Mental Health
Dose-Dependent Risk of Psychosis in ADHD Patients Treated with Prescription Amphetamine Loreen Straub* Loreen Straub Jun Liu Joseph P. Skinner Lauren Moran
A recent cohort study reported an increased risk of psychosis in ADHD patients initiating amphetamine vs. methylphenidate. Subsequently, a case-control study suggested a dose-response association between prescription amphetamine and psychosis, but limitations included small samples and potential selection bias.
Using the Merative MarketScan Commercial Claims Database (2005-2022), we conducted a large cohort study based on a prevalent new user design to assess psychosis risk by amphetamine dose.
After initial restrictions, ADHD patients (ages 13-64) were categorized into 3 amphetamine exposure groups: high-dose (>30 daily dextroamphetamine equivalents), medium-dose (>15-≤30), and low-dose (≤15) users. Patients were 1:1 matched (high vs. medium; high vs. low) on prior exposure duration, year, and propensity score, accounting for a broad confounder range. Psychosis incidence was based on a validated algorithm. Follow-up continued until psychosis occurrence, death, disenrollment, exposure end or switch, 1 year, or study end. Cox proportional hazards models estimated hazard ratios (HR).
The cohort included 37,377 high-dose, 144,280 medium-dose, and 480,474 low-dose users; 32,927 patients remained in each group after matching. Before matching, the 1-year psychosis incidence per 1,000 patients was 2.68 (95% CI: 1.99-3.60; high dose), 2.20 (1.85-2.61; medium dose) and 1.89 (1.70-2.11; low dose), respectively, yielding crude HRs of 1.23 (0.87-1.73; high vs. medium) and 1.43 (1.05-1.96; high vs. low). Matched HRs were 1.23 (0.77-1.96) and 1.82 (1.06-3.11). Sensitivity analyses confirmed robustness across varying prescription gap periods and outcome definitions. Ongoing analyses include subgroup stratifications and replication in other datasets (e.g., nationwide Medicaid data).
Our findings suggest that caution should be exercised when prescribing high amphetamine doses, particularly given the uncertain clinical benefits. Regular screening for psychotic symptoms is recommended.
