Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents

  • Review
  • Intervention

Authors


Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric conditions affecting children and adolescents. Amphetamines are among the most commonly prescribed medications to manage ADHD. There are three main classes of amphetamines: dexamphetamine, lisdexamphetamine and mixed amphetamine salts, which can be further broken down into short- and long-acting formulations. A systematic review assessing their efficacy and safety in this population has never been conducted.

Objectives

To assess the efficacy and safety of amphetamines for ADHD in children and adolescents.

Search methods

In August 2015 we searched CENTRAL, Ovid MEDLINE, Embase, PsycINFO, ProQuest Dissertation and Theses, and the Networked Digital Library of Theses and Dissertations. We also searched ClinicalTrials.gov, and checked the reference lists of relevant studies and reviews identified by the searches. No language or date restrictions were applied.

Selection criteria

Parallel-group and cross-over randomized controlled trials (RCTs) comparing amphetamine derivatives against placebo in a pediatric population (< 18 years) with ADHD.

Data collection and analysis

Two authors independently extracted data on participants, settings, interventions, methodology, and outcomes for each included study. For continuous outcomes, we calculated the standardized mean difference (SMD) and for dichotomous outcomes we calculated the risk ratio (RR). Where possible, we conducted meta-analyses using a random-effects model. We also performed a meta-analysis of the most commonly reported adverse events in the primary studies.

Main results

We included 23 trials (8 parallel-group and 15 cross-over trials), with 2675 children aged three years to 17 years. All studies compared amphetamines to placebo. Study durations ranged from 14 days to 365 days, with the majority lasting less than six months. Most studies were conducted in the United States; three studies were conducted across Europe. We judged 11 included studies to be at a high risk of bias due to insufficient blinding methods, failing to account for dropouts and exclusions from the analysis, and failing to report on all outcomes defined a priori. We judged the remaining 12 studies to be at unclear risk of bias due to inadequate reporting.

Amphetamines improved total ADHD core symptom severity according to parent ratings (SMD -0.57; 95% confidence interval (CI) -0.86 to -0.27; 7 studies; 1247 children/adolescents; very low quality evidence), teacher ratings (SMD -0.55; 95% CI -0.83 to -0.27; 5 studies; 745 children/adolescents; low quality evidence), and clinician ratings (SMD -0.84; 95% CI -1.32 to -0.36; 3 studies; 813 children/adolescents; very low quality evidence). In addition, the proportion of responders as rated by the Clinical Global Impression - Improvement (CGI-I) scale was higher when children were taking amphetamines (RR 3.36; 95% CI 2.48 to 4.55; 9 studies; 2207 children/adolescents; very low quality evidence).

The most commonly reported adverse events included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches, and anxiety. Amphetamines were associated with a higher proportion of participants experiencing decreased appetite (RR 6.31; 95% CI 2.58 to 15.46; 11 studies; 2467 children/adolescents), insomnia (RR 3.80; 95% CI 2.12 to 6.83; 10 studies; 2429 children/adolescents), and abdominal pain (RR 1.44; 95% CI 1.03 to 2.00; 10 studies; 2155 children/adolescents). In addition, the proportion of children who experienced at least one adverse event was higher in the amphetamine group (RR 1.30; 95% CI 1.18 to 1.44; 6 studies; 1742 children/adolescents; low quality evidence).

We performed subgroup analyses for amphetamine preparation (dexamphetamine, lisdexamphetamine, mixed amphetamine salts), amphetamine release formulation (long acting versus short acting), and funding source (industry versus non industry). Between-group differences were observed for proportion of participants experiencing decreased appetite in both the amphetamine preparation (P < 0.00001) and amphetamine release formulation (P value = 0.008) subgroups, as well as for retention in the amphetamine release formulation subgroup (P value = 0.03).

Authors' conclusions

Most of the included studies were at high risk of bias and the overall quality of the evidence ranged from low to very low on most outcomes. Although amphetamines seem efficacious at reducing the core symptoms of ADHD in the short term, they were associated with a number of adverse events. This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations. Future trials should be longer in duration (i.e. more than 12 months), include more psychosocial outcomes (e.g. quality of life and parent stress), and be transparently reported.

摘要

安非他命治療兒童及青少年注意力不足過動症(ADHD)

背景

注意力不足過動症(ADHD)是常見影響兒童與青少年的精神疾患之一。安非他命是最常見用於治療ADHD的處方藥物,安非他命主要有三種不同的類型:dexamphetamine、lisdexamphetamine 和mixed amphetamine salts,可被進一步製成長效或短效劑型。目前尚未有關於此治療方法之療效和安全的系統性文獻回顧評估。

目的

評估安非他命治療兒童與青少年ADHD之療效和安全性。

搜尋策略

在2015年8月,我們搜尋了CENTRAL、Ovid MEDLINE、Embase、PsycINFO、ProQuest Dissertation and Theses,以及the Networked Digital Library of Theses and Dissertations等資料庫;也搜尋了ClinicalTrials.gov,並核對相關研究之文獻列表和檢索,搜尋中並無語言及日期限制。

選擇標準

在ADHD兒童(<18歲)中比較安非他命衍生物和安慰劑治療之平行設計和交叉設計的隨機對照試驗。

資料收集與分析

兩位作者獨立地萃取納入研究中的受試者、環境、介入、方法學與結果等資料。對於連續性變項,我們計算標準化平均差(SMD);二元變項則計算風險比(RR)。盡可能地,我們用隨機效應模型執行統合分析,也對於主要研究中的常見不良反應進行統合分析。

主要結果

我們納入23個試驗(8個平行試驗和15個交叉試驗),包含2675位從3歲至17歲的兒童。所有研究都將安非他命與安慰劑做比較。研究期間涵蓋14天至365天,多數執行短於6個月。大部分的研究在美國執行;僅其中3個橫跨歐洲。我們判斷11個納入的研究有高風險偏差,因其不充足的盲法,無法說明退出和排除試驗者,以及無法報告所有主要結果。我們認為剩下的12個研究因無適當報告而風險偏差不明。

安非他命改善ADHD核心症狀嚴重度依據父母評分(SMD -0.57; 95%信賴區間(CI) -0.86至-0.27; 7 個試驗; 1247位兒童/青少年;證據品質非常低),老師評分(SMD -0.55; 95%CI -0.83至-0.27; 5個試驗; 745位兒童/青少年;證據品質低),和醫師評分(SMD -0.84; 95%CI -1.32至-0.36; 3個試驗; 813位兒童/青少年;證據品質非常低)。此外,以臨床整體印象分數改善量表(CGI-I)評分,接受安非他命治療兒童改善比例較高(RR 3.36; 95%CI 2.48至4.55; 9個試驗; 2207位兒童/青少年;證據品質非常低)。

常見報告不良作用包括食慾下降、失眠/睡眠障礙、腹痛、噁心嘔吐、頭痛,和焦慮。服用安非他命的受試者有較高比例出現食慾下降(RR 6.31; 95% CI 2.58 至15.46; 11個試驗; 2467位兒童/青少年)、失眠(RR 3.80; 95% CI 2.12至6.83; 10個試驗; 2429位兒童/青少年)、腹痛(RR 1.44; 95% CI 1.03至2.00; 10個試驗; 2155位兒童/青少年)。此外,在安非他命治療組出現至少一項不良作用的孩童比例較高(RR 1.30; 95% CI 1.18至1.44; 6個試驗; 1742位兒童/青少年; 證據品質低)。

我們執行了關於安非他命製備(dexamphetamine, lisdexamphetamine, mixed amphetamine salts)、安非他命釋放劑型(長效或短效)、和經費來源(產業界或非產業界)的子群組分析。我們觀察到在安非他命製備子群(P < 0.00001)與安非他命釋放劑型子群(P value = 0.008)受試者出現食慾下降之比例以及安非他命釋放劑型子群(P value = 0.03)之殘留皆出現子群間差異。

作者結論

大部分納入的研究有高偏差風險且結果證據品質為低至非常低。儘管安非他命短期對於減輕ADHD核心症狀似乎有療效,但仍有相當數目的不良作用。此篇文獻回顧並無找到證據支持任一安非他命衍生物較優,且長效或短效安非他命劑型並無差異。未來的試驗應涵蓋更長時間(即大於12個月),包含更多社會心理預後(如生活品質、雙親壓力)和更透明的紀錄。

Résumé scientifique

Les amphétamines pour le traitement du trouble déficitaire de l'attention avec hyperactivité (TDAH) chez les enfants et les adolescents

Contexte

Le trouble déficitaire de l'attention avec hyperactivité (TDAH) est l'un des troubles psychiatriques les plus fréquents observés chez les enfants et les adolescents. Les amphétamines sont parmi les médicaments les plus couramment prescrits pour la prise en charge du TDAH. Il existe trois grandes classes d'amphétamines : les dexamphétamines, les lisdexamphétamines et les sels mixtes. Ces classes peuvent encore être divisées en fonction de la durée d'action des préparations (de courte ou longue durée). Une revue systématique évaluant leur efficacité et leur innocuité dans cette population n'a jamais été réalisée.

Objectifs

Évaluer l'efficacité et l'innocuité des amphétamines pour le traitement du TDAH chez les enfants et les adolescents.

Stratégie de recherche documentaire

En août 2015, nous avons effectué des recherches dans CENTRAL, Ovid MEDLINE, Embase, PsycINFO, ProQuest Dissertation and Theses et la Networked Digital Library of Theses and Dissertations. Nous avons également consulté ClinicalTrials.gov, et examiné les références bibliographiques des études et revues pertinentes identifiées lors de nos recherches. Aucune restriction de langue ou de date n'a été appliquée.

Critères de sélection

Les essais contrôlés randomisés (ECR) en groupes parallèles et croisés comparant des dérivés des amphétamines par rapport à un placebo dans une population pédiatrique (< 18 ans) atteinte de TDAH.

Recueil et analyse des données

Deux auteurs ont indépendamment extrait les données portant sur les participants, les contextes, les interventions, la méthodologie et les critères de jugement pour chaque étude incluse. Pour les résultats continus, nous avons calculé la différence moyenne standardisée (DMS) et pour les résultats dichotomiques, nous avons calculé le risque relatif (RR). Lorsque cela était possible, nous avons effectué une méta-analyse au moyen d'un modèle à effets aléatoires. Nous avons également effectué une méta-analyse des événements indésirables les plus fréquemment rapportés dans les études primaires.

Résultats principaux

Nous avons inclus 23 essais (8 en groupes parallèles et 15 en essais croisés), avec un total de 2675 enfants âgés de 3 à 17 ans. Toutes les études comparaient des amphétamines à un placebo. La durée des études allait de 14 à 365 jours et la majorité était d'une durée inférieure à six mois. La plupart des études ont été réalisées aux États-Unis ; trois études ont été menées en Europe. Nous avons estimé que 11 des études incluses présentaient un risque élevé de biais en raison de méthodes de mise en aveugle insuffisantes, parce que celles-ci ne parvenaient pas à prendre en compte les participants ayant mis fin à leur participation et ceux exclus de l'analyse, et lorsque certains des critères de jugement prédéterminés n'étaient pas rapportés. Nous avons estimé que les 12 autres études présentaient un risque de biais incertain en raison de leurs contenus inadéquatement rapportés.

