Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. 1215-1219 (doi:10.1542/peds.2006-0942)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilens, T. E.
Right arrow Articles by Biederman, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilens, T. E.
Right arrow Articles by Biederman, J.
Related Collections
Right arrow Office Practice
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

SPECIAL ARTICLE

Stimulants and Sudden Death: What Is a Physician to Do?

Timothy E. Wilens, MDa, Jefferson B. Prince, MDa,b, Thomas J. Spencer, MDa and Joseph Biederman, MDa

a Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
b Department of Child Psychiatry, North Shore Medical Center, Salem, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
STIMULANT USE AND RISK...
 SUMMARY
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Recently, a US Food and Drug Administration advisory committee raised concerns about cardiovascular risks and sudden death in children and adolescents with attention-deficit/hyperactivity disorder who are receiving stimulants.

METHODS. We comment on the risk of sudden death in children/adolescents taking stimulants compared with population rates, biological plausibility, and known cardiovascular effects of stimulants to determine specific risk.

RESULTS. There does not seem to be higher risk of sudden death in stimulant-treated individuals compared with the general population. Although there is evidence of biological plausibility, the known effects of the stimulants on cardiovascular electrophysiology and vital signs seem to be benign.

CONCLUSIONS. There does not seem to be compelling findings of a medication-specific risk necessitating changes in our stimulant treatment of children and adolescents with attention-deficit/hyperactivity disorder. The use of existing guidelines on the use of stimulants (and psychotropic agents) may identify children, adolescents, and adults who are vulnerable to sudden death.

Key Words: ADHD • attention-deficit/hyperactivity disorder • stimulant • methylphenidate • amphetamine • sudden death • cardiovascular • blood pressure • pulse • electrophysiology

Abbreviations: ADHD—attention-deficit/hyperactivity disorder • FDA—US Food and Drug Administration • SD—sudden death

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder presenting for treatment in youth in the United States, with 3% to 9% of youth affected.1,2 Among available treatment modalities for ADHD, pharmacotherapy is considered one of the fundamental treatments for this disorder.3,4 Within the medication armamentarium for ADHD, stimulants (methylphenidate and amphetamine) are the most widely used and continue to be considered first-line agents.3–6 As highlighted in recent US Food and Drug Administration (FDA) advisory committee recommendations and editorials,7 lingering concerns remain regarding the potential cardiovascular safety of psychostimulants despite the well-documented data demonstrating their short- and long-term efficacy in the treatment of ADHD3,8,9 The recently convened FDA pediatric advisory board recommended by a 15-to-0 vote that an informational booklet detailing the risk, benefits, and adverse effects of the stimulant medications be developed for parents, families, and providers. This controversy has been highlighted by the recent removal and subsequent reinstatement of extended-release mixed amphetamine salts in Canada (2005), added warnings of administration of mixed amphetamine salts in patients with preexisting structural cardiac effects, and the recent 8-to-7 vote by the FDA advisory panel recommending a "black-box" warning on the risk for sudden death (SD) in individuals receiving any stimulant (February 2006), which was not supported by another subsequent FDA advisory panel (March 2006). This state of affairs has left the field and the public in a state of high anxiety, making a reasonable approach to the care of patients with ADHD, in whom stimulants are being considered, difficult.

In considering the critical issue of SD, physicians, parents, and policy makers need to evaluate the evidence at hand. Specifically, we need to know first whether there is evidence of causality. This consideration involves estimating whether the risk of SD in individuals treated with stimulants exceeds that of the spontaneous risk for SD in the general population. Second, we need to assess the evidence for biological plausibility that treatment with stimulants produces dangerous cardiovascular outcomes. Against this background, clinicians should factor in the severity of the natural course of ADHD for which treatment with stimulants is being considered.


