To Örebro University

Background: Stimulant medications, particularly methyl-phenidate (MPH), are the cornerstone of ADHD management. However, uncertainty persists regarding the optimal second-line ADHD medications, when MPH is insufficient or poorly toler-ated. Atomoxetine (ATX), a non-stimulant, has long been recommended as a second-line therapy. In contrast, lisdexamfetamine (LDX) introduced more recently, became available in Europe only in the last decade.

Objectives: This study compares the risks of two most commonly prescribed second-line medications–LDX and ATX, following the switch from MPH, on four outcomes.

Methods: This longitudinal observational study included all Swedish individuals who initiated MPH and switched to LDX or ATX between 2014 and 2020. We assessed the risks of four outcomes: suicidal behavior, accidental injuries, substance use, and accidental poisoning. Information on outcome events and prescriptions was derived from the National Patient Register, Crime Register, Cause of Death Register, and Prescribed Drug Register (available until the end of 2020). Follow-up started from switch from MPH until death, emigration, two years post-switch, or December 31st, 2020, whichever came first. Baseline and time-varying covariates including demographics, comorbidities, psychotropic medication use, and healthcare utilization were considered within the target trial emulation framework.

Results: The study cohort included participants who started second-line treatment with LDX (n = 41,886) or ATX (n = 8,974) following MPH use (28,127 [55.3] males). The median age at switching to second-line medications was 17.0 (interquartile range, 12.2–28.9) years. Over a two-year period, the risk of out-comes was comparable between the two treatment groups (LDX vs. ATX): accidental injuries (83.0 vs. 85.2 per 10,000 individuals), suicides (12.4 vs. 11.7), substance use (32.4 vs. 27.9) and accidental poisonings (2.6 vs. 2.8). Pooled logistic regression showed similar relative risks for the examined outcomes (adjusted ORs [95% CI]: 1.06 [0.96, 1.18]; 1.11 [0.86, 1.48]; 1.16 [0.99, 1.36]; 0.89 [0.50, 1.74]).

Conclusions: Second-line ADHD medications LDX and ATX showed comparable effects on long-term clinically relevant out-comes. Further exploration of treatment heterogeneity and personalized approaches is warranted, considering differences in mode of action.