ISTANBUL, TURKEY — Stimulant therapy for boys with attention-deficit/hyperactivity disorder protected them into young adulthood against development of depression, anxiety disorders, and disruptive behavior disorders in a landmark 10-year prospective case-control study.
Perhaps equally important, the stimulant-treated children were significantly less likely to repeat a grade in school than boys with ADHD who did not receive stimulant therapy in this naturalistic observational study, Dr. Joseph Biederman reported at the annual congress of the European College of Neuropsycho-pharmacology.
“School failure is a major issue. I do not know how it is here in Europe, but in the U.S. repeating a grade is a very serious academic dysfunction. I tell my residents that the train of childhood passes through the station only once in life; if you miss that train you will not be able to recuperate,” said Dr. Biederman, professor of psychiatry at Harvard Medical School, Boston.
Stimulant therapy neither increased nor decreased the risk of a subsequent drug, alcohol, or nicotine use disorder during 10 years of follow-up. This finding is at odds with the previously reported 4-year follow-up in this same patient population, which showed that stimulant therapy had a protective effect against substance use disorders.
The reason for the divergent findings regarding development of substance use disorders at 4 and 10 years' follow-up is unclear. One possibility is that during the first 4 years, patients were still young enough to be under tight parental control. Another possible explanation is that stimulants delay but do not stop subsequent substance use disorders.
Regardless, the key take-away point is that these 10-year longitudinal data help alleviate widespread physician and parental concerns that prescribing stimulants to children with ADHD may predispose them to future substance use disorders. It's worth emphasizing that in this study, neither the age at which stimulant therapy began nor its duration was associated with subsequent substance use disorders, added Dr. Biederman, who is chief of the clinical and research program in pediatric psycho-pharmacology and adult ADHD at Massachusetts General Hospital.
The study involved 140 consecutive white boys with and 120 without ADHD who were a mean of 12 years old at study entry. Ten years later, 112 children with ADHD and 105 controls were available for reassessment. Eighty-two ADHD patients had been treated with stimulants for a mean of 6 years starting when they were on average 8.8 years old, and 30 were not treated with stimulants.
The study was undertaken because although stimulants are the mainstay of ADHD treatment and have convincingly been shown to improve the disorder's core symptoms, little was known about stimulant therapy's impact, if any, on the risk of developing the psychiatric comorbidities for which patients with ADHD are at high risk.
Stimulant therapy turned out to have a profound protective effect. At 10 years' follow-up, it was associated with a highly significant 78% reduction in the relative risk of developing major depression, compared with ADHD patients who did not take stimulants, a 79% decrease in conduct disorder, an 85% reduction in the risk of having two or more anxiety disorders, and a 79% reduction in oppositional defiant disorder, all diagnosed based on DSM-IV criteria. Stimulant-treated patients were also 75% less likely to have repeated a grade.
Moreover, stimulant-treated patients were 53% less likely to be diagnosed with bipolar disorder during 10 years of follow-up, a trend which approached but did not achieve statistical significance.
“This issue is of high clinical importance considering the large and bidirectional comorbidity between ADHD and bipolar disorder and the concern that treatment with stimulants may activate children with bipolar disorder,” Dr. Biederman observed.
One audience member asked how stimulant therapy could be effective both for control of ADHD symptoms and for preventing subsequent major depression, given that the neurobiology of the two disorders is quite different.
“I was very surprised by my own findings,” he acknowledged. “The short answer is I don't know. The longer answer … is that I suspect that the continued use of stimulant therapy allows the child to be more successful, minimizes friction at home, minimizes psychosocial vulnerabilities, and that in turn may reduce the risk of developing psychiatric comorbidities like depression.
He noted that this study carries a key message regarding the importance of medication adherence in ADHD.
“The adherence we have with stimulants, at least in the U.S., is among the worst in the entire field of medicine. One year out, 80% of children are no longer taking their medication. Given these data showing that treatment is so important to avert bad outcomes, adherence is extremely important,” Dr. Biederman said.
Another audience member commented that the study results cannot be considered definitive because participants were not randomized to stimulant therapy or a control group. Dr. Biederman replied that the days are long gone when a randomized placebo-controlled study of stimulants in ADHD would be possible. “These data are the best we're going to have,” he said.
ADHD affects up to 10% of children and 5% of adults the world over. Ten-year follow-up data from the investigators' parallel study of girls with ADHD are now being analyzed.
The ongoing longitudinal study is supported by the National Institutes of Health. Dr. Biederman disclosed receiving research support from and serving as a consultant and/or advisory board member to numerous pharmaceutical companies.
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