   STIMULANT USE AND RISK OF SD
TOP
 ABSTRACT
 STIMULANT USE AND RISK...
SUMMARY
 CONCLUSIONS
 REFERENCES
 
What Is the Evidence That Stimulants Increase the Risk for SD?
Although tragic, SD occurs at a rare but stable rate in the general population. Estimates indicate that the risk for SD in children and adolescents is between 0.6 and 6 in 100000 per year.10 SD increases with age, with the risk in adults reaching upward of 1 in 1000 per year.11 Of interest, the risk for SD in juvenile and adult athletes is higher, with SD occurring typically during the peak exercise or immediate postexercise periods.12 SD is presumed to be of cardiac origin in half of the cases, with structural heart defects (eg, idiopathic hypertrophic subaortic stenosis) accounting for the majority of abnormalities identified, followed by anomalous origin of cardiac vessels and aortic dissection and rupture.11 Although some retrospective data suggest that 50% of the individuals with SD had symptoms preexisting the catastrophic event including syncope, palpitations, chest pain, or dizziness; other studies have suggested that the vast majority of patients present with SD as their first and only symptom.11,13,14 Thus, prospective identification of these risks may reduce SD rates in the general population.12 Critical in the evaluation of SD risk associated with treatment with stimulants is the comparison of risk in similarly aged individuals in the general population.

As an important qualifier, many of the numbers used for calculation are approximations based on assumptions, use data, and spontaneous report. Data collected over the period of 1999–2003 indicate that, using the World Health Organization classification, there have been 25 reports of SD in patients treated with stimulants: 8 of them while on methylphenidate (7 pediatric and 1 adult) and 17 of them while on amphetamine (12 pediatric and 5 adults). The adjusted rates per million prescriptions over this period for pediatric subjects was calculated to be 0.16 for methylphenidate and 0.36 for amphetamines; rates in adults were 0.07 for methylphenidate and 0.53 for amphetamine. Because of the very rare occurrences, no meaningful comparison could be made between amphetamine- and methylphenidate-associated SD.

In comparing the risk for SD in stimulant-treated children and adolescents, the FDA Psychopharmacology Pediatric Advisory Board during their meeting on March 22, 2006, concluded that the stimulant medications do not pose an undue cardiovascular risk in children and adolescents. A review in stimulant-treated adults is still pending; however, a previous FDA review of the cardiovascular risk associated with the use of amphetamine in children and adults did not find undue risk other than increased risk in patients with underlying heart defects (www.fda.gov/cder/drug/advisory/adderall.htm).

Another line of evidence to examine in establishing a true link between stimulants and SD is the pathophysiologic correlates of the SD. A majority of patients suffering SD during treatment with stimulants had autopsies. A structural cardiac defect was identified in 8 of 12 cases of SD during treatment with amphetamine and 4 of 7 that occurred during treatment with methylphenidate. These defects included a variety of cardiac abnormalities, with hypertrophic cardiomyopathies reported most commonly. It is important to note that autopsy evidence of cardiac anomalies requires special procedures that are not always performed, such as fine serial sectioning of the myocardium. Therefore, the usefulness of a "negative" autopsy depends on the quality of the procedure. Nevertheless, the risk and distribution of the cardiac dysfunction and structural abnormalities reported in patients receiving stimulants are strikingly similar to the characteristics of SD reported in the general population11: half of the cases of SD in the general population were found to have structural cardiac defects at autopsy.11 What remains missing from many of the cases are the specifics of the SD reports, such as timing and potential confounds of coadministered agents (prescribed, illicit, or over-the-counter), actual doses and blood levels of medications taken, concurrent illnesses, metabolic abnormalities, preexisting cardiovascular symptoms, exercise proximity, and other issues that may contribute to SD.