Les amphétamines amélioraient la gravité globale des symptômes principaux du TDAH selon les évaluations des parents (DMS -0,57 ; intervalle de confiance (IC) à 95 % de -0,86 à -0,27 ; 7 études ; 1247 enfants / adolescents ; preuves de très faible qualité), les évaluations des enseignants (DMS -0,55 ; IC à 95 % de -0,83 à -0,27 ; 5 études ; 745 enfants / adolescents ; preuves de faible qualité), et les évaluations des cliniciens (DMS -0,84 ; IC à 95 % de -1,32 à -0,36 ; 3 études ; 813 enfants / adolescents ; preuves de très faible qualité). En outre, la proportion de personnes répondant au traitement, évaluée par l'échelle de l'Amélioration de l'Impression Clinique Globale (l'échelle CGI-I) était plus élevée lorsque les enfants prenaient des amphétamines (RR 3,36 ; IC à 95 % de 2,48 à 4,55 ; 9 études ; 2207 enfants / adolescents ; preuves de très faible qualité).

Les événements indésirables les plus couramment signalés incluaient une diminution de l'appétit, l'insomnie / des troubles du sommeil, des douleurs abdominales, des nausées / vomissements, des céphalées et de l'anxiété. Les amphétamines étaient associées à une plus grande proportion de participants ressentant une diminution de l'appétit (RR 6,31 ; IC à 95 % de 2,58 à 15,46 ; 11 études ; 2467 enfants / adolescents), des insomnies (RR 3,80 ; IC à 95 % de 2,12 à 6,83 ; 10 études ; 2429 enfants / adolescents), et des douleurs abdominales (RR 1,44 ; IC à 95 % de 1,03 à 2,00 ; 10 études ; 2155 enfants / adolescents). En outre, la proportion d'enfants ayant vécu au moins un événement indésirable était plus élevée dans le groupe ayant pris des amphétamines (RR 1,30 ; IC à 95 % de 1,18 à 1,44 ; 6 études ; 1742 enfants / adolescents ; preuves de faible qualité).

Nous avons réalisé des analyses de sous-groupes en fonction de la préparation des amphétamines (dexamphétamine, lisdexamphétamine et sels mixtes), de la formulation de la libération des amphétamines (action prolongée versus courte durée d'action) et de la source de financement des essais (financés par l'industrie ou non). Des différences entre les groupes ont été observées quant à la proportion de participants ressentant une diminution de l'appétit à la fois pour les sous-groupes de la préparation des amphétamines (P < 0,00001), de la formulation de la libération des amphétamines (P = 0,008), ainsi que pour la rétention dans le sous-groupe de la formulation de la libération des amphétamines (P = 0,03).

Conclusions des auteurs

La plupart des études incluses présentaient un risque élevé de biais et la qualité globale des preuves était faible à très faible sur la plupart des critères de jugement. Bien que les amphétamines semblent efficaces pour réduire les principaux symptômes du TDAH au court terme, ceux-ci ont été associés à un certain nombre d'effets indésirables. Cette revue n'a trouvé aucune preuve favorisant un quelconque dérivé des amphétamines par rapport à un autre, et n'a pas mis en évidence de différences entre les préparations de courte ou longue durée d'action. Les futurs essais devraient être de durée plus longue (c'est-à-dire supérieure à 12 mois), inclure davantage les résultats psychosociaux (par ex : la qualité de vie et le stress vécu par les parents), et ces essais devraient être rapportés de manière transparente.

Resumen

Anfetaminas para el trastorno de déficit de atención e hiperactividad (TDAH) en niños y adolescentes

Antecedentes

El trastorno de déficit de atención e hiperactividad (TDAH) es una de las afecciones psiquiátricas más frecuentes que afectan a niños y adolescentes. Las anfetaminas se encuentran entre los fármacos que se prescriben con mayor frecuencia para el tratamiento del TDAH. Existen tres clases principales de anfetaminas: dexamfetamina, lisdexamfetamina y sales mixtas de anfetamina, que se pueden descomponer adicionalmente en formulaciones de acción corta y prolongada. Nunca se ha realizado una revisión sistemática que evalúe su eficacia y seguridad en esta población.

Objetivos

Evaluar la eficacia y la seguridad de las anfetaminas como tratamiento del TDAH en niños y adolescentes.

Métodos de búsqueda

En agosto 2015, se hicieron búsquedas en CENTRAL, Ovid MEDLINE, Embase, PsycINFO, ProQuest Dissertation and Theses, y en Networked Digital Library of Theses and Dissertations. También se realizaron búsquedas en ClinicalTrials.gov, y se verificaron las listas de referencias de los estudios y las revisiones pertinentes identificados mediante las búsquedas. No se aplicaron restricciones de idioma o de fecha.

Criterios de selección

Ensayos controlados aleatorios (ECA) de grupos paralelos y cruzados (crossover) que compararon derivados de la anfetamina contra placebo en una población pediátrica (< 18 años) con TDAH.

Obtención y análisis de los datos

Dos autores extrajeron de forma independiente los datos sobre los participantes, los contextos, las intervenciones, la metodología y los resultados de cada estudio incluido. Para los resultados continuos se calculó la diferencia de medias estandarizada (DME) y para los resultados dicotómicos se calculó el cociente de riesgos (CR). De ser posible se realizaron metanálisis mediante el modelo de efectos aleatorios. También se realizó un metanálisis de los eventos adversos informados con más frecuencia en los estudios primarios.

Resultados principales

Se incluyeron 23 ensayos (ocho de grupos paralelos y 15 ensayos cruzados) con 2675 niños de tres a 17 años de edad. Todos los estudios compararon anfetaminas con placebo. Las duraciones de los estudios variaron desde 14 días a 365 días, la mayoría con una duración menor de seis meses. La mayoría de los estudios se realizaron en los Estados Unidos; Se realizaron tres estudios en Europa. Se consideró que 11 estudios incluidos tuvieron alto riesgo de sesgo debido a métodos de cegamiento insuficientes, la imposibilidad de justificar los abandonos y las exclusiones del análisis y la imposibilidad de informar todos los resultados definidos a priori. Se consideró que los 12 estudios restantes tuvieron riesgo incierto de sesgo debido al informe insuficiente.

Las anfetaminas mejoraron la gravedad de los síntomas centrales totales del TDAH según las calificaciones de los padres (DME -0,57; intervalo de confianza [IC] del 95%: -0,86 a -0,27; siete estudios; 1247 niños/adolescentes; pruebas de muy baja calidad), las calificaciones de los maestros (DME -0,55; IC del 95%: -0,83 a -0,27; cinco estudios; 745 niños/adolescentes; pruebas de baja calidad) y las calificaciones de los médicos (DME -0,84; IC del 95%: -1,32 a -0,36; tres estudios; 813 niños/adolescentes; pruebas de muy baja calidad). Además, la proporción de los que responden al tratamiento evaluada por la escala Clinical Global Impression - Improvement (CGI-I) fue mayor cuando los niños recibieron anfetaminas (CR 3,36; IC del 95%: 2,48 a 4,55; nueve estudios; 2207 niños/adolescentes; pruebas de muy baja calidad).

Los eventos adversos informados con más frecuencia incluyeron reducción del apetito, insomnio / dificultad para dormir, dolor abdominal, náuseas / vómitos, cefaleas y ansiedad. Las anfetaminas se asociaron con una proporción mayor de participantes que experimentaron reducción del apetito (CR 6,31; IC del 95%: 2,58 a 15,46; 11 estudios; 2467 niños/adolescentes), insomnio (CR 3,80; IC del 95%: 2,12 a 6,83; diez estudios; 2429 niños/adolescentes), y dolor abdominal (CR 1,44; IC del 95%: 1,03 a 2,00; diez estudios; 2155 niños/adolescentes). Además, la proporción de niños que experimentaron al menos un evento adverso fue mayor en el grupo de anfetamina (CR 1,30; IC del 95%: 1,18 a 1,44; seis estudios; 1742 niños/adolescentes; pruebas de baja calidad).

Se realizaron análisis de subgrupos por la preparación de anfetaminas (dexamfetamina, lisdexamfetamina, sales mixtas de anfetamina), la formulación de liberación de anfetaminas (acción prolongada versus acción corta) y la fuente de financiamiento (industria versus no industria). Se observaron diferencias entre los grupos en la proporción de participantes que experimentaron reducción del apetito en los subgrupos de preparación de anfetaminas (p < 0,00001) y formulación de liberación de anfetaminas (valor de p = 0,008), así como en la retención en el subgrupo de formulación de liberación de anfetaminas (valor de p = 0,03).

Conclusiones de los autores

En su mayoría los estudios incluidos tuvieron alto riesgo de sesgo y la calidad general de las pruebas varió de baja a muy baja en la mayoría de los resultados. Aunque las anfetaminas parecen eficaces para reducir los síntomas centrales del TDAH a corto plazo, estos fármacos se asociaron con varios eventos adversos. Esta revisión no encontró pruebas que apoyen a ningún derivado de la anfetamina sobre otro, y no muestra diferencias entre las preparaciones de anfetaminas de acción prolongada y de acción corta. Los ensayos futuros deben tener una duración más prolongada (es decir, más de 12 meses), incluir más resultados psicosociales (p.ej. calidad de vida y estrés de los padres) e informarse de manera transparente.

Plain language summary

Amphetamines for attention deficit hyperactivity disorder in children and adolescents

Background
Attention deficit hyperactivity disorder (ADHD) is a common problem affecting children and adolescents. ADHD is characterized by inattention (being easily distracted, unable to focus on one task), impulsivity (fidgety; constantly moving), and hyperactivity (impatient; acts without thinking). One of the most common treatments for managing ADHD is the drug class of amphetamines, which are a class of stimulant medications. They are thought to reduce the severity of symptoms associated with ADHD.

Review question

Do children and adolescents (under 18 years of age) diagnosed with ADHD benefit from treatment with amphetamines to reduce the core symptoms of ADHD, compared to other children and adolescents who receive no drug or a fake drug (placebo)?

Study characteristics
As of August 2015, we identified 23 randomized controlled trials (RCTs: a type of scientific experiment in which people are randomly assigned to one of two or more treatments), which included 2675 children and adolescents between three years and 17 years of age. These studies compared amphetamines to placebo. Three different kinds of amphetamines were investigated: dexamphetamine, lisdexamphetamine and mixed amphetamine salts. The duration of the included studies ranged from 14 days to 365 days. The RCTs were conducted in the United States and Europe.

