To the Editor: Nissen (April 6 issue)1 recommends attachinga "black box" warning regarding serious cardiovascular risksto the labeling of stimulant medications used to treat attentiondeficit–hyperactivity disorder (ADHD). We agree that patientsafety is paramount and that the long-term benefits and risksof stimulant treatment are not known definitively, yet we areconcerned that such a warning will discourage patients and theirfamilies from using effective treatment. Untreated ADHD is associatedwith an elevated risk of substance abuse, academic failure,and motor vehicle accidents and an increased rate of psychiatricdisorders.2
The 14-month, controlled Multimodal Treatment Study of Childrenwith Attention Deficit–Hyperactivity Disorder (MTA study),sponsored by the National Institute of Mental Health, revealeda high rate of response to stimulants (more than 70 percent)and large effect sizes (0.6 to 1.2 standard deviations), withsignificantly lower rates of improvement for subjects who underwentpsychotherapy.3,4,5 Nissen's concern about the use of stimulantsin older adults at high risk for cardiac disease is warranted,but the article does not provide the firm evidence the Foodand Drug Administration (FDA) requires to issue a black-boxwarning for all age groups.
Thomas Anders, M.D. American Academy of Child and Adolescent Psychiatry Washington, DC 20016
Steven Sharfstein, M.D. American Psychiatric Association Arlington, VA 22209
References
Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med 2006;354:1445-1448. [Free Full Text]
Harpin VA. The effect of ADHD on the life of an individual, their family, and community from preschool to adult life. Arch Dis Child 2005;90:Suppl 1:i2-i7. [Free Full Text]
The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder: Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry 1999;56:1073-1086. [Free Full Text]
Greenhill LL, Kollins S, Abikoff H, et al. Efficacy of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry (in press).
Wigal T, Greenhill LL, Chuang S, et al. Tolerability and safety of methylphenidate in preschooler children with ADHD. J Am Acad Child Adolesc Psychiatry (in press).
To the Editor: We participated in the Drug Safety and Risk ManagementAdvisory Committee, which was convened on February 9, 2006,to produce recommendations to the FDA about how best to studythe rare occurrences of cardiovascular adverse events associatedwith medications used in the treatment of ADHD, including methylphenidate,amphetamine products, and atomoxetine.1 We are concerned thata vote for a black-box warning was called without a discussionof content or language for such a warning; that the discussiondid not thoroughly explore the risk associated with these medicationsfor adults and children but implied that the risk might be higherfor adults than for children; that recommendations about howbest to convey the risk to children, adults, and families werenot addressed; and that the concern about the increased useof these medications was confused with concern about the actualrisk.
We also participated in the Pediatric Advisory Committee, whichwas convened on March 22, 2006, to discuss how families andphysicians might best be informed of the risk associated withthese medications. The discussion, which lasted for 11 hours,was informed by presentations by 7 FDA epidemiologists and physicians,41 speakers in the public forum, and 2 representatives of pharmaceuticalcompanies.
The Pediatric Advisory Committee recommended that the FDA includewarnings, in the "highlights" section of the newly formattedlabeling, that children with structural heart defects, cardiomyopathy,or heart-rhythm disturbances may be at risk for adverse cardiacevents, including sudden death; that children with symptomsof psychosis and mania are at risk for adverse neuropsychiatricevents; and that children require follow-up visits and the monitoringof blood pressure, pulse, and growth measures2,3 (Table 1).None of the committee members, when asked directly by FDA officials,said that a black-box warning was warranted.
Table 1. Assessment of the Risks and Benefits of Medications for the Treatment of ADHD.
The committee further recommended that the FDA — withinput from professional, private, and public groups —design a guide for parents and physicians that would explainthe risks of these medications in readily accessible language,modeled on successful guides used to inform parents about vaccinationsfor children.
We are impressed that the process of the March 22 meeting ofthe Pediatric Advisory Committee allowed for the airing of highlydisparate and often passionate views regarding these issues.This process facilitated a frank and productive discussion bypatients, family members, pediatricians, cardiologists, pharmacologists,child psychiatrists, and epidemiologists in a transparent, respectful,and public forum.