What Is the Evidence That Stimulants Are Associated With Severe Cardiovascular Risk?
A growing body of work exists about the short- and long-term effects of stimulant treatment on cardiovascular parameters in children, adolescents, and adults with ADHD who are receiving stimulants. These data, limited to healthy subjects without known preexisting cardiac anomalies, consistently demonstrate small, statistically significant, but not clinically meaningful increases in blood pressure and pulse as well as minimal changes during electrocardiography.3,9,15–24 For example, recent multisite pediatric studies with methylphenidate19,21,22,25,26 and amphetamine23,24,27 that included >2000 children documented mild, statistically significant increases in both systolic (2–4 mmHg) and diastolic (1–3 mmHg) blood pressure and heart rate (3–5 beats per minute) that persisted at the same magnitude with continued treatment to 2 years. During the March 22, 2006, meeting of the FDA Pediatric Psychopharmacology Advisory Panel, investigators for the ongoing Multimodal Treatment of ADHD follow-up protocol reported (over 6 years of follow-up) no differences in blood pressure or pulse between those treated with medication and those not treated with medications. Short-term 24-hour ambulatory blood pressure monitoring has also shown similar findings.9,20 In both short and longer-term studies, there were low drop-out rates secondary to abnormal cardiovascular parameters and <1% of medically healthy children and adolescents noted to have isolated systolic or diastolic hypertension (eg, >90th percentile for age) or clinical symptoms referable to cardiovascular symptoms (eg, chest discomfort, syncope, palpitations). Studies of adults reflect those of children and adolescents, although, not surprisingly, higher rates of hypertension have been observed28,29 because blood pressure naturally increases with age.30 Higher drop-out rates, resulting from exceeding the normal blood pressure cutoffs, in clinical trials has been observed in adults relative to children,28–30 although dropouts are also observed in the placebo groups (eg, natural occurrence of hypertension).29,30

One consideration in determining potential causality is biological plausibility; in other words, is there some inherent physiochemical characteristic of the medication that may predispose someone to an adverse physiologic response? The stimulant medications are catecholaminergic (noradrenergic and dopaminergic) and have sympathomimetic qualities.31 Catecholaminergic agents, theoretically, can affect the rate, cardiac conduction, and repolarization and rhythmicity of the heart.32 However, not all catecholaminergic agents are alike; for instance, isoproterenol has substantial effects on all aspects of cardiac electrophysiology, whereas the stimulants used to treat ADHD have a significantly milder effect.

The stimulant medications have both chronotropic (heart rate) and ionotropic (contractility) effects. Electrocardiographic effects of stimulants include predictable increases of heart rate that are rarely in the range of diagnosed tachycardia (140 beats per minute in children and 120 beats per minute in adolescents).31 Studies indicate no changes in the PR (atrial conduction), QRS (intraventricular conduction), or QT/QTc intervals (repolarization).23,33 Studies in adults reflect those in children, with no known changes in atrial or ventricular conduction or repolarization in clinical trials.28 In all of the studies of stimulants in children, adolescents, and adults (>300 controlled trials; N > 5000 children and adolescents) of various length, to our knowledge, there has been no SD reported.3,31


   SUMMARY
TOP
 ABSTRACT
 STIMULANT USE AND RISK...
 SUMMARY
CONCLUSIONS
 REFERENCES
 
Given the existing data, the rates of SD in children, adolescents, and adults who are treated with stimulants are exceedingly rare. Furthermore, it remains very unclear whether the risk for SD is actually higher in patients receiving stimulants than in the general population. Moreover, the anatomic characteristics identified on autopsy of patients suffering SD during treatment with stimulant medications are similar to those reported in SD in the general population. Therefore, without a specific association, there is no causality.

Conceptually, stimulants have a theoretical biological plausibility to set a cascade of events that may result in SD. However, the stimulants’ relatively benign effects coupled with the lack of electrocardiographic changes (in some cases being more benign than over-the-counter and other treatments) do not seem to be sufficient to result independently in SD. Whether the stimulants interact with "vulnerable" patients such as those with presumed preexisting cardiac disease to create rhythm disturbances remains unclear, and if these disturbances are operant, they are probably occurring at an extremely low baseline rate. At the meeting on March 22, 2006, the FDA Pediatric Psychopharmacology Advisory Panel concluded that there was no evidence of increased risk of SD in healthy children with ADHD who are treated with stimulant medication. Moreover, the panel equated the putative risk of SD in children with ADHD who have preexisting structural abnormalities and are treated with stimulants to that of strenuous exercise in this population.