Key results
We found that amphetamines were effective at improving the core symptoms of ADHD in the short term, but that they were also linked to a higher risk of experiencing adverse events such as sleep problems, decreased appetite, and stomach pain. We found no evidence that one kind of amphetamine was better than another, and found no difference between amphetamines that act for longer periods of time versus those that act for shorter periods of time.

Quality of the evidence

The quality of the included studies was low to very low because of problems in their design and large differences between the studies. Well-designed and clearly reported RCTs that are longer in duration are needed, so we may better understand the long-term effects (both positive and negative) of amphetamines.

Laički sažetak

Amfetamini za liječenje poremećaja nedostatka pozornosti ili hiperaktivnog poremećaja (ADHD) u djece i adolescenata

Dosadašnje spoznaje
Poremećaj nedostatka pozornosti i hiperaktivni poremećaj (ADHD) čest je problem koji pogađa djecu i adolescente. ADHD je obilježen nedostatkom pozornosti (lako se gubi pozornost, nemogućnost fokusiranja na jedan zadatak), impulzivnošću (nemir, neprestano pokretanje) i hiperaktivnošću (nestrpljivost, djelovanje bez razmišljanja). Među najčešćim terapijama za liječenje ADHD-a su lijekovi iz skupine amfetamina, koji imaju stimulativno djelovanje. Smatra se da amfetamini ublažavaju težinu simptoma povezanih s ADHD-om.

Istraživačko pitanje

Može li djeci i adolescentima (mlađim od 18 godina) koji pate od ADHD-a pomoći terapija amfetaminima za smanjenje glavnih simptoma ADHD-a u usporedbi s drugim lijekovima ili lažnim lijekom (placebo)?

Obilježja istraživanja
Pronađene su 23 randomizirane kontrolirane studije (vrsta znanstvenog istraživanja u kojem su ispitanici nasumce raspoređeni u dvije ili više skupine), koje su objavljene do kolovoza 2015. i uključile ukupno 2675 djece i adolescenata u dobi između 3 i 17 godina. Te su studije usporedile amfetamine i placebo. Istražene su tri vrste amfetamina: deksamfetamin, lisdeksamfetamin i mješane soli amfetamina. Studije su trajale od 14 do 365 dana. Pokusi su provedeni u SAD-u i Europi.

Ključni rezultati
Amfetamini su bili djelotvorni za poboljšanje glavnih simptoma ADHD-a kroz kratko vrijeme, ali su također bili povezani s većim rizikom od štetnih posljedica kao što su problemi sa spavanjem, smanjeni apetit i bol u trbuhu. Nisu pronađeni dokazi da je jedna vrsta amfetamina bolja od neke druge, i nije utvrđena razlika između različitih amfetamina koji djeluju dulje vrijeme od onih koji djeluju kraće vrijeme.

Kvaliteta dokaza

Kvaliteta uključenih studija bila je niska ili vrlo niska zbog problematičnog ustroja istraživanja i velikih razlika među studijama. Nužne su veće studije koje će biti napravljene na kvalitetan način i koje će autori propisno opisati, kako bismo mogli bolje razumjeti dugoročne učinke (i pozitivne i negativne) terapije ADHD-a amfetaminima.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Применение амфетаминов в лечении синдрома дефицита внимания и гиперактивности у детей и подростков

Актуальность
Синдром дефицита внимания и гиперактивности (СДВГ) - распространенная проблема, затрагивающая детей и подростков. СДВГ характеризуется невнимательностью (отсутствие концентрации, неспособность сфокусироваться на одном задании), импульсивность (суетливость; постоянные движения) и гиперактивность (нетерпеливость, бездумные действия). Одним из наиболее распространенных методов лечения СДВГ является использование группы лекарств - амфетаминов, являющихся стимуляторами нервной системы. Считается что эта группа лекарств снижает тяжесть симптомов, связанных с СДВГ.

Вопрос обзора

Получают ли дети и подростки, у которых диагностирован СДВГ, пользу от лечения амфетаминами в снижении основных симптомов СДВГ, в сравнении с другими детьми и подростками, которые не получают лекарства или получают поддельное лекарство (плацебо)?

Характеристика исследований
По состоянию на Август 2015 года, мы выявили 23 рандомизированных клинических испытания (РКИ - тип научного эксперимента, в котором людям случайным образом назначают одно, два или более методов лечения), в которых приняло участие 2675 детей и подростков в возрасте от 3 до 17 лет. В этих исследованиях сравнивали амфетамины с плацебо. Были исследованы три разных типа амфетаминов: дексамфетамин (dexamphetamine), лисдексамфетамин (lisdexamphetamine) и смесь солей амфетамина. Длительность включенных исследований варьировала от 14 до 365 дней. РКИ были проведены в США и Европе.

Основные результаты
Мы обнаружили, что амфетамины были эффективны в улучшении основных симптомов СДВГ в краткосрочной перспективе, но при этом прием амфетаминов также был связан с высоким риском побочных эффектов, таких как проблемы со сном, снижение аппетита и боли в желудке. Мы не нашли доказательств что один вид амфетаминов был лучше другого, а также не нашли разницы между амфетаминами с пролонгированным действием и теми, которые имеют короткий период действия.

Качество доказательств

Качество включенных исследований было от низкого до очень низкого из-за проблем с их дизайном и серьезными различиями между исследованиями. Необходимо проведение продолжительных, хорошо продуманных и четко документированных РКИ, чтобы мы могли лучше понимать долгосрочные эффекты (позитивные и негативные) применения амфетаминов.

Заметки по переводу

Перевод: Мындря Сергей. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

淺顯易懂的口語結論

安非他命治療兒童及青少年注意力不足過動症

背景
注意力不足過動症(ADHD)是常見影響兒童與青少年的問題。ADHD的特徵是不專注(容易分心,無法專注在一項工作),易衝動(煩躁不安,經常動來動去),和過動(不耐煩,不思而行)。常見的ADHD治療之一為安非他命,是一種興奮型藥物。他們被認為能減輕ADHD症狀嚴重度。

回顧問題

相較於不使用藥物或安慰劑治療,使用安非他命治療是否有利被診斷為ADHD之兒童與青少年(小於18歲)減輕ADHD核心症狀?

研究特徵
在2015年8月,我們找出23個隨機對照試驗(RCTs:一種隨機分派受試者接受任一或多種治療的科學試驗),包含2675位從3歲至17歲的兒童與青少年。這些研究將安非他命與安慰劑相比較。我們調查了3種安非他命:dexamphetamine, lisdexamphetamine和mixed amphetamine salts。研究期間涵蓋14天至365天。這些隨機對照試驗是在美國和歐洲執行。主要結果我們發現安非他命短期對於減輕ADHD核心症狀有效,但有相當高風險造成不良作用,如睡眠問題、食慾下降和胃痛。我們並無找到證據支持任一安非他命衍生物較優,且長效或短效安非他命劑型並無差異。

證據品質

納入的研究證據品質為低至非常低,因為研究設計和各研究彼此差異甚大。仍需要設計完善和紀錄清楚且長時間的隨機對照試驗,以助於我們更了解安非他命著長期正面與負面效果。

譯註

翻譯者:周孜容
服務單位:臺大醫院實習醫師
職稱:臺北醫學大學醫學系七年級

審稿者:江吉文
服務單位:衛生福利部屏東醫院 藥劑科
職稱:藥師

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Résumé simplifié

Les amphétamines pour le traitement du trouble déficitaire de l'attention avec hyperactivité chez les enfants et les adolescents

Contexte
Le trouble déficitaire de l'attention avec hyperactivité (TDAH) est un problème courant qui affecte les enfants et les adolescents. Le TDAH se caractérise par une inattention (le fait d'être facilement distrait ou incapable de se concentrer sur une tâche), une impulsivité (la personne bouge constamment), et une hyperactivité (la personne est impatiente et agit sans réfléchir). L'un des traitements les plus courants pour la prise en charge du TDAH correspond aux amphétamines, qui sont une classe de médicaments stimulants. Ils sont supposés réduire la gravité des symptômes associés au TDAH.

Question de la revue

Est-ce que les enfants et les adolescents âgés de moins de 18 ans et présentant un diagnostic de TDAH peuvent tirer profit d'un traitement à base d'amphétamines ayant pour objectif de réduire les principaux symptômes du TDAH par rapport à d'autres enfants et adolescents qui ne reçoivent pas de médicament ou un médicament factice (placebo) ?

Caractéristiques de l'étude
En août 2015, nous avons identifié 23 essais contrôlés randomisés (ECR : un type d'expérience scientifique dans lequel les patients sont assignés de manière aléatoire à un des deux (ou plus) traitements), qui incluaient 2675 enfants et adolescents âgés de 3 à 17 ans. Ces études comparaient des amphétamines à un placebo. Trois types différents d'amphétamines ont été étudiés : la dexamphétamine, la lisdexamphétamine et des sels mixtes d'amphétamine. La durée des études incluses variait de 14 à 365 jours. Les ECR ont été réalisés aux États-Unis et en Europe.

Résultats principaux
Nous avons constaté que les amphétamines étaient efficaces pour améliorer les principaux symptômes du TDAH au court terme, mais qu'elles étaient également associées à un risque plus élevé d'événements indésirables tels que des troubles du sommeil, une diminution de l'appétit et des douleurs à l'estomac. Nous n'avons trouvé aucune preuve indiquant qu'un type d'amphétamines était plus efficace qu'un autre et nous n'avons pas trouvé de différences entre les amphétamines qui agissent sur une plus longue durée par rapport à celles ayant un effet plus court.

Qualité des preuves

La qualité des études incluses était faible à très faible en raison de problèmes dans leur conception et des différences considérables entre les études. Des ECR bien conçus et clairement rapportés, réalisés sur de plus longues durées sont nécessaires, de sorte que nous puissions mieux comprendre les effets au long terme (tant positifs et négatifs) des amphétamines.

Notes de traduction

Traduction réalisée par Martin Vuillème et révisée par Cochrane France

Streszczenie prostym językiem

Związki na bazie amfetaminy w zespole nadpobudliwości psychoruchowej z deficytem uwagi u dzieci i młodzieży

Wprowadzenie
Zespół nadpobudliwości psychoruchowej z deficytem uwagi (ADHD) jest powszechnym problem wśród dzieci i młodzieży. ADHD charakteryzuje się brakiem uwagi (łatwość do rozpraszania się, niemożność skupienia uwagi na jednym zadaniu), impulsywnością (nerwowość; bycie w ciągłym ruchu) i nadpobudliwością (niecierpliwość; działanie bez wcześniejszego myślenia). Jednym z najczęstszych schematów leczniczych służących do kontrolowania ADHD jest terapia lekami opartymi na bazie amfetaminy, które są klasyfikowane jako leki pobudzające. Uważa się, że pomagają one zredukować nasilenie objawów związanych z ADHD.

Pytanie badawcze

Czy dzieci i młodzieży (w wieku poniżej 18 lat) z ADHD odnoszą korzyści z leczenia związkami amfetaminy, służącymi do zmniejszenia objawów ADHD, w porównaniu z innymi dziećmi i młodzieżą, którzy nie otrzymują leków lub otrzymują leczenie pozorowane (placebo)?

