Psychosis with Methylphenidate or Amphetamine in Patients with ADHD

Abstract

Background: The prescription use of the stimulants methylphenidate and amphetamine for the treatment of attention deficit-hyperactivity disorder (ADHD) has been increasing. In 2007, the Food and Drug Administration mandated changes to drug labels for stimulants on the basis of findings of new-onset psychosis. Whether the risk of psychosis in adolescents and young adults with ADHD differs among various stimulants has not been extensively studied.

Methods: We used data from two commercial insurance claims databases to assess patients 13 to 25 years of age who had received a diagnosis of ADHD and who started taking methylphenidate or amphetamine between January 1, 2004, and September 30, 2015. 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. To estimate hazard ratios for psychosis, we used propensity scores to match patients who received methylphenidate with patients who received amphetamine in each database, compared the incidence of psychosis between the two stimulant groups, and then pooled the results across the two databases.

Results: We assessed 337,919 adolescents and young adults who received a prescription for a stimulant for ADHD. The study population consisted of 221,846 patients with 143,286 person-years of follow up; 110,923 patients taking methylphenidate were matched with 110,923 patients taking amphetamines. There were 343 episodes of psychosis (with an episode defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication) in the matched populations (2.4 per 1000 person-years): 106 episodes (0.10%) in the methylphenidate group and 237 episodes (0.21%) in the amphetamine group (hazard ratio with amphetamine use, 1.65; 95% confidence interval, 1.31 to 2.09).

Conclusions: Among adolescents and young adults with ADHD who were receiving prescription stimulants, new-onset psychosis occurred in approximately 1 in 660 patients. Amphetamine use was associated with a greater risk of psychosis than methylphenidate. (Funded by the National Institute of Mental Health and others.).

Figure 1.. Study Cohorts.

Incident users of methylphenidate or amphetamine were defined as patients who received a new prescription for one of these drugs, with no previous prescription claims for the stimulant during the 12 months before cohort entry. ADHD denotes attention deficit–hyper­ activity disorder, and CNS central nervous system.

Figure 2.. Overview of the Study Design.

The washout period required that patients be enrolled in medical and prescription drug services for 365 days before initial use of a stimulant. Cohort entry is defined as the date of the first prescription claim for methylphenidate or amphetamine.

Figure 3.. Prescription of Methylphenidate or Amphetamine and Number of Psychotic Episodes According to Age at Cohort Entry and Year of Cohort Entry.

Shown are the combined data from two administrative claims databases (Optum Clinformatics and IBM MarketScan) on the number of patients for whom methylphenidate or amphetamine was prescribed, according to age at cohort entry (Panel A) and year of cohort entry (Panel B). In Panel B, the number of patients who entered the cohort in 2015 is lower than in other years because cohort entry ended on September 30, 2015 (the time of the transition from the 9th revision of the International Classification of Diseases to the 10th revision). The bars in Panel B represent the number of patients who started taking a stimulant, according to year of cohort entry; the dotted and solid lines represent the number of psychotic episodes according to year of cohort entry. A psychotic episode was defined as a new diagnosis code for psychosis and a prescription for an antipsychotic medication.