Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis

Abstract

SummaryBackgroundThe benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults.MethodsWe did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976.Findings133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only diff...

An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations

“…There are currently no reliable predictors of response to a particular stimulant [123]. While stimulants have long been recommended as first-line pharmacotherapy for ADHD, there are inconsistencies in the treatment recommendations in current guidelines [133]. Most guidelines and consensus statements recommend stimulants without identifying an agent of first choice nor offer any distinctions between MPH and AMP [2,11,13,14], whereas some recommend MPH over AMP for children [15,133].…”

“…While stimulants have long been recommended as first-line pharmacotherapy for ADHD, there are inconsistencies in the treatment recommendations in current guidelines [133]. Most guidelines and consensus statements recommend stimulants without identifying an agent of first choice nor offer any distinctions between MPH and AMP [2,11,13,14], whereas some recommend MPH over AMP for children [15,133]. Because AMP is thought to work through a different mechanism of action than MPH, a lack of response to one class of psychostimulant does not preclude response to another class [122,123].…”

“…formulation and/or class of stimulant). Interestingly, a recent systematic review and network metaanalysis on the comparative efficacy and tolerability of medications used for managing ADHD in children, adolescents and adults concluded that the preferred first pharmacological choice for the treatment of ADHD in children and adolescents is MPH, whereas AMP is preferred in adults [133]. Lastly, since isometric mixtures are not bioequivalent, pharmacological differences in the ratios of enantiomers may also contribute to clinical differences [123].…”

Twenty years of research on attention-deficit/hyperactivity disorder (ADHD): looking back, looking forward

“…For the pharmacological interventions, a comprehensive network meta-analysis36 of 133 double-blind RCTs demonstrated high to moderate effect sizes (in terms of efficacy) for the different medications versus placebo. Standardised mean differences (SMD) ranged from −1.02 (95% CI −1.19 to −0.85) for amphetamines to −0.56 (95% CI −0.66 to −0.45) for atomoxetine (methylphenidate: −0.78, 95% CI −0.93 to −0.62).…”

The advantages of an ADHD classification from the perspective of teachers

“…According to some teachers, a DSMclassification points the direction in which solutions may be found and implemented, and suggests what will be of benefit to a pupil. While some researchers indeed suggest that a good and timely DSM-diagnosis leads to correct treatment (Cortese, Adamo, and Del Giovane 2018;Moore et al 2016), it is notable that the drafters of the definition of ADHD themselves report differently, namely that a DSM diagnosis is of limited value in planning for the treatment of individual children (Kupfer, First, and Regier 2002).…”