Charakterystyka badań
Do sierpnia 2015 roku zidentyfikowaliśmy 23 randomizowane badania z grupą kontrolną (RCTs, to rodzaj eksperymentu naukowego, w którym osoby są losowo przydzielane do jednej z dwóch lub więcej interwencji), które obejmowały 2675 dzieci i młodzieży w wieku od 3 do 17 lat. W badaniach tych porównywano związki na bazie amfetaminy z placebo. Analizowane były trzy różne rodzaje związków na bazie amfetaminy: dekstroamfetamina, lisdeksamfetamina i mieszane sole amfetaminy. Czas trwania włączonych badań wahał się od 14 do 365 dni. Analizowane RCTs przeprowadzono w Stanach Zjednoczonych i Europie.

Główne wyniki
Odnaleźliśmy dane wskazujące, że związki amfetaminy były skuteczne w zakresie poprawy głównych objawów ADHD w krótkiej obserwacji, ale jednocześnie wiązały się z większym ryzykiem działań niepożądanych, takich jak: zaburzenia snu, zmniejszenie apetytu i ból brzucha. Nie znaleźliśmy żadnych danych naukowych wskazujących, że jeden rodzaj pochodnej amfetaminy był lepszy od innego, ponadto nie znaleźliśmy różnicy pomiędzy związkami amfetaminy, które działają w dłuższym okresie czasu w porównaniu z tymi działającymi krócej.

Jakość danych naukowych

Jakość włączonych badań wahała się od niskiej do bardzo niskiej ze względu na niedociągnięcia w metodologii i znaczne różnice pomiędzy badaniami. Potrzebne są dobrze zaprojektowane, dłużej trwające i jasno raportowane badania RCTs, byśmy mogli lepiej rozumieć skutki (zarówno pozytywne, jak i negatywne) działania związków na bazie amfetaminy w dłuższej perspektywie czasu.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Zając Redakcja: Magdalena Koperny, Małgorzata Kołcz

Resumen en términos sencillos

Anfetaminas para el trastorno de déficit de atención e hiperactividad en niños y adolescentes

Antecedentes
El trastorno de déficit de atención e hiperactividad (TDAH) es un problema frecuente que afecta a niños y adolescentes. El TDAH se caracteriza por desatención (se distrae fácilmente, incapaz de centrarse en una tarea), impulsividad (intranquilidad; movimientos constantes) e hiperactividad (impaciente; actúa sin pensar). Uno de los tratamientos más frecuentes para tratar el TDAH es la clase de fármacos anfetaminas, que son una clase de fármacos estimulantes. Se piensa que reducen la gravedad de los síntomas asociados con el TDAH.

Pregunta de la revisión

¿Los niños y adolescentes (menores de 18 años de edad) diagnosticados con TDAH se benefician del tratamiento con anfetaminas para reducir los síntomas centrales del TDAH, en comparación con otros niños y adolescentes que no reciben fármacos o reciben un fármaco falso (placebo)?

Características de los estudios
Hasta agosto de 2015 se identificaron 23 ensayos controlados aleatorios (ECA: un tipo de experimento científico en el cual las personas se asignan al azar a uno de dos o más tratamientos), que incluyeron a 2675 niños y adolescentes entre tres años y 17 años de edad. Estos estudios compararon las anfetaminas con el placebo. Se investigaron tres tipos diferentes de anfetaminas: dexanfetamina, lisdexanfetamina y sales mixtas de anfetamina. La duración de los estudios incluidos varió de 14 a 365 días. Los ECA se realizaron en los Estados Unidos y Europa.

Resultados clave
Se encontró que las anfetaminas fueron eficaces para mejorar los síntomas centrales del TDAH a corto plazo, pero también se vincularon a un riesgo mayor de experimentar eventos adversos como problemas del sueño, reducción del apetito y dolor del estómago. No se encontraron pruebas de que una clase de anfetamina fuera mejor que otra y no se encontraron diferencias entre las anfetaminas que actúan durante períodos más largos versus las que actúan durante períodos más cortos.

Calidad de la evidencia

La calidad de los estudios incluidos fue baja a muy baja debido a problemas en el diseño y a diferencias grandes entre los estudios. Se necesitan ECA bien diseñados y claramente informados con una duración más prolongada, de manera que se puedan comprender mejor los efectos a largo plazo (positivos y negativos) de las anfetaminas.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. 1Downgraded one level due to the majority of studies included in this outcome having a high risk of bias.
    2 Downgraded one level due to this outcome including comparisons of different amphetamine derivatives and release formulations.
    3Downgraded one level due to presence of significant statistical heterogeneity (I² > 50%).
    4Downgraded one level due to wide 95% CI indicating that the intervention effect for this outcome is highly variable.

Amphetamines compared with placebo for attention deficit hyperactivity disorder in children and adolescents

Patient or population: children or adolescents with ADHD

Settings: Beligum, France, Germany, Hungary, Italy, Netherlands, Norway, Poland, Spain, Sweden, United Kingdom, United States

Intervention: amphetamines (i.e. dexamphetamine, lisdexamphetamine, mixed amphetamine salts)

Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
Number of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
PlaceboAmphetamine
Total ADHD symptom score - parent ratings (ADHD Rating Scale, Fourth Version; Conners' Rating Scale; Conners' Global Index; Conners' Abbreviated Symptom Questionnaire)

Follow-up: 7 to 49 days
-The mean total score in the intervention groups was 0.57 standard deviations lower (-0.86 to -0.27) SMD -0.57 (-0.86 to -0.27)1247
(7)
⊕⊝⊝⊝
Very low 1,2,3
Moderate effect**

Total ADHD symptom score - teacher ratings (ADHD Rating Scale, Fourth Version; Conners' Rating Scale; Conners' Global Index; Conners' Abbreviated Symptom Questionnaire)

Follow-up: 7 to 35 days

-The mean total score in the intervention groups was 0.55 standard deviations lower (-0.83 to -0.27) SMD -0.55 (-0.83 to -0.27)745
(5)
⊕⊕⊝⊝
Low 1,2
Moderate effect**
Total ADHD symptom score - clinician ratings (ADHD Rating Scale, Fourth Version)

Follow-up: 7 to 28 days
-The mean total score in the intervention groups was 0.84 standard deviations lower (-1.32 to -0.36) SMD -0.84 (-1.32 to -0.36)813
(3)
⊕⊝⊝⊝
Very low 1,2,3
Large effect**
Proportion of responders (Clinical Global Impressions - Improvement (CGI-I) scale) 187 per 1000 605 per 1000

RR 3.36

(2.48 to 4.55)

2207
(9)
⊝⊝⊝⊝
Very low 1,2,3,4
-

Academic performance (Permanent Product Measure of Performance; Wechsler Intelligence Scale for Children - Revised; Barnell Lot, Ltd Math Test; Wide Range Achievement Test)

Follow-up: 7 to 21 days

-The mean score in the intervention groups was 0.51 standard deviations higher (0.31 to 0.70) SMD 0.56 (0.39 to 0.73)826
(8)
⊕⊕⊝⊝
Low 1,2
Moderate effect**
Retention: proportion of participants who completed the trial 825 per 1000 864 per 1000 RR 1.03
(0.97 to 1.10)
2381
(11)
⊕⊝⊝⊝
Very low 1,2,3
-
Proportion of participants who experienced at least 1 adverse event 366 per 1000 582 per 1000

RR 1.30

(1.18 to 1.44)

1742
(6)
⊕⊕⊝⊝
Low 1,2
-

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
**Magnitude of effect sizes have been defined according to Cohen 1988 (< 0.2 = small, 0.5 to 0.8 = moderate, > 0.8 = large)

ADHD: Attention deficit hyperactivity disorder; CI: Confidence interval; GRADE: Grades of recommendation, assessment, development and evaluation; RR: Risk ratio; SMD: Standardized mean difference

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Attention deficit hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric conditions, affecting around 5% of children worldwide (Polanczyk 2007). ADHD is characterized by three core symptoms: inattention, impulsivity and hyperactivity, which are more frequently displayed than would be typical in children of the same age (APA 2000). The core symptoms are often presented to various degrees in different children, breaking ADHD down into three subtypes: the predominantly inattentive type, the predominantly hyperactive-impulsive type, and the combined type (i.e. children displaying both inattention and hyperactivity) (APA 2000). The condition is often diagnosed at a young age, usually between the ages of three and six years (NIMH 2009). The potential for comorbidity is extremely high in this population and comorbidities are present in almost two-thirds of pediatric ADHD cases, with the most common being oppositional defiant disorder (50%), conduct disorder (35%), anxiety disorder (33%), and depression (33%) (AHRQ 1999; Mayes 2009).

The symptoms of ADHD have been shown to permeate a child's performance across multiple settings, having long-term effects on their academic performance and social development. Studies have also shown that children with ADHD are more likely to be irritable, impatient, and aggressive (NIH 2000). In addition, families who have children with ADHD often experience higher levels of parental stress and frustration, marital disruption, and social isolation (Edwards 1995). It has been estimated that 50% of childhood ADHD cases will persist into adolescence and adulthood (Biederman 1993), making it a chronic lifetime condition for many.

Description of the intervention

A wide variety of treatments have been used for the management of ADHD, including psychosocial interventions, dietary management, herbal and homeopathic remedies, and biofeedback. However, for the past few decades, the psychostimulant, methylphenidate, has been the first line of treatment (APA 2000), and has been found to be effective in 70% to 90% of school-aged children (NIH 2000; Wigal 1999). Amphetamines are the second most frequently prescribed psychostimulant for pediatric ADHD, and are becoming an increasingly popular alternative for children who fail to respond to methylphenidate (Buck 2002). There are currently three different amphetamine preparations available, including: dexamphetamine (dextroamphetamine or d-amphetamine sulfate), which comes in both short-acting and long-acting formulations; lisdexamphetamine, which is available as a long-acting formulation (Vyvanase); and mixed amphetamine salts, which also comes in both short-acting as well as long-acting preparations (Buck 2002; The Medical Letter 2007).

How the intervention might work

Although the pathophysiology of ADHD is poorly understood, evidence has suggested that ADHD may be the result of insufficient production of norepinephrine and dopamine in the prefrontal cortex (Arnsten 2006). As such, the executive functions carried out by the prefrontal cortex are impaired, resulting in forgetfulness, distractibility, impulsivity, and inappropriate social behaviours (Anderson 1999). Others believe that the limbic system plays a major role in the pathophysiology of ADHD, and it is thought that hyperactivity and impulsivity result from abnormally low tonic dopamine activity within this region of the brain (Moore 2011). In either case, as a psychostimulant, amphetamines are thought to both promote marked neurotransmitter release into the synaptic cleft as well as disrupt normal reuptake of neurotransmitters, thereby increasing levels of norepinephrine and dopamine in these regions of the brain and affecting executive functioning (Arnsten 2006; Swanson 2007). A Cochrane Review of amphetamines for ADHD in adults found they improved short-term symptom severity (Castells 2011).

