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Psychosis in Young Adults with ADHD More Likely with Amphetamines Than Methylphenidate

Key findings

  • In a cohort study involving 221,846 adolescents and young adults with ADHD (attention deficit-hyperactivity disorder) for whom methylphenidate or amphetamine was prescribed, 343 patients received a diagnosis of psychosis and a prescription for an antipsychotic medication
  • 0.10% of patients who received methylphenidate and 0.21% of those who received amphetamine had a psychotic episode, respectively
  • The incidence of a psychotic episode was 1.78 per 1000 person-years in the methylphenidate group and 2.83 per 1000 person-years in the amphetamine group (hazard ratio, 1.65)
  • The median time between dispensing of the first stimulant and the psychotic episode was 128 days (interquartile range, 48–333 days)

In 2007, the Food and Drug Administration required manufacturers of stimulants to add a warning to package inserts stating the drugs "may cause treatment-emergent psychotic or manic symptoms in patients with no prior history."

Roy H. Perlis, MD, director of the Center for Quantitative Health at Massachusetts General Hospital, and colleagues suspected that not all stimulants prescribed for ADHD carry equal risk of psychosis. Methylphenidate and amphetamine alter dopamine release and re-uptake. However, previous research has shown that amphetamine's action upon dopamine links to primary psychosis.

Using administrative claims data, the researchers have confirmed that the risk of psychosis in adolescents and young adults with ADHD is greater with amphetamine than methylphenidate. Their report appears in The New England Journal of Medicine.

The researchers identified 337,919 eligible patients in two U.S. nationwide databases of medical claims that together provided information on 253 million patients. These were patients with ADHD who were first dispensed amphetamine–dextroamphetamine, dextroamphetamine, lisdexamfetamine, methylphenidate or dexmethylphenidate between January 1, 2004, and September 30, 2015. The patients had to be 13 to 25 years old at cohort entry (the time when a stimulant was first dispensed).

Propensity-score Matching

To account for potential confounders, the researchers gathered data on variables that could explain the initial prescription of amphetamine versus methylphenidate. Examples include the year of cohort entry, ADHD severity and coexisting psychiatric disorders, conduct or substance use disorders. They then calculated propensity scores, which predicted assignment to amphetamine or methylphenidate based on these covariates. The researchers matched 110,923 of the patients who entered the cohort on amphetamine with 110,923 of the patients who entered on methylphenidate.

Looking for Presence of Psychosis

The outcome of interest was a new inpatient or outpatient diagnosis of psychosis, along with a prescription claim for antipsychotic medication within 60 days. The research team identified 343 episodes of psychosis in the matched population:

  • Methylphenidate group: 106 episodes (0.10%); 1.78 per 1000 person-years of follow-up
  • Amphetamine group: 237 episodes (0.21%); 2.83 per 1000 person-years of follow-up

Across the two databases, the pooled hazard ratio for psychosis was 1.65 (95% CI, 1.31–2.09). The median time between dispensing of the first stimulant and the psychotic episode was 128 days (interquartile range, 48–333 days).

How Important Is the Difference?

The absolute rates of psychosis (0.10% and 0.21%) were low, the authors acknowledge. So too was the difference between groups in the incidence of psychosis (about one per 1000 person-years).

However, considering the prevalence of exposure to stimulants, that difference may be clinically significant. In the two databases taken together, they identified two million patients who received amphetamine, including current users who were excluded from the study cohort. Therefore, even a difference of one per 1000 person-years confers additional risk of psychosis on thousands of patients.

Learn more about the Center for Quantitative Health

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