Child and Adolescent Psychiatry/Pediatrics

Article information
Title: Nourredine M, Jurek L, Hamza T, Cipriani A, Subtil F, Parlatini V, Farhat LC, Veronesi GF, Efthimiou O, Salanti G, Cortese S. Pharmacological interventions for ADHD: a systematic review and dose-effect network meta-analysis. Lancet Psychiatry. 2026 Jun;13(6):485-495. doi: 10.1016/S2215-0366(26)00091-X. Erratum in: Lancet Psychiatry. 2026 Jun 12:S2215-0366(26)00175-6. doi: 10.1016/S2215-0366(26)00175-6. PMID: 42134365.
PubMed ID: 42134365
First Author Last Name: Healy

Abstract:
Background:
Optimizing the dosage of pharmacological treatments for ADHD is key to maximizing their benefits, yet most clinical guidelines provide only limited information on this issue. Dose-effect relationships have not been comprehensively assessed across all ADHD medications and age groups, despite growing concerns about subtherapeutic prescribing. We aimed to estimate dose-effect curves for efficacy and tolerability of ADHD medications (stimulants and non-stimulants) across age groups.

Methods:
We conducted a systematic review and dose-effect network meta-analysis of double-blind randomized controlled trials (RCTs) evaluating oral monotherapy (stimulants and non-stimulants) in individuals aged 5 years and older meeting standardized ADHD criteria. Studies involving genetic syndromes, treatment-resistant populations, or withdrawal-phase designs were excluded. We retrieved eligible studies from the MED-ADHD database, updated on Feb 17, 2025, without language restrictions. We included published and unpublished aggregated-level data. The primary outcome was efficacy (measured using validated clinical scales), and the secondary outcome was tolerability (discontinuation due to adverse events). Within-study bias was assessed with the Cochrane Risk of Bias Tool (version 2). We summarized dose-effect associations using a hierarchical Bayesian model with restricted cubic splines. Separate analyses were conducted for children or adolescents (aged <18 years) and adults (aged ≥18 years). The distribution of key effect modifiers was used to examine transitivity of the network. People with lived experience were involved in the conceptualization and design of the study, and in the interpretation of the findings. The protocol was pre-registered on OSF.

Findings:
Our 2017 search identified 9948 potential references for inclusion and our Feb 17, 2025 search identified 5148 references. Of these 15 096 references, 8467 were excluded after title and abstract screening, and a further 5862 references were excluded after a full-text read. Of the 767 remaining reports, 164 were included in the systematic review and 113 RCTs (45 in adults and 68 in children and adolescents) were included in the dose-effect network meta-analysis. The 68 RCTs on children and adolescents included 14 138 participants (9981 [70·6%] males and 4157 [29·4%] females) and the 45 RCTs on adults included 11 016 participants (5958 [54·0%] males and 5056 [46·0%] females). Data on ethnicity or race were inconsistently reported across RCTs. We found distinct dose-effect patterns by medication class and age group. In children and adolescents, methylphenidate, amphetamines, and guanfacine showed increasing median efficacy up to 45 mg/day, 25 mg/day and 4 mg/day, respectively, with no evidence of additional benefit at higher doses, although estimates at higher doses were characterized by wide credible intervals. In adults, amphetamines showed a plateau above approximatively 50 mg/day, whereas methylphenidate efficacy increased without evidence of a plateau, possibly due to sparse data. Dose-dependent increases in discontinuation probability due to adverse events were observed for amphetamines (above 25 mg/day for children and 50 mg/day for adults) and methylphenidate (above 50 mg/day for adults, with no clear dose-dependent risk for children). We found no evidence of dose-effect patterns for atomoxetine (in fixed-doses studies) and modafinil. Multiple sensitivity analyses confirmed the robustness of these findings. We found no evidence of intransitivity.

Interpretation:
Our findings challenge both therapeutic inertia-accepting suboptimal response without further dose titration-and uncritical dose escalation beyond licensed limits, when potential harms outweigh expected benefits. Our findings can inform clinical guidelines and should support shared decision-making regarding ADHD medication dosage.

Annotation

The finding:
This large-scale systematic review and dose–response network meta-analysis examined randomized trials of ADHD medications in children and adults across licensed and unlicensed doses to determine how medication dose influences therapeutic benefits and adverse effects. Both stimulant and non-stimulant treatments showed a consistent pattern in which increasing doses were associated with greater symptom improvement at higher doses and higher rates of side effects and treatment discontinuation. Stimulants tended to produce larger reductions in core ADHD symptoms, whereas non-stimulants showed modest clinical effects with better tolerability. In adults, methylphenidate (but not amphetamine) doses over FDA-licensed doses were superior in efficacy. This study demonstrates the variability in the dose needed to achieve optimal response, suggesting that fixed or minimally titrated dosing approaches may lead to under-treatment in some patients.

Strength and weaknesses:
The authors were able to compare multiple medications and dose ranges within a single analytic framework. The use of dose–response modeling provides better clinical insight than standard comparisons of medications at single doses. Inclusion of pediatric and adult populations makes the findings relevant across the lifespan, particularly for clinicians managing patients during various transitions of care.
At the same time, the included trials differ significantly in design, duration, and patient population, which introduces heterogeneity that may affect precision of estimates. The findings may not fully translate to real-world patients with medical comorbidity, polypharmacy, or psychosocial complexity, as seen in CL psychiatry. The analysis focuses on short- and intermediate-term outcomes, not long-term safety and benefits. Finally, while population-level dose patterns are clarified, the impact on individual treatment response will require clinical judgment.

Relevance:
The study provides a framework for planning the dosing strategy in ADHD pharmacotherapy. It reinforces that treatment failure may sometimes reflect insufficient dose optimization rather than true medication inefficacy. The findings support continuity of ADHD treatment principles across development, highlighting that dose titration remains essential as patients move from pediatric to adult care. In hospital settings, where stimulant medications may be discontinued or reduced, this study highlights the need for thoughtful re-titration upon reinitiation to restore clinical benefit while minimizing adverse effects. More broadly, the study reiterates an emphasis on individualized, data-informed prescribing.