Why it is important to do this review

Despite being one of the most thoroughly researched disorders in medicine, one of the major controversies regarding ADHD is the use of psychostimulants as a treatment option. While current evidence suggests that amphetamines may be beneficial for improving the core symptoms of ADHD, their effects on academic and social domains remain inconsistent and unclear (NIH 2000). Wide variations in the use and prescription of amphetamines across communities suggest that there is a lack of consensus among practitioners regarding which people with ADHD should be treated with amphetamines. Charach 2011 and Miller 1999 have conducted reviews assessing amphetamines for pediatric ADHD; however, the former focused only on long-term effectiveness of amphetamines (i.e. > 12 months), while the latter is not only out of date, but also focused solely on the dexamphetamine preparation. It is imperative for healthcare providers, parents, and those diagnosed with ADHD to be aware of the most suitable treatment options available, and how they differ in terms of their efficacy and safety profiles. Our synthesis of all available, randomized controlled trials assessing the efficacy and safety of amphetamines for pediatric ADHD will provide evidence to better inform clinical practice and further research relating to ADHD management. While assessing amphetamines against other ADHD treatments, such as methylphenidate, psychotherapy and antidepressants is important, establishing whether amphetamines are superior to placebo is a necessary first step. Thus, this review will focus only on the amphetamine versus placebo comparison.

Objectives

To assess the efficacy and safety of amphetamines for ADHD in children and adolescents.

Methods

Criteria for considering studies for this review

Types of studies

Parallel-group and cross-over randomized controlled trials (RCTs).

Types of participants

Children and adolescents under 18 years of age and diagnosed with ADHD using specified diagnostic criteria such as the Diagnostic and Statistical Manual of Mental Disorders Third Edition (DSM-III) (APA 1987), Fourth Edition (DSM-IV) (APA 2000), or equivalent (note: since the fifth edition (DSM-5) was released during the conduct of this review, studies utilizing this criteria are not included). We included trials that involved children/adolescents with some comorbid conditions (oppositional defiant disorder, conduct disorder, and anxiety). We excluded trials whose inclusion criteria included children/adolescents with psychiatric comorbidity that require highly specialized treatment programs (for example, autism, bipolar disorder, and psychosis).

Types of interventions

Intervention

Any oral form of amphetamine (i.e. amphetamine, dexamphetamine, lisdexamphetamine and mixed amphetamine salts), at any dose.

Control

Placebo.

Types of outcome measures

Primary outcomes
  1. Change in core ADHD symptoms* (inattention, hyperactivity, impulsivity), as measured by a validated scale rated by children, parents, teachers, clinicians, or investigators such as Conners’ Parent Rating Scale - Revised (CPRS-R) (Conners 1998a), Conners’ Teacher Rating Scale - Revised (CTRS-R) (Conners 1998b), or the ADHD Rating Scale, Fourth Version (ADHD-RS-IV) (DuPaul 1998).

Secondary outcomes
  1. Clinical improvement*, as measured by, for example, the Clinical Global Impression - Improvement scale (CGI-I) (Guy 1976).

  2. Clinical severity, as measured by, for example, the Clinical Global Impression - Severity scale (CGI-S) (Guy 1976).

  3. Academic performance*, as measured by any validated tool that purports to assess academic performance such as the Wechsler Intelligence Scale for Children (WISC) (Wechsler 1991).

  4. Quality of life, as measured by a validated scale such as the Pediatric Quality of Life Inventory - 32 (PedsQL-32) (Varni 1998).

  5. Retention: proportion of randomized participants who completed the trial*.

  6. Adverse events (such as nausea, insomnia/sleep problems, and decreased appetite).

    1. Proportion of adverse events.

    2. Proportion of participants who experienced at least one adverse event*, as reported in the trials.

    3. Proportion of participants who withdrew due to any adverse event.

Outcomes marked with an asterisk (*) were used to populate Summary of findings for the main comparison.

Time frames were denoted as short term (up to six months), medium term (between six and 12 months), and long term (over 12 months).

See Table 1 for further information.

Table 1. Protocol decisions not used in this review
  1. ADHD: attention deficit hyperactivity disorder.
    ADHD-RS-IV: Attention Deficit Hyperactivity Rating Scale, Fourth Version.

Types of outcome measures

Primary outcomes

Multiple perspectives (i.e. teacher, parent, clinician) are considered the gold standard when assessing the core symptoms of ADHD. As such, we will not favor one perspective over another. In the event that reports do not agree with one another, for example, teacher reports disagree with parent reports on the improvement of core symptoms, this may be quite telling about how a child’s environment impacts their ADHD given the varying demands between a school environment and home environment. This will be interpreted accordingly in the discussion.

Secondary outcomes

We will assess 'parental stress' as a secondary outcome.

Measures of treatment effect

Dichotomous outcome data

When a single study has utilized more than one measure to assess the same construct (e.g. ADHD core symptoms as assessed by teacher-rated ADHD-RS-IV and teacher ratings of the Conners’ ADHD Rating Scale), treatment effects will be averaged across outcome measures in order to arrive at a single treatment effect for use in the meta-analysis.

Continuous outcome data

For continuous outcomes, where the same rating scale has been used for all studies, we will calculate mean differences.

Unit of analysis issues

Cross-over trials

For meta-analyses that use that use a mean difference, we will compute standard deviations for the cross-over trials taking into account correlation. If correlation coefficients are not available, we will impute them from other studies or use 0.5 as a conservative estimate (Follman 1992).

For cross-over trials where carry-over is thought to be a problem, where no washout period is present, or when only data from the first period are available, we will analyze data from the first period only.

Studies with multiple time points

In studies where results are presented for several periods of follow-up, we will analyze each outcome at each point in a separate meta-analysis with other comparable studies taking measures at a similar time frame post-randomization. Time frames will reflect short-term (up to six months), medium-term (between 6 months and 12
months), and long-term (over 12 months) outcomes.

Assessment of reporting biasesFor each primary meta-analysis in which we have identified a sufficient number of studies (n ≥ 10) for inclusion, we will draw funnel plots in order to assess the possibility of publication bias.
Subgroup analysis and investigation of heterogeneity

We will conduct the following subgroup analyses.

  1. Presence of comorbidities (i.e. oppositional defiant disorder, conduct disorder, or both) versus no comorbid conditions.

  2. ADHD subtype: inattentive type versus hyperactive-impulsive type versus combined type

Sensitivity analysis

We will conduct the following sensitivity analyses.

  1. Based on the risk of bias assessment of the studies: we will restrict each outcome meta-analysis to those studies with a low risk of bias. A study is defined as having a low risk of bias if all domains of the risk of bias tool score a low risk of bias.

  2. Based on publication status: unpublished versus published studies.

  3. Missing data: we will conduct a sensitivity analysis of the imputed standard deviation versus a lower imputed standard deviation.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases in May 2013, July 2014, and again on 12 August 2015.

  1. Cochrane Central Register of Controlled Trials (CENTRAL; 2015 Issue 7; Ovid), which includes the Specialised Register of the Cochrane Developmental, Psychosocial and Learning Problems Group.

  2. Ovid MEDLINE (1948 to Week 1, August 2015).

  3. Embase (1974 to Week 1, August 2015; Ovid).

  4. PsycINFO (1806 to Week 1, August 2015; Ovid).

  5. ProQuest Dissertations and Theses (all available years).

  6. Networked Digital Library of Theses and Dissertations (ndltd.org; all available years).

  7. ClinicalTrials.gov (clinicaltrials.gov; all available years).

No language or date restrictions were applied.

Please see Appendix 1 to Appendix 7 for our search strategies.

Searching other resources

We inspected the reference lists of identified RCTs and review articles to identify additional publications.

Data collection and analysis

Selection of studies

Two review authors (SP and LS) independently screened all titles and abstracts retrieved from the search to identify those that appeared to meet the inclusion criteria. The same authors then obtained the full-text articles of those studies and assessed their eligibility. Disagreements were resolved by SV.

Data extraction and management

Two review authors (SP and LS) independently extracted data related to study methods, participant characteristics, and outcomes by using a pre-designed data collection form. Disagreements were resolved through discussion. SP entered all relevant data into Review Manager (RevMan 2014).

We emailed study authors up to three times (minimum one month wait between contact) to obtain missing or unclear data.

Assessment of risk of bias in included studies

Using the Cochrane 'Risk of bias' tool (Higgins 2011a), two review authors (SP and LS) independently assessed each included study as being at low risk, high risk, or unclear (uncertain) risk of bias for each of the seven domains explained in Appendix 8. Disagreements were resolved through discussion.

Measures of treatment effect

Dichotomous outcome data

We calculated the risk ratio (RR) and 95% confidence intervals (CIs) for dichotomous outcomes.

Continuous outcome data

For continuous outcomes, we used the Hedges’ method to calculate standardized mean differences (SMDs) with individual study weights calculated as the inverse of the variance, presented with 95% CIs (Hedges 1994). To ensure that all scales were pointing in the same direction, we multiplied the mean value of one set by -1 (Deeks 2011). We combined change scores and endpoint scores, however when both types of scores were available in the same study, priority was given to change scores since they adjust for any imbalances in baseline characteristics.

See Table 1 for further methods archived for future updates of this review.

Unit of analysis issues

Cross-over trials

Since we calculated SMDs for all our continuous outcomes, we treated cross-over studies as if they were parallel and computed a pooled standard deviation. Although this method does not account for the correlation in cross-over studies, it prevented any overestimation of effect sizes, which is desirable when computing SMDs. Carry-over was not reported in any of the cross-over studies.

See Table 1 for further methods archived for future updates of this review.

Studies with multiple comparisons

For studies with more than two independent comparisons, such as amphetamine versus placebo versus psychotherapy, we excluded the psychotherapy arm. We handled studies with multiple and correlated interventions, for example, lisdexamphetamine versus mixed amphetamine salts versus placebo, or 10 mg dexamphetamine versus 20 mg of dexamphetamine versus placebo in the following way. For continuous outcomes of parallel-group studies, we calculated means using the formulae described in Table 7.7.a of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). For dichotomous outcomes of parallel-group studies, we summed the number of events across intervention arms. For continuous outcomes of cross-over studies, we averaged both the means and the standard deviations of the relevant intervention arms across the groups. For dichotomous outcomes of cross-over studies, we randomly dropped one arm and used the other in the meta-analysis.

Studies with multiple time points

We analysed studies separately according to their time frame. Time frames were denoted as short term (up to six months), medium term (between six and 12 months), and long term (over 12 months). All but one study (Gillberg 1997) were considered short term. Since Gillberg 1997 was the only medium-term study, it was excluded from the meta-analysis.

See Table 1 for further analyses archived for future updates of this review.

