A case-control study in children and adolescents adds to evidence
supporting a link between the use of stimulants, commonly used to treat
attention-deficit/hyperactivity disorder (ADHD), and an increase in the risk
of sudden death in this population.
The researchers in a study led by Madelyn Gould, Ph.D., M.P.H., and
published online June 15 in AJP in Advance examined mortality data
and death certificates from states' vital-statistics reports from 1985 through
1996 and identified 564 cases of sudden unexplained death (including from
sudden cardiac dysrhythmia and unknown causes) in children and adolescents
aged 7 to 19. A control group of 564 youths who died as passengers in motor
vehicle accidents were matched to the case series for age, sex, year of death,
and data source.
Gould is a professor of clinical epidemiology in psychiatry at Columbia
University College of Physicians and Surgeons and a research scientist at the
New York State Psychiatric Institute.
The analysis found a significant association between sudden unexplained
death and the use of a stimulant at the time of death.
Ten (1.8 percent) of the youth in the sudden-death group were taking the
stimulant methylphenidate. In comparison, two (0.4 percent) in the control
group were taking stimulants, one of whom was taking methylphenidate. The risk
increase was statistically significant, with an odds ratio of 7.4 (95 percent
confidence interval: 1.4 to 74.9). This association remained statistically
significant in a sensitivity analysis excluding cases in which the youth were
using concomitant tricyclic antidepressants.
Because of numerous case reports of sudden death that have been linked to
stimulant use and the known cardiovascular effects of these drugs, the Food
and Drug Administration (FDA) has been monitoring and analyzing
stimulant-related, adverse-reaction reports for several years.
The Canadian regulatory agency, Health Canada, suspended the marketing of
mixed amphetamine salts briefly in 2005 out of concern about a possible
association between the drug and sudden cardiac death, but later allowed its
return after a stronger warning was added to the product labeling.
Both countries' regulatory agencies currently recommend that stimulants not
be used in children or adults with structural cardiac abnormalities,
cardiomyopathy, or other cardiac abnormalities.
On the same day the study was published, the FDA issued a public
announcement urging parents not to stop a child's stimulant medication on the
basis of this study alone. "Given the limitations of this study's
methodology, the FDA is unable to conclude that these data affect the overall
risk and benefit profile of stimulant medications used to treat ADHD in
children," according to the announcement, which also noted that the FDA
and the Agency for Healthcare Research and Quality are sponsoring a large
epidemiological study on this issue, and additional data are forthcoming.
"[The Gould study] is the first methodologically rigorous study to
identify a link between therapeutic use of stimulant medication and sudden
unexplained deaths in children without demonstrated heart
abnormalities," wrote Benedetto Vitiello, M.D., and Kenneth Towbin,
M.D., in an editorial accompanying the study. Nevertheless, they cautioned
that as sudden unexplained death is very rare in children and adolescents,
this study had to rely on small numbers, and "it is not possible to
quantify the risk beyond estimating that it is very small."
Vitiello is chief of the National Institute of Mental Health (NIMH) Child
and Adolescent Treatment and Preventive Intervention Research Branch. Towbin
is chief of Clinical Child and Adolescent Psychiatry in the Mood and Anxiety
Disorder Program at NIMH.
Although retrospective studies are at risk of being contaminated by
confounding factors and inherent biases, it would be nearly impossible to
conduct prospective, randomized clinical trials to prove the link between
stimulant use and sudden death, since the rate is so small, the editorial
noted; however, a biological basis exists for the cardiovascular risks of
these drugs. Considering the widespread use of stimulants for ADHD and the
substantial rates of diversion and misuse, especially among high school and
college students, clinicians should be careful when prescribing them."
Stimulants are not innocuous and ... their therapeutic use requires
careful diagnostic assessment, diligent safety screening, and ongoing
monitoring," Vitiello and Towbin wrote.
The study was funded by the FDA and NIMH.