE, Biederman J, Baldessarini RJ, Geller B, Schleifer D, Spencer TJ, Birmaher B, Goldblatt A. Cardiovascular effects of therapeutic doses of tricyclic antidepressants in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35:1491–1501. Review.[Medline] [Order article via Infotrieve]
10. Wilens TE, Biederman J, Baldessarini RJ, Puopolo PR, Flood JG. Electrocardiographic effects of desipramine and 2-hydroxydesipramine in children, adolescents, and adults treated with desipramine. J Am Acad Child Adolesc Psychiatry. 1993;32:798–804.[Medline] [Order article via Infotrieve]
11. Fletcher SE, Case CL, Sallee FR, Hand LD, Gillette PC. Prospective study of the electrocardiographic effects of imipramine in children. J Pediatr. 1993;122:652–654.[Medline] [Order article via Infotrieve]
12. Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacother. 1995;29:619–624.[Abstract]
13.
Woosley RL, Chen Y, Freiman JP, Gillis RA. Mechanism of
the cardiotoxic actions of terfenadine [see comments in
JAMA. 1993;269:1550–1552]. JAMA.
1993;269:1532–1536.
14.
Wagner KD, Fershtman M. Potential mechanism of
desipramine-related sudden death in children.
Psychosomatics. 1993;34:80–83.
15. Elliott GR, Popper CW. Tricyclic antidepressants: the QT interval and other cardiovascular parameters. J Child Adolesc Psychopharmacol. 1990;1:187–189.
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