For more than a decade, a black box warning from the Food and Drug Administration has accompanied the ADHD drug atomoxetine cautioning users of an increased risk of suicidal thoughts. But University of Florida College of Pharmacy researchers found no evidence that children taking atomoxetine were at an increased risk of suicide or suicide attempts.
"Parents generally struggle to weigh the risks and benefits associated with ADHD drug treatment options," said Almut Winterstein, Ph.D., a professor and chair of pharmaceutical outcomes and policy at the College of Pharmacy and co-author of the study. "Having the suicidality safety concern studied and shown that it does not exist will help parents and doctors make more informed decisions related to the treatment of ADHD."
UF researchers evaluated a half million children with attention-deficit hyperactivity disorder, or ADHD, in 26 states for four years. The study assessed whether atomoxetine, which is not classified as a stimulant, was associated with an increased risk of suicidal events when compared with stimulant drugs typically prescribed for ADHD. The findings, which showed no increased risk of suicide attempts among 5- to 18-year-olds treated with atomoxetine compared with those receiving stimulant treatment, were published in the journal Pediatrics on April 26, 2016.
ADHD is the most common mental health disorder in children and adolescents. The Centers for Disease Control and Prevention reports that one in 10 American children ages 4 to 17 have received a diagnosis, and more than 2.7 million children take medication to control the disease.
Stimulants are the most commonly prescribed medication for ADHD. Stimulants can temporarily increase energy levels and concentration, alleviating symptoms of ADHD such as inattention and hyperactivity. Doctors have long prescribed stimulants, despite side effects that include increased heart rate, elevated blood pressure and addiction concerns.
"While atomoxetine has the qualities of a stimulant, it is not classified as one," Winterstein said. "Atomoxetine is not a controlled substance, and people are less likely to abuse it."
Atomoxetine was approved by the Food and Drug Administration, or FDA, as a non-stimulant treatment option for ADHD in 2002. In 2005, a black box warning was added to the drug after a meta-analysis of clinical trial data involving more than 2,200 patients seemed to show a significantly higher risk of suicidal thoughts in patients taking atomoxetine. Five suicidal events occurred, all taking place in children younger than 12 within 32 days of treatment.
"This was a case where there was some evidence that atomoxetine might increase suicidal thoughts, but the evidence was not conclusive," Winterstein said. "The FDA decided to go ahead with the black box warning, but whether this risk translates into an increased risk of actual suicidal events remained unknown."
A black box warning is the strongest type of warning that the FDA can require for a drug. It appears on a prescription drug's label and warns of serious or life-threatening risks associated with taking the drug.
Of the 300,000 children UF researchers studied using atomoxetine or stimulants as a first-line treatment, 140 suicide events were observed. For the 220,000 patients taking atomoxetine as a second treatment option, 90 suicide events were observed. UF researchers found no statistical significance in these results that suggested atomoxetine increased the risk of suicidal events compared with stimulants.
UF researchers also analyzed drug use data that showed a steep increase in atomoxetine usage after FDA approval followed by a gradual decline when safety concerns emerged.
"The massive safety concern associated with the drug label warning probably affected the prescription choices made by physicians," Winterstein said. "Our study's findings indicate that increased suicidal event concerns are not warranted, and some adolescents might benefit from having the black box warning removed from the medication."
Winterstein identified adolescent users because this age group is more likely to abuse stimulants and other drugs compared with younger children and has the most to gain from having a non-stimulant drug option.
The study's lead author, Stephan Linden, Ph.D., completed the research as part of his doctoral thesis at UF. He is now a global epidemiologist at Boehringer Ingelheim, a pharmaceutical company in Germany.
"Risk of Suicidal Events With Atomoxetine Compared to Stimulant Treatment: A Cohort Study" Stephan Linden, Regina Bussing, Paul Kubilis, Tobias Gerhard, Richard Segal, Jonathan J Shuster, Almut G Winterstein. Pediatrics, May 2016.