Balancing the Risks
The theoretical risk of using stimulants needs to be balanced against the very real risks of leaving ADHD untreated. The vast literature shows that stimulants are highly effective for ADHD.3,25,31 For instance, cross-sectional and longitudinal studies show that ADHD is a risk for substantial morbidity, including academic, occupational, and interpersonal failure, sexual promiscuity, criminality, and injuries.34–36 Increased risk for motor vehicle accidents, one of the leading causes of death in adolescents and young adults, has been documented in ADHD, with reversal in driving deficits with stimulant treatment.37,38 Untreated individuals with ADHD have twice the risks for cigarette smoking39 and early-onset substance abuse,40 which are independently linked to premature death in adults. Not surprisingly, stimulant treatment in those with ADHD has been shown to reduce the initiation of both cigarette smoking and substance abuse.41,42 The morbidity and mortality either directly or indirectly ascribed to ADHD or its sequela are substantial and notably reduced in the presence of stimulant treatment. Hence, the risk/benefit ratio at both a clinical and public health level underscores the consequences of undertreating ADHD or leaving it untreated.43

What Cardiovascular Monitoring Should be Undertaken with Stimulant Treatment?
On the basis of the findings encompassing the most recent data available, it seems prudent to follow the established guidelines by the American Heart Association Panel on Psychotropic Agents in Children and Adolescents that previously reviewed data on the stimulants.44 Although stimulants were not identified as associated with SD, the panel suggested querying for independent risk factors for SD before initiating medication and during treatment, namely, family history of premature SD (<30 years) and personal history of syncope, palpitations, chest pain, or dizziness of unknown etiology, especially during exercise.44 Blood pressure and pulse should be examined at baseline and periodically during treatment. As reaffirmed during the FDA Pediatric Psychopharmacology Advisory Panel on March 22, 2006, other than clinical history and usual physical examination, there is no good way to screen for occult structural cardiac disease. In medically healthy children and adolescents to be administered stimulants, there is no need to complete an echocardiogram or 12-lead or Holter electrocardiograph.44 In those patients with the aforementioned symptoms, referral for a more thorough workup is indicated.44 In adults, an appropriate cardiac workup based on the risk factors of the individual is suggested.


   CONCLUSIONS
TOP
 ABSTRACT
 STIMULANT USE AND RISK...
 SUMMARY
 CONCLUSIONS
REFERENCES
 
The available data do not seem adequate to warrant major changes in our current treatment of ADHD with stimulants. Balanced against the paucity of convincing data on adverse cardiovascular effects of stimulants are the morbidity and mortality associated with not treating the disorder appropriately. Stimulants remain among the most effective and safe intervention for ADHD.4,45 The application of previously developed American Heart Association guidelines devoted to the use of psychotropic agents in children and adolescents seems prudent in identifying those at risk for adverse cardiovascular outcomes independently and potentially through an interaction with these treatments. Specific unsolicited warnings directed to patients and their families about SD risk associated with stimulants seems premature given the lack of clear association and current state of knowledge. Given these findings, it would be unfortunate to create an atmosphere of unwarranted fear and deter the appropriate, medically indicated, and monitored use of stimulants for ADHD, one of the most useful treatments in child psychiatry and pediatrics over the past 5 decades.


   ACKNOWLEDGMENTS
 
The funding for this study was provided by National Institutes of Health grant K24 DA016264 (to Dr Wilens).


   FOOTNOTES
 
Accepted May 3, 2006.

Address correspondence to Timothy E. Wilens, MD, YAW 6A, Massachusetts General Hospital, 55 Parkman St, Boston, MA 02114. E-mail: twilens{at}partners.org

Financial Disclosure: Dr Wilens receives research support from Alza Corporations/Ortho-McNeil, Eli Lilly, the National Institute on Drug Abuse (NIDA), Neurosearch, and Shire Laboratories. He is on the speaker’s bureaus of Ortho-McNeil, Novartis Pharmaceuticals, and Shire Laboratories, and a consultant for Abbott, Glaxo/SKB, Janssen Pharmaceutica, the NIDA, the National Institute on Mental Health (NIMH), Pfizer, Saegis Pharmaceuticals, and Sanofi-Synthelabo. Dr Spencer receives research support from Shire Laboratories, Eli Lilly, Novartis Pharmaceutical, Wyeth Ayerst, and McNeil Consumer and Specialty Pharmaceuticals, and is on the advisory board for Shire Laboratories, Eli Lilly, Glaxo/SKB, Pfizer, McNeil Consumer and Specialty Pharmaceuticals, and Novartis Pharmaceuticals. Dr Prince in the last 12 months has received honorarium from Cephalon, Shire Laboratories, PsychCME, Vital Issues in Medicine, and McNeil Consumer and Specialty Pharmaceuticals. He is on the speaker’s bureau for McNeil Consumer and Specialty Pharmaceuticals. Dr Biederman receives research support from Shire Laboratories, Eli Lilly, Pfizer, McNeil Consumer and Specialty Pharmaceuticals, Abbott, Bristol-Myers-Squibb, New River Pharmaceuticals, Cephalon, Janssen Pharmaceutica, Neurosearch, Stanley Medical Institute, Novartis Pharmaceuticals, Lilly Foundation, Prechter Foundation, the NIMH, the National Institute of Child Health and Human Development, and the NIDA. He is on the speaker’s bureaus for Shire Laboratores, Eli Lilly, McNeil Consumer and Specialty Pharmaceuticals, Cephalon, UCB Pharma, and Novartis. He is on the advisory board for Eli Lilly, Shire Laboratories, McNeil Consumer and Specialty Pharmaceuticals, Janssen Pharmaceutica, Novartis Pharmaceuticals, and Cephalon.


