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.

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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.

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  • Are you looking for a pharmacy where you can easily get vyvanse and other ADD products just visit the web page authenticmeds.com
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  • I took Concerta for one month and had extreme paranoia prior to a surgery. (I trust surgeons generally). Paranoid, I asked my caring husband why he took time off work to go with me, and why he was taking time off for that week for me. After the surgery was over, I was no longer paranoid and was very happy my husband was with me. 3 weeks later I was prescribed Adderall. I had extreme irritability at times. I argued with my husband and would become paranoid. Finally, after 6 months of this, he asked for a divorce. He would tell me I was exhausting. (Mania beginning) The doctor added Lexapro to help with anxiety and crying. I became manic— not sure if this is psychosis to zone out into terror and forgetting my husband has been a helpful man to become extremely afraid when he was talking about us going to court. (I would rather have surgery than court.) Is this heightened paranoia to the point of not realizing this is my caring husband considered psychosis? (I stopped both meds in March). I have lost an incredible husband due to these meds. I wish I could ensure to him medically that this would never happen again. I would love another chance to be the awesome wife I was trying to be when I sought help for attention disorder.

    • Horrible story! I am so sorry! Any chance you can explain to him what happened to you and try to reconnect? This is criminal damage done by the system, yet there appears to be no accountability whatsoever.

  • When son started hallucinating when put on the patch, we took him off immediately. We didn’t need to go to the doctor to get antipsychotics when we knew what caused it. We started homeschooling the next year….NO more vitamin R since that time, over 10 years ago. B didn’t have a ritalin deficiency. When are parents going to grow up? See Allen Frances’s Saving Normal before we mess up another generation. He was responsible for a 4000% increase in drug treatment of bi-polar. He ought to know what is going on. No one can give us common sense, we have to find it ourselves.

    • We also resorted to home schooling as a way to avoid the school system’s inability to deal with our very bright, very active, very impatient young boys. I truly believe school is the main cause of “ADHD!” And well done to you for seeing the truth and getting your child off of the drugs when you saw what was happening.

  • After all these years, they suddenly go through insurance information to look for problems. Clearly no research has been done since they started handing these drugs out at random. There has not been any on the long term effects either. The drug industry to too corrupt to allow anything but well funded research that appears to be positive. The only “research” allowed anymore involves picking through insurance claims, which may not tell the entire story. ADHD was a popular diagnosis and little was done to define the actual disorder. It was all by design, since it meant more drugs could be prescribed and profits generated.

  • “Within sixty days…” Does that mean within sixty days of starting the drug or within sixty days of stopping? Some long term analyses of ADHD meds have suggested risks are cumulative, which is to say .1% or .2% per eight week period.

    Studies done before ADHD became big business found that even short-term stimulant consumption can be intensely disruptive. In 1990, a hospital-based study of 45 ADHD-diagnosed 6-12 year-olds observed physical and psychic disruptions in patients taking Ritalin in a three week period. One child spent 36 hours playing with Legos. Another spent seven straight hours raking leaves, “after which he still felt compelled to rake individual leaves as they fell.”

    That 1990 study: https://www.ncbi.nlm.nih.gov/pubmed/2217661 Similar findings from 1989: https://www.ncbi.nlm.nih.gov/pubmed/2808260

    • The study answers my question: “the outcome was a new diagnosis of psychosis for which an antipsychotic medication was prescribed during the first 60 days after the date of the onset of psychosis.”

      Two possible gaps between the analysis and patients’ real-life experiences…

      First, the average patient in the study was medicated for half a year — 221,846 patients with 143,286 person-years of follow-up — whereas many people diagnosed with ADHD are medicated for years.

      Second, the Harvard study doesn’t tally any patients whose psychotic experiences abated, without recourse to antipsychotics, when they stopped stimulants. Dr. Moran might be able to guess the size of this excluded cohort based on her own practice, in which “young patients, many of them college age, showed up on her inpatient ward with psychosis after having used stimulants.”

      Did Dr. Moran immediately prescribe antipsychotics in all these cases, or, having intuited that the episodes might be iatrogenic, wait to observe each patient once she/he was off stimulants?

    • A Canadian retrospective study in the early 2000s showed over 6% of kids on stimulants having some kind of psychotic symptoms. One in 660 is an incredibly low estimate, and only includes overt psychotic breaks that led to a prescription of antipsychotic drugs (“with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication”).

      Of course, this begs the very important question of why they would give these kids antipsychotic drugs instead of taking them off the drugs that were making them psychotic in the first place. I would HOPE that there were 10 times that many who had psychotic breaks where the doctors were smart enough to pull them off the stimulants instead of adding a new drug to “treat” the adverse effects the doctors themselves caused. Which would bring the total up to one in 66 having a psychotic break, a much more believable number, but still not taking into account the many less severe psychotic symptoms reported in the Canadian study.

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