Dose-response, net clinical benefit and optimal dose ranges of stimulants in children and adolescents with ADHD: a network meta-analysis

Stimulant treatment with methylphenidate (MPH) and amphetamines (AMP) is first-line for children and adolescents with attention-deficit/hyperactivity disorder (ADHD), but quantitative guidance on comparative efficacy and dose selection within licensed dose ranges remains limited. This study aimed to compare dose-response relationships for MPH and AMP and identify dose ranges that balance symptom improvement and adverse event-related discontinuation across benefit-risk preferences. CENTRAL, PubMed, and Embase were searched from inception to August 12, 2025 for double-blind randomized trials of fixed-dose MPH or AMP in patients aged 5-18 years with ADHD. A Bayesian random-effects dose-response network meta-analysis estimated symptom change and discontinuation due to adverse events. Benefits and harms were integrated using net clinical benefit (NCB) across a range of risk-preference values to reflect real-world variation in benefit-harm trade-offs. Forty-eight trials (4,964 participants) were included. For both drugs, efficacy increased with dose and then plateaued (approximately 45 mg/day for MPH and 25 mg/day for AMP), while adverse event-related discontinuation rose steadily with higher doses. Across plausible preferences, AMP generally achieved higher maximal NCB than MPH. Under neutral preferences, population-level NCB was highest at approximately 18-46 mg/day for MPH (peak 30-39 mg/day) and 12-26 mg/day for AMP (peak 18-20 mg/day). By combining dose-response modeling with a net clinical benefit translation, we identified preference-sensitive, comparative dose ranges for MPH and AMP to support more transparent stimulant selection and dose titration in routine care.