After 50 years of prescription use, stimulants used by children and adolescents carry a rare risk of sudden death, according to a study published online in advance of print June 15 in the American Journal of Psychiatry.
In 2006, the FDA contacted Madeline Gould, PhD, MPH, and her colleagues at Columbia University Medical Center and the New York State Psychiatric Institute to know whether they could determine whether stimulant use might be causing heart disease and sudden death. The federal drug regulators already had 11 cases reported by physicians throughout the country and more deaths might have been unreported. The Columbia group had spent the previous decade studying the risks of tricyclic antidepressants in young people. By the time the FDA asked about stimulants, the antidepressant study had been put to rest because the tricyclics had been all but replaced by the safer class of selective serotonin reuptake inhibitors.
With the epidemiological method decided, the researchers designed a case-control study to assess what they thought was a rare outcome. There had been few published studies and the numbers varied anywhere from 0.8 to 8.0 per 100,000. They set out to identify cases and controls across most states through vital statistics records from 1985 to 1996. They identified 564 children and adolescents between ages 7 and 19 years who died suddenly and for no apparent reason. They also identified an equal number of young people who died as passengers in car accidents. In each case, they collected death certificates, medical examiner reports, and autopsy reports; they also contacted the parents to understand the child's medical and drug history.
At the end of the study, they wanted confirmation of amphetamine use in both groups and to assess whether there was a higher incidence of stimulant use in those signed out as unexplained deaths. According to Dr. Gould, in ten of the sudden deaths, 1.8 percent of the total cases, they found the stimulant methylphenidate on the toxicology report. By contrast, only two of the young people who died in motor vehicle accidents had been taking a stimulant and only one of them had been prescribed methylphenidate. The other young person had a stimulant and marijuana in blood tests.
The odds of a young person swallowing a methylphenidate drug and dying suddenly was seven times more than in those taking stimulants at the time they died in a car accident.
During the study, the investigators were careful to consider every confounding factor, including asthma, which had been linked to attention deficit hyperactivity disorder (ADHD).
“There is an association between stimulant use and sudden death but it is a rare event,” said Dr. Gould. The scientists concluded that: “This finding should be considered in the context of other data about the risk and benefit of stimulants in medical treatment.” It is estimated that 2.5 million children are prescribed stimulant medication. Dr. Gould said that it is “biologically plausible because of the significant increases in heart rate and blood pressure.” They had data on 42,000 patient years and they would have needed 2 million patient years to identify any cardiac events. A case control study allows scientists to estimate what the prevalence would be in the population at large. The precise matching of subjects gives the study findings the power to detect rare findings, the scientists said. The downside of a case-control design is that it can't make a direct link to the cause of the death.
“Parents should not be hysterical,” Dr. Gould added. “This risk is rare and ADHD, left untreated, could have dire consequences as well. But physicians should just be aware of the possibility and consider alternative therapies when children have a known heart problem.”
The federal researchers stress that this is the first study and that more research is needed. The case-control design relied on low numbers, considering how rare the event of sudden death is, they said.
Francisco Xavier Castellanos, MD, the Brooke and Daniel Neidich Professor of Child and Adolescent Psychiatry at New York University School of Medicine and a scientist at the New York University Child Study Center, likens the risk of sudden death among young people taking stimulant medicines to the odds of lightning striking. “More work needs to be done to determine if decongestants or other medications could also be involved in sudden death”.•