Dealing with missing data

We emailed study authors up to three times (with at least one month between contacts) to obtain missing data. For those studies that did not report outcomes using intention-to-treat analysis and for which missing data were unobtainable, we used the number of randomized participants as the denominator for dichotomous variables. For continuous outcomes, we used the sample size to calculate the mean and standard deviations in the study. For studies that did not report standard deviations, we calculated it from P values, CIs, or standard errors (as described in section 7.7.3.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b)). We did not use any imputations to deal with missing data.

Assessment of heterogeneity

We assessed statistical heterogeneity by examining the I² statistic (Higgins 2003), which quantifies the degree of heterogeneity in a meta-analysis, and Chi² statistic (P value less than 0.10 as evidence of heterogeneity). We also reported Tau² estimates for each random-effects meta-analysis (Deeks 2011).

We explored heterogeneity by conducting a series of subgroup analyses (Subgroup analysis and investigation of heterogeneity), which were selected a priori and based on preliminary evidence from other studies (Castells 2011; Lundh 2012).

Assessment of reporting biases

See Table 1 for methods archived for future updates of this review.

Data synthesis

We synthesized the results in a meta-analysis using the random-effects model since studies were fairly heterogeneous in terms of their study design (inclusion of parallel-group and cross-over trials), intervention protocols, and study duration. We used the inverse variance method for continuous outcomes, and the Mantel-Haenszel method for dichotomous outcomes.

Summary of findings

In Summary of findings for the main comparison, we present data on the following outcomes: total ADHD symptom score - parent ratings, total ADHD symptom score - teacher ratings, total ADHD symptom score - clinician ratings, proportion of responders, academic performance, proportion of participants who completed the trial, and proportion of participants who experienced at least one adverse event. We presented continuous outcomes as SMDs and 95% CIs, and dichotomous outcomes as RRs and 95% CIs. Data regarding number of participants and studies were presented for each outcome. We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE Working Group 2004) to determine the quality of the evidence, where evidence was downgraded if (1) the majority (> 50%) of included studies had a high risk of bias; (2) the outcome included comparisons of different amphetamine derivatives and release formulations; (3) the outcome had significant statistical heterogeneity (I² > 50%); and (4) the outcome had wide 95% CIs indicating that the intervention effect was highly variable.

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analyses.

  1. Type of amphetamine: dextroamphetamine, lisdexamphetamine, or mixed amphetamine salts.

  2. Type of amphetamine release formulation: long acting (extended release) or short acting (immediate release).

  3. Funding source: with or without pharmaceutical industry funding. Since some studies failed to report their funding source, we grouped studies as 'industry funded', 'publicly funded', or 'not reported'.

We conducted subgroup analyses on the following outcomes, which had a sufficient number of studies (more than five), regardless of the degree of statistical heterogeneity present in the main analysis:

  1. total score on core symptom ADHD scale - parent ratings;

  2. proportion of responders according to CGI-I (Guy 1976);

  3. academic performance;

  4. retention: proportion of participants who completed the trial;

  5. proportion of participants who dropped out/withdrew due to an adverse event;

    1. proportion of participants experiencing decreased appetite;

    2. proportion of participants experiencing insomnia;

    3. proportion of participants experiencing abdominal pain; and

    4. proportion of participants experiencing headaches.

We calculated a pooled effect size for each subgroup.

We were unable to conduct a subgroup analysis when all of the studies in a particular meta-analysis belonged to only one strata of any subgroup.

See Table 1 for further analyses archived for future updates of this review.

Sensitivity analysis

We repeated our meta-analyses using a fixed-effect model.

See Table 1 for further analyses archived for future updates of this review.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.

Results of the search

Figure 1 summarizes the flow of studies through the screening process. The electronic databases retrieved 7011 records while other sources yielded 198 records. After removing duplicates, we identified 5210 records for further consideration. After screening titles and available abstracts, we examined the full texts of 324 records, 34 met our inclusion criteria. From these, we identified 23 studies, four of which had multiple reports. These were: Borcherding 1990 (four reports), Coghill 2013 (three reports), Donnelly 1989 (two reports; one of which was the pilot, and the other was the full study), and Ramtvedt 2013 (two reports). In addition, we identified two ongoing clinical trials (Fanton 2009; NCT01711021); although recruitment has ended for both of these trials, none of the results have been published. We contacted the authors of both studies three times yielding no response. One non-English language study is awaiting classification until we can ascertain if it was randomized and whether participants had a formal diagnosis of ADHD (Glos 1973). This information is unobtainable given our inability to contact the author. Another study also awaits classification as only the abstract has been published (Itil 1974). Information on whether treatments were randomized and whether participants had a formal diagnosis is needed. We contacted the authors three times yielding no response.

Figure 1.

Study flow diagram

Included studies

Twenty-three studies met the inclusion criteria: 15 studies were cross-over trials (Barkley 2000; Biederman 2007a; Borcherding 1990; Childress 2015; Donnelly 1989; James 2001; Manos 1999; McCracken 2003; Nemzer 1986; Ramtvedt 2013; Sharp 1999; Shekim 1986; Short 2004; Swanson 1998a; Wigal 2009a), while eight studies were parallel-group trials (Biederman 2002; Biederman 2007b; Coghill 2013; Findling 2011; Giblin 2011; Gillberg 1997; Pliszka 2000; Spencer 2006a).

Ten studies included a single comparison of an amphetamine derivative versus placebo (Borcherding 1990; Childress 2015; Coghill 2013; Donnelly 1989; Gillberg 1997; Nemzer 1986; Pliszka 2000; Ramtvedt 2013; Sharp 1999; Shekim 1986), and 11 studies compared more than one dose of an amphetamine derivative with placebo (Barkley 2000; Biederman 2002; Biederman 2007b; Findling 2011; Giblin 2011; Manos 1999; McCracken 2003; Short 2004; Spencer 2006a; Swanson 1998a; Wigal 2009a); two studies compared more than one amphetamine derivative, each at various doses, versus placebo (Biederman 2007a; James 2001).

Participants

In total, the 23 included studies recruited 2675 children and adolescents aged between three years and 17 years, 72% (n = 1925) of whom were boys; one study did not report the number of included boys and girls (Pliszka 2000).

Twenty-two studies used various versions of the DSM criteria to confirm ADHD diagnosis in their participants, including criteria from the Third Edition (DSM-III; four trials; n = 102; Borcherding 1990; Donnelly 1989; Nemzer 1986; Shekim 1986); Third Edition Revised (DSM-III-R; one trial; n = 62; Gillberg 1997); Fourth Edition (DSM-IV; eight trials; n = 899; Barkley 2000; Biederman 2002; James 2001; Manos 1999; McCracken 2003; Sharp 1999; Short 2004; Swanson 1998a), and Fourth Edition, Text Revision (DSM-IV-TR; nine trials; n = 1553; Biederman 2007a; Biederman 2007b; Childress 2015; Coghill 2013; Findling 2011; Giblin 2011; Ramtvedt 2013; Spencer 2006a; Wigal 2009a). Pliszka 2000 (n = 59) diagnosed ADHD using the Diagnostic Interview Schedule for Children (Costello 1985).

Interventions

Twelve studies assessed mixed amphetamine salts (Barkley 2000; Biederman 2002; Biederman 2007a; Childress 2015; Gillberg 1997; James 2001; Manos 1999; McCracken 2003; Pliszka 2000; Short 2004; Spencer 2006a; Swanson 1998a); seven studies used dextroamphetamine (Borcherding 1990; Donnelly 1989; James 2001; Nemzer 1986; Ramtvedt 2013; Sharp 1999; Shekim 1986); and six studies looked at lisdexamphetamine (Biederman 2007a; Biederman 2007b; Coghill 2013; Findling 2011; Giblin 2011; Wigal 2009a). Two studies assessed two amphetamine derivatives (Biederman 2007a; James 2001).

Twelve studies randomized children and adolescents to set doses or dosing schedules (Barkley 2000; Biederman 2002; Biederman 2007b; Coghill 2013; Findling 2011; Giblin 2011; Manos 1999; McCracken 2003; Ramtvedt 2013; Short 2004; Spencer 2006a; Swanson 1998a). Seven studies used weight-based dosing (Borcherding 1990; Donnelly 1989; James 2001; Nemzer 1986; Pliszka 2000; Sharp 1999; Shekim 1986), while six studies titrated children and adolescents to their optimal dose (Biederman 2007a; Childress 2015; Gillberg 1997; Pliszka 2000; Shekim 1986; Wigal 2009a). Two studies used both weight-based dosing and titration (Pliszka 2000; Shekim 1986). The mean (range) doses investigated in the included studies were 34.22 mg/day (7.8 mg/day to 90 mg/day) for dextroamphetamine, 50.24 mg/day (30 mg/day to 70 mg/day) for lisdexamphetamine, and 19.86 mg/day (5 mg/day to 120 mg/day) for mixed amphetamine salts.

Duration

Study intervention length ranged from 14 days to 365 days, with a median of 28 days. Only one study was longer than 63 days (Gillberg 1997).

Location

Twenty studies were conducted in the United States (Barkley 2000; Biederman 2002; Biederman 2007a; Biederman 2007b; Borcherding 1990; Childress 2015; Donnelly 1989; Findling 2011; Giblin 2011; James 2001; Manos 1999; McCracken 2003; Nemzer 1986; Pliszka 2000; Sharp 1999; Shekim 1986; Short 2004; Spencer 2006a; Swanson 1998a; Wigal 2009a). One multicenter trial was conducted in 48 centers across 10 countries: Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, and the United Kingdom (Coghill 2013). The two remaining studies were conducted in Sweden (Gillberg 1997) and Norway (Ramtvedt 2013).

Outcomes

Details of all ADHD core symptom outcome measures used by study can be found in the Characteristics of included studies and Table 2. The most commonly used outcome tool for the primary outcome included the Conners' Rating Scales (Conners 1998a; Conners 1998b) and the ADHD-RS-IV (DuPaul 1998).

For secondary outcomes, the most commonly utilized outcome tool for academic performance was the Permanent Product Measure of Performance (PERMP; Swanson 1998b). Only one study assessed quality of life (Findling 2011), and used the Youth Quality of Life - Research Version questionnaire (YQOL-R; Salum 2012)

Table 2. ADHD core symptom outcome measures by study
  1. ADHD: attention deficit hyperactivity disorder.
    IOWA: inattention/overactivity with aggression.
    SKAMP: Swanson, Kotkin, Agler, M-Flynn and Pelham scale.