Marsha D. Rappley, M.D. Michigan State University East Lansing, MI 48824 rappley{at}msu.edu
John W. Moore, M.D. UCLA Medical Center Los Angeles, CA 90095
Deborah Dokken, M.P.A. 2802 Blaine Dr. Chevy Chase, MD 20815
To the Editor: The vast increase in the diagnosis of ADHD andthe frequency of treatment for the condition in children is,unfortunately, no longer a phenomenon specific to the UnitedStates. According to the latest Drug Prescription Report,1 thenumber of daily doses of methylphenidate that are prescribedin Germany has reached 26 million per year. Although the population-adjustedvolume in the United States is still 8 to 10 times that amount,the number of prescriptions for the drug for German childrenrose by a factor of 20 during the past 10 years, with no signsof abating. The use of methylphenidate by adults is similarlyon the rise. It is to be hoped that the FDA's warning aboutthe cardiovascular risks of ADHD drugs will curtail this worrisomedevelopment.
Leszek Wojnowski, M.D. Johannes Gutenberg University D-55101 Mainz, Germany wojnowski{at}uni-mainz.de
References
Schwabe U, Paffrath D. Arzneiverordnungsreport 2005. Berlin: Springer-Verlag, 2005.
Dr. Nissen replies: Anders and Sharfstein are concerned thatwarnings regarding serious cardiovascular risks associated withADHD drugs would "discourage" patients from receiving treatment.I strongly disagree. I cannot accept the paternalistic notionthat patients and caregivers are better off without informationabout drug risks. The presence of a black-box warning and amandatory patient guide would probably stimulate useful discussionsamong patients, parents, and physicians about risks, benefits,and alternative therapies. An appropriate warning might alsoslow the exponential growth in the use of amphetamines and similarstimulants, which has reached epidemic proportions in the UnitedStates, resulting in the treatment of nearly 10 percent of preadolescentboys.1
Rappley et al. express concern that a black-box warning wasrecommended by the Drug Safety and Risk Management AdvisoryCommittee without adequate discussion of its content. Unfortunately,discussion was limited because the FDA-supplied background materialsand questions for the committee did not allow for the possibilityof enhanced warnings.2 The committee chose an independent courseof action after reviewing data regarding adverse events, includingcases of sudden death, and concluded that a warning was needed.These cases included that of a 13-year-old boy who died withinone hour after receiving the first dose of mixed amphetaminesalts; the boy was found to have had hypertrophic cardiomyopathyon autopsy.2 Advisory committees never specify the languageof such warnings, which is the responsibility of the FDA. Ibelieve that the appearance of information in the "highlights"section of the drug label will have virtually no effect on prescribingpractices. Even a boxed warning has been shown to have a minimaleffect on the inappropriate use of drugs.3 The table includedwith this letter is highly misleading. Many studies have demonstratedthat only 1 to 10 percent of serious adverse events are reportedto the FDA through the Adverse Event Reporting System. Accordingly,any calculation of an incidence rate for adverse events fromsuch data is considered unreliable by FDA drug-safety staff,even for pediatric patients.4
Both letters seem to ignore a fundamental fact that increasingheart rate and blood pressure5 by the administration of powerfulcardiac stimulants is inherently risky. Closely related sympathomimeticamines, such as ephedra and phenylpropanolamine, have been deemedsufficiently risky that the FDA has recommended banning theseagents to protect the public health.
Wojnowski expresses concern about the increase in the use ofstimulants by a factor of 20 in Germany but points out thatsuch use in the United States is still 8 to 10 times as high.I share his concern.
The figure that appeared in my Perspective article shows anincorrect structure for epinephrine, which lacks the nonmethylatedamine that is pictured. In addition, pseudoephedrine is an epimerof ephedrine, not an enantiomer, as described on page 1447.
Steven E. Nissen, M.D. Cleveland Clinic Cleveland, OH 44195
Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA 2000;284:3036-3039. [Free Full Text]
Mosholder AD, Pamer CA. Postmarketing surveillance of suicidal adverse events with pediatric use of antidepressants. J Child Adolesc Psychopharmacol 2006;16:33-36. [CrossRef][Web of Science][Medline]
Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2005;66:253-259. [Web of Science][Medline]
Bates, G.
(2009). Drug treatments for attention-deficit hyperactivity disorder in young people. Adv. Psychiatr. Treat.
15: 162-171
[Abstract][Full Text]
Vetter, V. L., Elia, J., Erickson, C., Berger, S., Blum, N., Uzark, K., Webb, C. L.
(2008). Cardiovascular Monitoring of Children and Adolescents With Heart Disease Receiving Medications for Attention Deficit/Hyperactivity Disorder: A Scientific Statement From the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation
117: 2407-2423
[Full Text]
Correction
to
Nissen, 
Previous