   REFERENCES
TOP
 ABSTRACT
 STIMULANT USE AND RISK...
 SUMMARY
 CONCLUSIONS
 REFERENCES
 

  1. Costello J, Angold A, Burns, et al. The Great Smoky Mountains Study of Youth: goals, design, methods, and the prevalence of DSM-III-R disorders. Arch Gen Psychiatry. 1996;53 :1129 –1136[Abstract/Free Full Text]
  2. Bauermeister JJ, Canino G, Bird H. Epidemiology of disruptive behavior disorders. In: Greenhill L, ed. Child and Adolescent Psychiatric Clinics of North America. Philadelphia, PA: WB Saunders; 1994:177–194
  3. American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(2 suppl):26S–49S
  4. American Academy of Pediatrics, Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108 :1033 –1044[Abstract/Free Full Text]
  5. Wilens TE, Biederman J, Spencer TJ. Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med. 2002;53 :113 –131[CrossRef][Web of Science][Medline]
  6. Pliszka SR, Greenhill LL, Crismon ML, et al. The Texas Children’s Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. Attention- deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2000;39 :908 –919[CrossRef][Web of Science][Medline]
  7. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006; 354: 1445–1448[Free Full Text]
  8. Aman MG, Werry JS. Methylphenidate in children: effects upon cardiorespiratory function on exertion. Int J Ment Health. 1975;4 :119 –131[Web of Science]
  9. Samuels JA, Franco K, Wan F, Sorof JM. Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial. Pediatr Nephrol. 2006; 21: 92–95[CrossRef][Web of Science][Medline]
  10. Wren C. Sudden death in children and adolescents. Heart. 2002;88 :426 –431[Free Full Text]
  11. Berger S, Kugler JD, Thomas JA, Friedberg DZ. Sudden cardiac death in children and adolescents: introduction and overview. Pediatr Clin North Am. 2004;51 :1201 –1209[CrossRef][Web of Science][Medline]
  12. Basso C, Corrado D, Thiene G. Cardiovascular causes of sudden death in young individuals including athletes. Cardiol Rev. 1999;7 :127 –135[Medline]
  13. Van Camp SP, Bloor CM, Mueller FO, Cantu RC, Olson HG. Nontraumatic sports death in high school and college athletes. Med Sci Sports Exerc. 1995;27 :641 –647[Web of Science][Medline]
  14. Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes: clinical, demographic, and pathological profiles. JAMA. 1996;276 :199 –204[Abstract/Free Full Text]
  15. Aman MG, Werry JS. The effects of methylphenidate and haloperidol on the heart rate and blood pressure of hyperactive children with special reference to time of reaction. Psychopharmacologia. 1975;43 :163 –168[CrossRef][Web of Science][Medline]
  16. Safer DJ. The relative cardiovascular safety of psychostimulants used to treat attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol. 1992;2 :279 –290[Medline]
  17. Findling RL, Short EJ, Manos MJ. Short-term cardiovascular effects of methylphenidate and Adderall. J Am Acad Child Adolesc Psychiatry. 2001;40 :525 –529[CrossRef][Web of Science][Medline]
  18. Brown RT, Sexson SB. A controlled trial of methylphenidate in black adolescents: attentional, behavioral, and physiological effects. Clin Pediatr (Phila). 1988;27 :74 –81[Abstract/Free Full Text]
  19. Wilens TE, Biederman J, Lerner M; Concerta Study Group. Effects of once-daily osmotic-release methylphenidate on blood pressure and heart rate in children with attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2004;24 :36 –41[CrossRef][Web of Science][Medline]
  20. Stowe CD, Gardner SF, Gist CC, Schulz EG, Wells TG. 24-hour ambulatory blood pressure monitoring in male children receiving stimulant therapy. Ann Pharmacother. 2002;36 :1142 –1149[Abstract]