Outcome Outcome measure (respondent) Studies Measure used in meta-analysis
InattentionADHD Rating Scale, Fourth Version (parent ratings) Biederman 2007bNo (data presented in an unusable format)
ADHD Rating Scale, Fourth Version (clinician ratings) Findling 2011Yes
Spencer 2006aYes
Wigal 2009aYes
ADHD Rating Scale, Fourth Version (investigator/research personnel ratings) Coghill 2013Yes
Conners’ Rating Scale (parent ratings) Borcherding 1990Yes
Gillberg 1997No (only study that included long-term data)
Conners’ Rating Scale (teacher ratings) Gillberg 1997No (only study that included long-term data)
IOWA Conners’ Rating Scale Pliszka 2000Yes
SKAMP scale (teacher ratings) Swanson 1998aNo (data not available)
SKAMP scale (investigator/research personnel ratings) Biederman 2007aYes
McCracken 2003Yes
Hyperactivity/impulsivityADHD Rating Scale, Fourth Version (parent ratings) Biederman 2007bNo (data presented in an unusable format)
ADHD Rating Scale, Fourth Version (clinician ratings) Findling 2011Yes
Spencer 2006aYes
Wigal 2009aYes
ADHD Rating Scale, Fourth Version (investigator/research personnel ratings) Coghill 2013Yes
Conners’ Rating Scale (parent ratings) Gillberg 1997No (only study that included long-term data)
James 2001Yes
Conners’ Rating Scale (teacher ratings) Gillberg 1997No (only study that included long-term data)
James 2001Yes
Total core symptom scoreADHD Rating Scale, Fourth Version (parent ratings) Barkley 2000Yes
Biederman 2007bYes
ADHD Rating Scale, Fourth Version (teacher ratings) Barkley 2000Yes
ADHD Rating Scale, Fourth Version (clinician ratings) Findling 2011Yes
Spencer 2006aYes
Wigal 2009aYes
ADHD Rating Scale, Fourth Version (investigator/research personnel ratings) Coghill 2013Yes
Giblin 2011No (no data available)
Conners’ Rating Scale (parent ratings) Biederman 2007bNo (data presented in an unusable format)
Coghill 2013Yes
Giblin 2011No (data not available)
Gillberg 1997No (only study that included long-term data)
Nemzer 1986Yes
Sharp 1999No (data not available)
Short 2004No (data presented in an unusable format)
Conners’ Rating Scale (teacher ratings) Borcherding 1990No (no data available)
Donnelly 1989Yes
Gillberg 1997No (only study that included long-term data)
Nemzer 1986Yes
Sharp 1999No (data not available)
Short 2004No (data presented in an unusable format)
Conners’ Global Index (parent ratings) Biederman 2002Yes
Pliszka 2000Yes
Conners’ Global Index (teacher ratings) Biederman 2002Yes
Conners’ Abbreviated Symptom Questionnaire (parent ratings) Manos 1999Yes
Conners’ Abbreviated Symptom Questionnaire (teacher ratings) Manos 1999Yes
ADHD Questionnaire (developed within study) (parent ratings) Ramtvedt 2013No (data presented in an unusable format)
ADHD Questionnaire (developed within study) (teacher ratings) Ramtvedt 2013No (data presented in an unusable format)
SKAMP scale (investigator/research personnel ratings) Childress 2015Yes

Excluded studies

We excluded a total of 290 studies. We excluded 264 clearly irrelevant reports and formally excluded 26 studies for the following reasons: 17 studies because they were not RCTs or used multiple cross-over designs (this review only included single cross-over RCTs); three studies because there was no placebo comparison, three studies because they did not use formal ADHD diagnostic criteria; one study because it had no direct amphetamine - placebo comparison; one study because participants had ineligible comorbid conditions; and one study because it included adults.

See also Characteristics of excluded studies tables.

Risk of bias in included studies

A more in depth risk of bias assessment for each study can be found in Characteristics of included studies. In addition, Figure 2 provides a summary of this assessment.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Only three studies reported on how the random sequence was generated and were assessed as being at 'low' risk of bias on this domain (Biederman 2007b; Childress 2015; Findling 2011). We rated the other 20 studies as 'unclear' risk of bias as they did not adequately describe their methods of randomization.

Allocation concealment

Four studies described the methods used to conceal the allocation sequence and were rated as being at 'low' risk of bias on this domain (Biederman 2007a; Coghill 2013; Findling 2011; Manos 1999). The rest of the studies we assessed as 'unclear' risk of bias, as they did not sufficiently describe their methods of allocation concealment.

Blinding

Performance bias

Although blinding was intended in all of the studies, we assessed risk of bias by how authors described their amphetamine and placebo capsules and rated 10 studies as being at 'low' risk of bias on this domain (Biederman 2007b; Coghill 2013; James 2001; Manos 1999; Nemzer 1986; Pliszka 2000; Sharp 1999; Short 2004; Swanson 1998a; Wigal 2009a). We rated one study as being at 'high' risk of bias on this domain since they described their intervention and placebo as not being identical (Ramtvedt 2013). The other 12 studies we marked as being at 'unclear' risk of bias since they were not explicit about the similarities between the two interventions.

Detection bias

Only two studies explicitly stated that outcome assessors were blinded to interventions and therefore we judged them to be at 'low' risk of bias (Manos 1999; Short 2004). The other 21 studies we rated as 'unclear' risk of bias since they were not explicit about which parties were blinded to the intervention assignment.

Incomplete outcome data

We rated thirteen studies that adequately addressed dropouts and used appropriate statistical methods to compensate for dropouts as having a 'low' risk of bias on this domain (Biederman 2002; Biederman 2007a; Biederman 2007b; Childress 2015; Donnelly 1989; Findling 2011; Gillberg 1997; James 2001; McCracken 2003; Pliszka 2000; Sharp 1999; Spencer 2006a; Wigal 2009a). Seven studies failed to provide reasons for dropouts and failed to address any exclusions from their analyses, and therefore we rated them as having a 'high' risk of bias (Barkley 2000; Borcherding 1990; Coghill 2013; Ramtvedt 2013; Shekim 1986; Short 2004; Swanson 1998a). The three remaining studies did not discuss dropouts in their reports and we rated them as being at 'unclear' risk of bias (Giblin 2011; Manos 1999; Nemzer 1986).

Selective reporting

We assessed 17 studies as having 'unclear' risk of bias on this domain as the study protocols for most of them were not available, so we could not assess reporting bias (Barkley 2000; Biederman 2002; Biederman 2007b; Borcherding 1990; Donnelly 1989; Giblin 2011; Gillberg 1997; James 2001; Manos 1999; McCracken 2003; Nemzer 1986; Pliszka 2000; Sharp 1999; Shekim 1986; Short 2004; Swanson 1998a; Wigal 2009a). We rated four studies as having a 'low' risk of bias, as they appropriately reported on all outcomes defined in their protocols (Biederman 2007a; Childress 2015; Findling 2011; Spencer 2006a). Two studies we assessed as having a 'high' risk of bias since they failed to report on all outcomes mentioned in their registered protocols (Coghill 2013; Ramtvedt 2013).

Other potential sources of bias

We rated three studies as being at 'unclear' risk of bias on this domain since the validity of their primary outcome tools were not described (Borcherding 1990; Donnelly 1989; Ramtvedt 2013). The other 20 studies appeared to be free of other potential sources of bias and therefore we rated them as being at 'low' risk of bias on this domain.

Effects of interventions

See: Summary of findings for the main comparison

We included 19 studies in meta-analyses, however, two of those studies had measured other outcomes that were relevant to this review, but were not reported in their results (Borcherding 1990; Swanson 1998a). Biederman 2007b had reported some of their results as bar graphs, which, when extracted using graphic digitizer software, gave implausible results and therefore was excluded from the meta-analysis on those outcomes. Four studies were excluded from all meta-analyses: Giblin 2011 had not reported data on any of the relevant outcomes in this review; Gillberg 1997 was the only medium-term study and therefore could not be combined with the other short-term studies; Ramtvedt 2013 had aggregated their parent- and teacher-rated ADHD scores; and Short 2004 assessed amphetamines versus methylphenidate versus placebo and pooled the amphetamine and methylphenidate data in their results; we were unable to isolate the amphetamine versus placebo comparison.

Primary outcome

Change in core ADHD symptoms

We conducted a series of meta-analyses for the primary outcome, change in core ADHD symptoms (inattention, hyperactivity, impulsivity), as measured by a validated scale rated by children, parents, teachers, clinicians, or investigators (Analysis 1.1 to Analysis 1.11).

For all 11 outcomes, amphetamines were superior to placebo for reducing the core symptoms of ADHD.

  1. Total ADHD symptom score - parent ratings (SMD -0.57; 95% CI -0.86 to -0.27; Tau² = 0.10; I² = 77%; 7 studies; 1247 children/adolescents; Analysis 1.1).

  2. Hyperactivity/impulsivity - parent ratings (SMD -0.54; 95% CI -0.89 to -0.19; Tau² = 0.00; I² = 0%; 2 studies; 132 children/adolescents; Analysis 1.2).

  3. Total ADHD symptom score - teacher ratings (SMD -0.55; 95% CI -0.83 to -0.27; Tau² = 0.04; I² = 41%; 5 studies; 745 children/adolescents; Analysis 1.3).

  4. Hyperactivity/impulsivity - teacher ratings (SMD -1.13; 95% CI -1.63 to -0.62; 1 study; 70 children/adolescents; Analysis 1.4).

  5. Inattention - teacher ratings (SMD -1.43; 95% CI -2.35 to -0.52; 1 study; 24 children/adolescents; Analysis 1.5).

  6. Total ADHD symptom score - clinician ratings (SMD -0.84; 95% CI -1.32 to -0.36; Tau² = 0.16; I² = 88%; 3 studies; 813 children/adolescents; Analysis 1.6).

  7. Hyperactivity/impulsivity - clinician ratings (SMD -0.75; 95% CI -1.28 to -0.23; Tau² = 0.20; I² = 90%; 3 studies; 813 children/adolescents; Analysis 1.7).

  8. Inattention - clinician ratings (SMD -0.78; 95% CI -1.26 to -0.30; Tau² = 0.16; I² = 88%; 3 studies; 813 children/adolescents; Analysis 1.8).

  9. Total ADHD symptom score - investigator/research personnel ratings (SMD -1.15; 95% CI -1.87 to -0.44; Tau² = 0.37; I² = 94%; 3 studies; 630 children/adolescents; Analysis 1.9).

  10. Hyperactivity/impulsivity - investigator/research personnel ratings (SMD -1.46; 95% CI - 1.83 to -1.08; Tau² = 0.03; I² = 41%; 2 studies; 280 children/adolescents; Analysis 1.10).

  11. Inattention - investigator/research personnel ratings (SMD -0.73; 95% CI -1.42 to -0.04; Tau² = 0.46; I² = 94%; 4 studies; 634 children/adolescents; Analysis 1.11).

It is important to note, however, that the majority of these meta-analyses included between one and three studies, and that Analysis 1.1, Analysis 1.6, Analysis 1.7, Analysis 1.8, Analysis 1.9, and Analysis 1.11 had considerable heterogeneity present with I² ranging from 77% to 94%. Only three outcomes included more than three studies: total ADHD symptom score - parent ratings (seven studies; Analysis 1.1; Figure 3), total ADHD symptom score - teacher ratings (five studies; Analysis 1.3; Figure 4), and total ADHD symptom score - investigator/research personnel ratings (four studies; Analysis 1.11).

