1E-01 - Dose-Dependent Risk of Psychosis in Patients with Attention-Deficit/Hyperactivity Disorder Treated with Prescription Amphetamine

Background: A recent cohort study reported an increased risk of psychosis in patients with attention-deficit/hyperactivity disorder (ADHD) initiating prescription amphetamine vs. methylphenidate. Subsequently, a case-control study further suggested a dose-response association between prescription amphetamine use and psychosis, but limitations included small samples and potential selection bias due to the restriction to hospitalized patients with severe mental health conditions.

Objectives: This study aimed to assess psychosis risk by prescription amphetamine dose in a large, heterogeneous cohort of ADHD patients.

Methods: Using the Merative MarketScan Commercial Claims Database (2005-2022), we conducted a large cohort study based on a prevalent new user design. After initial cohort restrictions, ADHD patients (ages 13-64 years) were categorized into three amphetamine exposure groups: those who initiated at or increased to a high dose (>30 daily dextroamphetamine equivalents), those who initiated at or increased to a medium dose (>15 to ≤30), and those who initiated at a low dose (≤15) or increased their dose while staying within the low-dose category. Patients were 1:1 matched (high- vs. medium-dose, and high- vs. low-dose) on prior exposure duration, calendar year, and propensity score, accounting for a broad range of potential confounders. Psychosis incidence was determined using a validated algorithm. Follow-up continued until psychosis occurrence, death, disenrollment, end of amphetamine use, exposure switch, 1 year, or study end. Cox proportional hazards models estimated hazard ratios (HR).

Results: 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. Patient characteristics were generally balanced across comparator groups prior to matching.
Before matching, the 1-year incidence of psychosis per 1,000 patients was 2.68 (95% CI: 1.99-3.60) among high-dose users, 2.20 (1.85-2.61) among medium-dose users and 1.89 (1.70-2.11) among low-dose users, yielding crude HRs of 1.23 (0.87-1.73; high vs. medium) and 1.43 (1.05-1.96; high vs. low). Respective HRs were 1.23 (0.77-1.96) and 1.82 (1.06-3.11) after matching. Findings were robust across sensitivity analyses, including varying gap periods between amphetamine prescriptions and modified outcome definitions. Ongoing analyses include subgroup stratifications (e.g., incident vs. prevalent users), and replication in other datasets (including nationwide Medicaid data).

Conclusions: 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 strongly recommended.