  21. Wilens T, McBurnett K, Stein M, Lerner M, Spencer T, Wolraich M. ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study. J Am Acad Child Adolesc Psychiatry. 2005;44 :1015 –1023[CrossRef][Web of Science][Medline]
  22. Biederman J, Quinn D, Weiss M, et al. Efficacy and safety of Ritalin LA, a new, once-daily, extended-release dosage form of methylphenidate hydrochloride, in children with ADHD. Paediatr Drugs. 2003;5 :833 –841[CrossRef][Medline]
  23. Biederman J, Lopez FA, Boellner SW, Chandler MC. A randomized, double-blind, placebo-controlled, parallel-group study of SLI381 (Adderall XR) in children with attention-deficit/hyperactivity disorder. Pediatrics. 2002;110 :258 –266[Abstract/Free Full Text]
  24. Wilens T, Spencer T, Biederman J. Short- and long-term cardiovascular effects of mixed amphetamine salts extended-release in adolescents with ADHD. CNS Spectr. 2005;10 :22 –30[Web of Science][Medline]
  25. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children With ADHD. Arch Gen Psychiatry. 1999;56 :1073 –1086[Abstract/Free Full Text]
  26. Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo-controlled trial of dexmethylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2004;43 :1406 –1414[CrossRef][Web of Science][Medline]
  27. Findling RL, Biederman J, Wilens T, et al. Short- and long-term cardiovascular effects of mixed amphetamine salts extended release in children. J Pediatr. 2005;147 :348 –354[CrossRef][Web of Science][Medline]
  28. Weisler RH, Biederman J, Spencer TJ, Wilens TE. Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10 :35 –43[Web of Science][Medline]
  29. Spencer T, Biederman J, Wilens T, et al. A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57 :456 –463[CrossRef][Web of Science][Medline]
  30. Wilens T, Hammerness P, 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]
  31. Wilens TE, Spencer T. The stimulants revisited. In: Stubbe C, ed. Child and Adolescent Psychiatric Clinics of North America. 3rd ed. Philadelphia, PA: Saunders; 2000:573–603
  32. Garson A, Bricker JT, McNamara DG. The Science and Practice of Pediatric Cardiology. Philadelphia, PA: Lea and Febiger; 1990
  33. Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, controlled trial of OROS methylphenidate once a day in children with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108 :883 –892[Abstract/Free Full Text]
  34. Weiss G, Hechtman L, Milroy T, Perlman T. Psychiatric status of hyperactives as adults: a controlled prospective 15-year followup of 63 hyperactive children. J Am Acad Child Psychiatry. 1985;24 :211 –220[Web of Science][Medline]
  35. Mannuzza S, Klein R, Bessler A, Malloy P, LaPadula M. Adult psychiatric status of hyperactive boys grown up. Am J Psychiatry. 1998;155 :493 –498[Abstract/Free Full Text]
  36. Biederman J, Monuteaux M, Mick E, et al. Young adult outcome of attention deficit hyperactivity disorder: a controlled 10 year prospective follow-up study. Psychol Med. 2006; 36: 167–179[CrossRef][Web of Science][Medline]
  37. Barkley RA, Murphy KR, Dupaul GI, Bush T. Driving in young adults with attention deficit hyperactivity disorder: knowledge, performance, adverse outcomes, and the role of executive functioning. J Int Neuropsychol Soc. 2002;8 :655 –672[CrossRef][Web of Science][Medline]
  38. Cox DJ, Merkel L, Penberthy JK, Kovatchev B, Hankin CS. Impact of methylphenidate delivery profiles on driving performance of adolescents with attention-deficit/hyperactivity disorder: a pilot study. J Am Acad Child Adolesc Psychiatry. 2004;43 :269 –275[CrossRef][Web of Science][Medline]
  39. Milberger S, Biederman J, Faraone S, Chen L, Jones J. ADHD is associated with early initiation of cigarette smoking in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1997;36 :37 –44[CrossRef][Web of Science][Medline]
