Adolescents and young adults being treated for attention-deficit hyperactivity disorder may be at a higher risk of having a psychotic event if they are provided amphetamine medicines, such as Adderall and Vyvanse, instead of medications based on the compound methylphenidate, such as Ritalin or Concerta, according to a study published Wednesday.
The risk of psychosis was generally low, occurring in one in 660 patients, according to the study, which was published in the New England Journal of Medicine.
The risk is “low enough that you can’t say, ‘just don’t prescribe Adderall,’” said Dr. Lauren Moran, the study’s lead author. “But from a public health perspective, there’s so many millions of people being prescribed these medications that it actually leads to thousands of people at increased risk of psychosis.” Moran is an assistant professor at Harvard Medical School, and a psychiatrist who treats inpatient schizophrenic and bipolar patients at McLean Hospital.
The study is unlikely to affect which medications are used in most cases, but it could lead doctors to look more carefully at potential risk factors for other mental illnesses when they prescribe medicines for ADHD. The method by which the data were collected is also noteworthy: Researchers used “real-world evidence,” a term that refers to data collected in the course of medical practice, not in the gold-standard of randomized, controlled clinical trials.
The study was conducted with Aetion, a New York City health data startup founded by another Harvard researcher. Moran has no financial relationship with Aetion.
“I don’t think it’s a shocking finding,” said Dr. Anthony L. Rostain, a professor of psychiatry and pediatrics at the University of Pennsylvania’s Perelman School of Medicine. A small risk of psychosis is listed in the package insert for any stimulant prescription, he noted. “It will just simply be important to mention to people that the amphetamine-based compounds have a slightly higher risk… I think the take-home here should be that everyone should be informed when they are starting a medicine about risks like psychosis.” Rostain has been a consultant to Arbor Pharmaceuticals, an amphetamine maker, and to Shire, which sells Vyvanse and developed Adderall; that company is now part of the Japanese drug giant Takeda (TAK).
The study used a database of insurance claims — notifications of what care patients received that are used by the payment system — that was analyzed by Aetion. The study started by looking for patients between 13 and 26 who received a diagnosis of ADHD and began taking methylphenidate or amphetamine between January 2005 and September 2015. It found 110,923 who had received each type of medicine that could be matched based on age and other risk factors. Patients with signs of existing psychosis, such as a prescription for an antipsychotic medicine, were excluded.
Then the researchers looked to see if each patient had received a diagnosis of psychosis that was severe enough to warrant antipsychotic medicine within 60 days. In that group, there were 343 episodes of psychosis, 106 in the methylphenidate group, a rate of 0.1 percent, and 237 in the amphetamine group, a rate of 0.21 percent. The amphetamine users had a 65 percent increase in the risk of a psychotic event, which can include delusions or hallucinations.
Both Moran and Rostain said differences in how the medicines work in the brain might be one reason for the difference. Both raise levels of the neurotransmitter dopamine, which is involved in a host of brain functions. Methylphenidate works by blocking dopamine from being removed from the brain. Amphetamines, by contrast, both block dopamine from being removed and increase the production of dopamine. They also both noted that one of the risk factors for psychosis is the use of drugs in ways other than directed, overuse. Rostain noted snorting amphetamine pills as one potential risk.
Moran became interested in the issue because she had young patients, many of them college age, showing up on her inpatient ward with psychosis after having used stimulants. She initially did the project as part of project in a class run by Sebastian Schneeweiss, a professor of medicine and epidemiology at Harvard Medical School and a key adviser to Aetion. The results were so intriguing that they decided to address them as a bigger, more rigorous study.
Schneeweiss said in an interview that Aetion was founded because of “a huge demand for real-world evidence that comes close to causal conclusions” and that such an effort, which required well-paid software engineers, couldn’t have come together within Harvard. The company is working with the Food and Drug Administration to see if its databases can replicate the results of randomized trials, which randomly assign patients to one treatment or another. Aetion’s software platform, he said, is “transparent with audit trails with all the bells and whistles that regulators are requiring to make regulatory decisions based on these studies.” Aetion has raised a total of $77 million from investors including McKesson (MCK) Ventures, Sanofi (SNY), and UCB, according to Pitchbook.
The next step, Moran and Schneeweiss said, will be to conduct further studies to help doctors identify which patients might be more at risk of a psychotic episode.