Some ADHD Meds Tied to a Higher Psychosis Risk Than Others

Deborah Brauser

March 20, 2019

Amphetamines are associated with a higher psychosis risk than methylphenidate in young patients who take these agents to treat attention deficit hyperactivity disorder (ADHD), new research suggests.

Lauren V. Moran, MD

Stimulants are recommended as first-line treatment for ADHD. Although methylphenidate is the most frequently prescribed stimulant in many countries, amphetamines are the most commonly prescribed agents in the United States.

Assessing data on more than 220,000 adolescents and young adults starting on a stimulant for ADHD, investigators found that about 1 in 660 participants experienced new-onset psychosis in the following 4 to 5 months.

Among those patients, the risk for psychosis was almost twice as high with the use of amphetamines than with methylphenidate.

"For prescribers, I think the take-home point is that it's really important to screen for potential risk factors," such as a prior history of bipolar or other psychiatric disorder, a family history of psychiatric illness, or use of cannabis, lead author Lauren V. Moran, MD, assistant professor at Harvard Medical School in Boston and a psychiatrist at McLean Hospital, Belmont, Massachusetts, told Medscape Medical News.

"If patients have those risk factors, I would shy away from using the amphetamines. You don't want to have two things that could potentially further increase the risk for psychosis," she added.

The findings were published in the March 21 issue of the New England Journal of Medicine.

Little Comparative Research

Although the US Food and Drug Administration mandated labelling changes for stimulants in 2007 warning of the possibility of treatment-related psychotic or manic symptoms, current ADHD guidelines note that methylphenidate and amphetamines are the most effective treatments for the condition, "with no specification of preference for one over the other," the investigators write.

"Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied," they add.

The researchers note that both drugs cause the release of dopamine and inhibit the dopamine transporter.

"However, dopamine release is four times as high with amphetamine as with methylphenidate, whereas methylphenidate is a more potent inhibitor of dopamine transporters," they write. "The changes in neurotransmission observed in primary psychosis are more consistent with those induced by amphetamine."

Moran noted that there are many college students in the area around McLean Hospital and that in her anecdotal experience as a psychiatrist working in a unit that treats patients with psychotic disorders, she's "been seeing cases of young individuals coming in with psychosis" after stimulant use.

"Although the use of these medications has been rising rapidly, I was personally surprised that there's been no real comparison studies for psychosis risk — especially because there are subtle biological differences," she said.

Amphetamines the Preferred Choice

In the current analysis, the researchers examined patient records from two US insurance claims databases: Optum Clinformatics and IBM MarketScan. They initially assessed 337,919 patients between the ages of 13 and 25 years who were diagnosed with ADHD and who received a first prescription for a stimulant from January 2004 through September 2015.

The final study population comprised 221,846 patients — with half taking methylphenidate or dexmethylphenidate (the "methylphenidate group") and the other half taking amphetamine-dextroamphetamine, dextroamphetamine, or lisdexamfetaimine (the "amphetamine group"). Among the total group, there were 143,286 person-years of follow-up.

Interestingly, 3.8 times as many patients received an amphetamine prescription in 2015 than in 2005, but only 1.6 times as many patients received a methylphenidate prescription during the same time period.

"It's unclear to me what exactly is driving the increased preference of prescribers to start somebody on amphetamine as compared to the Ritalin-type drugs," Moran noted.

In addition, 72.5% of the participants treated by family medicine or internal medicine physicians received an amphetamine prescription, as did 51.6% and 63.7% of those treated by pediatricians and psychiatrists, respectively.

The primary outcome for the study 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.

Diagnoses that qualified as psychosis included major depressive disorder or bipolar disorder with psychotic features, schizophrenia spectrum disorders, delusional disorder, hallucinations, and unspecified psychosis.

"We weren't really looking at transient symptoms of psychosis that go away after a couple of days. We were looking at more severe cases. A majority of the patients were hospitalized and discharged with a prescription for antipsychotics," Moran said.

To determine hazard ratios (HRs) for psychosis, propensity scores from patients who received methylphenidate were matched to those who received amphetamine in each database. The results were then pooled from both databases.

Psychiatrists More Cautious?

Results showed that 106 episodes of psychosis occurred in the full methylphenidate-receiving group (0.10%) vs 237 episodes that occurred in the full amphetamine-receiving group (0.21%).

The incidence rate of psychosis was 1.78 vs 2.83 episodes per 1000 person-years of drug exposure for each group, respectively. Median time from receipt of first stimulant to psychotic episode was 128 days.

The pooled HR for psychosis across both databases was 1.65 for the amphetamine group vs the methylphenidate group (95% confidence interval, 1.31 - 2.09).

Post hoc analyses showed that patients treated by family medicine/internal medicine physicians and pediatricians had a significantly higher risk for psychosis from use of amphetamine than with methylphenidate (HRs, 1.78 and 1.70, respectively) — but those treated by psychiatrists did not (HR, 1.38).

"However, the post hoc nature of the analyses and the inadequate power limit the interpretation of these findings," the investigators write.

"Patients referred to psychiatrists for ADHD may have cognitive deficits or behavioral features that are related to prodromal psychosis, and data on prodromal symptoms would not be captured in claims data. Psychosis may develop in these patients regardless of stimulant treatment," they add.

They also speculate that psychiatrists may be more cautious when prescribing amphetamines and may screen more for psychosis risk factors.

Moran noted that although the study wasn't a randomized controlled trial, "it reflects real-person practice. This is real-world evidence."

"Studies show that stimulants for ADHD might be more effective than non-stimulants, so it can be a little tricky. But definitely in someone who's had a psychotic reaction, or someone who has risk factors for psychosis, I'd avoid stimulants altogether," she said.

Debate Continues

"Despite meta-analyses that show the efficacy of stimulants in reducing ADHD symptoms, at least in the short term, the quality of evidence and the safety of these medications continue to be debated," Samuele Cortese, MD, PhD, Center for Innovation in Mental Health, University of Southampton, England, writes in an accompanying editorial.

He adds that there have been little data on the comparative risk for psychosis between methylphenidate and amphetamine.

The current results "are consistent" with a previous meta-analysis of randomized trials that suggested greater safety for methylphenidate, "at least at the group level," Cortese writes. But, he adds, the new findings "should not be considered definitive."

Study limitations cited include its observational nature, which cannot exclude confounding factors as well as a randomized trial would, and that it could not establish causality.

In addition, "whether psychosis is due to stimulant use, to inherent vulnerability to psychosis, or to the interaction of those factors remain unclear," Cortese writes.

"Despite uncertainties regarding causal mechanisms, the study by Moran and colleagues provides important data on the incidence of psychosis observed in routine practice among patients with ADHD," he adds. "These figures could inform decision making among patients, families, and physicians."

Cortese notes that although it isn't yet possible to identify which patients will have an episode of psychosis after being treated with a stimulant, strategies such as machine learning plus observational data may eventually "provide predictors at the individual patient level."

The study was funded by grants from the National Institute of Mental Health. Moran has disclosed no relevant financial relationships. Disclosures for the other study authors are fully listed in the original article.

N Engl J Med. 2019;380:1128-1138 and 1178-1180. Abstract, Editorial

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