  40. Wilens TE, Biederman J, Mick E, Faraone SV, Spencer T. Attention deficit hyperactivity disorder (ADHD) is associated with early onset substance use disorders. J Nerv Ment Dis. 1997;185 :475 –482[CrossRef][Web of Science][Medline]
  41. Wilens T, Faraone S, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003;111 :179 –185[Abstract/Free Full Text]
  42. Monuteaux MC, Biederman J, Spencer T. A randomized, double-blind, placebo-controlled clinical trial of bupropion for the prevention of smoking in youth with attention deficit-hyperactivity disorder. Presented at: NCI Tobacco Investigators Meeting: Synthesizing Research for the Public’s Health; San Diego, CA; June 2–4, 2004
  43. Goldman L, Genel M, Bezman RJ, Slanetz PJ. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA. 1998;279 :1100 –1107[Abstract/Free Full Text]
  44. Gutgesell H, Atkins D, Barst R, et al. Cardiovascular monitoring of children and adolescents receiving psychotropic drugs. Circulation. 1999;99 :979 –982[Free Full Text]
  45. Greenhill L, Osman B. Ritalin: Theory and Practice. New York, NY: Mary Ann Liebert; 1999
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Am. J. PsychiatryHome page
M. S. Gould, B. T. Walsh, J. L. Munfakh, M. Kleinman, N. Duan, M. Olfson, L. Greenhill, and T. Cooper
Sudden Death and Use of Stimulant Medications in Youths
Am J Psychiatry, September 1, 2009; 166(9): 992 - 1001.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
W. B. Brinkman, S. N. Sherman, A. R. Zmitrovich, M. O. Visscher, L. E. Crosby, K. J. Phelan, and E. F. Donovan
Parental Angst Making and Revisiting Decisions About Treatment of Attention-Deficit/Hyperactivity Disorder
Pediatrics, August 1, 2009; 124(2): 580 - 589.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
J. Conway, K. K. Wong, C. O'Connell, and A. E. Warren
Cardiovascular Risk Screening Before Starting Stimulant Medications and Prescribing Practices of Canadian Physicians: Impact of the Health Canada Advisory
Pediatrics, October 1, 2008; 122(4): e828 - e834.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
J. M. Perrin, R. A. Friedman, T. K. Knilans, the Black Box Working Group, and the Section on Cardiology and Cardiac Surgery
Cardiovascular Monitoring and Stimulant Drugs for Attention-Deficit/Hyperactivity Disorder
Pediatrics, August 1, 2008; 122(2): 451 - 453.
[Full Text] [PDF]

Home page
 CirculationHome page
V. L. Vetter, J. Elia, C. Erickson, S. Berger, N. Blum, K. Uzark, and C. L. Webb
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, May 6, 2008; 117(18): 2407 - 2423.
[Full Text] [PDF]

Home page
 PediatricsHome page
A. G. Winterstein, T. Gerhard, J. Shuster, M. Johnson, J. M. Zito, and A. Saidi
Cardiac Safety of Central Nervous System Stimulants in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Pediatrics, December 1, 2007; 120(6): e1494 - e1501.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
L. Furman
Stimulants and Sudden Death: What Is the Real Risk?
Pediatrics, February 1, 2007; 119(2): 409 - 409.
[Full Text] [PDF]

Home page
 PediatricsHome page
T. Wilens, J. Biederman, T. J. Spencer, and J. Prince
Stimulants and Sudden Death: What Is the Real Risk?: In Reply
Pediatrics, February 1, 2007; 119(2): 409 - 410.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Web of Science (21)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wilens, T. E.
Right arrow Articles by Biederman, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wilens, T. E.
Right arrow Articles by Biederman, J.
Related Collections
Right arrow Office Practice
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?