Figure 3.

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.1 Total ADHD symptom score - parent ratings.

Figure 4.

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.3 Total ADHD symptom score - teacher ratings.

Secondary outcomes

We conducted meta-analyses that compared amphetamines versus placebo on five of our six secondary outcomes (see Analysis 1.12; Analysis 1.13; Analysis 1.14; Analysis 1.15; Analysis 1.16).

Clinical improvement

The proportion of responders was higher in the amphetamine group (RR 3.36; 95% CI 2.48 to 4.55; Tau² = 0.14; I² = 72%; 9 studies; 2207 children/adolescents; Analysis 1.12)

Clinical severity

We found evidence of a significant difference between the two groups on the CGI-S (Guy 1976), in favour of amphetamine (SMD -0.86; 95% CI -1.72 to -0.01; Tau² = 0.25; I² = 64%; 2 studies; 86 children/adolescents; Analysis 1.13).

Academic performance

We found evidence that amphetamines may improve academic performance as compared to placebo (SMD 0.56; 95% CI 0.39 to 0.73; Tau² = 0.02; I² = 28%; 8 studies; 826 children/adolescents; Analysis 1.14).

Quality of life

As shown in the illustrative forest plot, the one study that provided data on quality of life (Findling 2011), found no difference between the two groups (SMD -0.01; 95% CI -0.27 to 0.25; 309 children/adolescents; see Analysis 1.15).

Retention

There was no difference between those given amphetamine and those given placebo for retention (RR 1.03; 95% CI 0.97 to 1.10; Tau² = 0.01; I² = 83%; 11 studies; 2381 children/adolescents; Analysis 1.16).

Adverse events
Proportion of adverse events

We performed a series of meta-analyses of the most commonly reported adverse events. A higher proportion of children and adolescents in the amphetamine group as compared to placebo group experienced decreased appetite (RR 6.31; 95% CI 2.58 to 15.46; Tau² = 1.59; I² = 85%; 11 studies; 2467 children/adolescents; Analysis 1.17); insomnia/trouble sleeping (RR 3.80; 95% CI 2.12 to 6.83; Tau² = 0.42; I² = 59%; 10 studies; 2429 children/adolescents; Analysis 1.18); abdominal pain (RR 1.44; 95% CI 1.03 to 2.00; Tau² = 0.04; I² = 13%; 10 studies; 2155 children/adolescents; Analysis 1.19); and nausea/vomiting (RR 1.63; 95% CI 1.04 to 2.56; Tau² = 0.08; I² = 26%; 6 studies; 1579 children/adolescents; Analysis 1.20). There were no differences between the amphetamine and placebo groups in the proportion of children and adolescents who experienced headaches (RR 0.93; 95% CI 0.75 to 1.16; Tau² = 0.00; I² = 0%; 9 studies; 2091 children/adolescents; Analysis 1.21) and anxiety/nervousness (RR 1.22; 95% CI 0.78 to 1.93; Tau² = 0.09; I² = 32%; 5 studies; 1088 children/adolescents; Analysis 1.22).

Proportion of participants who experienced at least one adverse event

The proportion of children and adolescents who experienced at least one adverse event was higher in the amphetamine group as compared to the placebo group (RR 1.30; 95% CI 1.18 to 1.44; Tau² = 0.00; I² = 1%; 6 studies; 1742 children/adolescents; see Analysis 1.23; Figure 5).

Figure 5.

Forest plot of comparison: 1 Amphetamines versus placebo, outcome: 1.23 Proportion of participants who experienced at least one adverse event.

Proportion of participants who withdrew due to any adverse event

There was no difference between the amphetamine and placebo groups in the proportion of children and adolescents who withdrew due to an adverse event (RR 1.60; 95% CI 0.86 to 2.98; Tau² = 0.00; I² = 0%; 9 studies; 2160 children/adolescents; Analysis 1.24).

Subgroup analyses

Type of amphetamine

We conducted a series of subgroup analyses according to type of amphetamine (dexamphetamine, lisdexamphetamine, and mixed amphetamine salts). Mixed amphetamine salts were associated with improved parent ratings of total ADHD symptoms as compared to dexamphetamine and lisdexamphetamine, however, there appeared to be no between-group differences (Chi² = 0.55, P value = 0.76; Analysis 2.1). Only one subgroup yielded between-group differences (Chi² = 26.06, P < 0.00001; Analysis 2.6; Figure 6). There were no between-group differences for any of the other outcomes.

Figure 6.

Forest plot of comparison: 2 Subgroup analysis 1: Type of amphetamine, outcome: 2.6 Proportion of participants experiencing decreased appetite.

Type of amphetamine release formulation

We conducted a subgroup analysis to explore the influence of long-acting versus short-acting amphetamine release formulations (Analysis 3.1 to Analysis 3.6). Both rentention: proportion of participants who completed the trial (Chi² = 4.50, P value = 0.03; Analysis 3.4) and proportion of participants experiencing decreased appetite (Chi² = 6.93, P value = 0.008; Analysis 3.5) yielded between-group differences.

Funding source

We wanted to explore the influence of industry-funded versus publicly-funded sources (Analysis 4.1 to Analysis 4.3). Since five studies did not report their source of funding, we introduced another subgroup, 'not reported'. No between-group differences were found.

Sensitivity analysis

We repeated the analyses by changing the statistical model from a random-effects model to a fixed-effect model. The results were similar (see Analysis 5.1 to Analysis 5.24).

Discussion

Summary of main results

We included 23 studies in this review, 19 of which we included in meta-analyses. Overall, this review found that amphetamines were more efficacious than placebo for reducing ADHD core symptom severity in the short-term, however, they did not influence retention in the trial and were associated with a number of adverse events. According to conventional cut-offs (Cohen 1988), the largest effect sizes observed (i.e. an SMD > 0.8) were teacher ratings of hyperactivity/impulsivity, teacher ratings of inattention, and clinician ratings of total ADHD symptoms. The meta-analyses with the most available data included parent and teacher ratings of total ADHD symptoms, both of which yielded low to moderate effect sizes.

The median study duration was only 28 days, therefore it was not possible to assess the long-term efficacy and safety of amphetamines for pediatric ADHD. This is particularly problematic in a condition such as ADHD, which may require treatment for years.

There was a lot of variation in the amphetamine derivatives and release formulations utilized in the included studies. As such, we conducted subgroup analyses to explore their differences. Minimal between-group differences were found, however, conclusions should not be drawn from these analyses as they are based on observational and not randomized comparisons. Furthermore, given that the majority of studies assessed mixed amphetamine salts and long-acting release formulations, the subgroups assessing other amphetamine derivatives (i.e. lisdexamphetamine, dexamphetamine), and short-acting release formulations, may not have been adequately powered to detect a true difference.

We performed a meta-analysis of the most commonly reported adverse events in the primary studies. These included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches and anxiety. Meta-analysis revealed that most adverse events occurred more often in the amphetamine groups than in the placebo groups.

Overall completeness and applicability of evidence

This review focused only on the amphetamine versus placebo comparison. While it is important to assess amphetamines versus other active therapies, such as other stimulants, psychotherapy or antidepressants, we believe it is important to first establish whether or not amphetamines are superior to placebo. We were unable to assess the long-term efficacy of amphetamines (i.e. beyond 12 months of use). The average duration of included studies was five weeks long, excluding one long-term study that was 12 months long (Gillberg 1997). Short-term trials are particularly problematic for chronic conditions, such as ADHD, as children will likely be on stimulant medications for much longer periods than have been studied. As mentioned earlier, adverse events occurred more frequently when children and adolescents were treated with amphetamines than when they were treated with placebo, however, it is important to point out the poor reporting around adverse events in the included studies. Some studies only reported on adverse events that were experienced by a certain percentage of children and adolescents, thereby potentially ignoring additional adverse events experienced at less than that fraction. Futhermore, many studies were unclear regarding their methods of collecting adverse events and whether they assessed the causality of these adverse events as it related to the interventions. Heterogeneity of terms used to describe adverse events was also a major hurdle when conducting this review, and limited our ability to appropriately synthesize the data. Finally, as with efficacy data, we were unable to assess the long-term safety profile of amphetamines given the lack of long-term trials.

Only one study explored the impact of amphetamines on children and adolescents' quality of life (Findling 2011). It found no effect, although this may be because the study was underpowered. This is a significant gap in the available evidence on the effects of amphetamines, and studies should include a focus on psychosocial factors such as parental stress or quality of life.

The external validity of our results was also limited by the inclusion/exclusion criteria of the included studies. Since we excluded studies that included children and adolescents with comorbidity other than conduct disorder, oppositional defiant disorder and anxiety, we cannot extrapolate the results of our review to patients with other commonly occurring comorbidity such as depression, and tic disorder.

Few trials reported on the ADHD subtype of their included children and adolescents. Therefore, we were unable to make any conclusions as regards the potential heterogeneity of effect of different formulations of amphetamines across different ADHD subtypes. Furthermore, since primary studies did not subgroup their results according to important prognostic factors, such as age and gender, we were unable to subgroup our meta-analyses, which would have been particularly relevant for clinicians.

Although our review did assess the proportion of children and adolescents who dropped out due to an adverse event and found no differences between amphetamine and placebo groups (Analysis 1.24), it is worth noting that many studies in the meta-analysis had zero events in the placebo group, resulting in potentially invalid results that overestimate variance. The high number of zero events may be attributable to a lack of power to detect these events given the much smaller sample sizes of the placebo groups (n = 900) as compared to the amphetamine groups (n = 1532).

Finally, it was difficult for us to accurately assess our results in a clinically meaningful way, since interpretation of scores is both sex- and age-dependent.

Quality of the evidence

The overall quality of the evidence ranged from low to very low as assessed by the GRADE approach, indicating that there is room for improvement amongst the current evidence about the efficacy of amphetamines in managing ADHD in children and adolescents. The studies appear to have a multitude of methodological issues making it difficult to draw strong clinical conclusions. Moreover, most studies failed to report on how the random sequence was generated (90%), how allocation was concealed (85%), the methods used to blind participants and personnel (55%), and the methods used to blind outcome assessors (90%). As such, we were unable to determine whether it was a reporting problem or a methodological problem.

Potential biases in the review process

Limitations of our review include not being able to account for correlation in cross-over studies given the formula for calculating SMDs, thereby yielding less precise effect sizes, which may result in overlooking any potential statistical heterogeneity between the studies. Furthermore, caution is warranted in the interpretation of our meta-analyses of adverse events that contain rare events. Most methods of meta-analysis, including the chosen Mantel-Haenszel approach, perform poorly with rare events; they can yield misleading results, have very wide CIs or the statistical power can be too low to detect a difference.

Given the small number of studies included in the primary meta-analyses (maximum of seven studies), we felt that a funnel plot would not provide meaningful information about potential publication bias, which may have led to an overestimation of treatment effects. Furthermore, the exclusion of one potentially eligible non-English study may have also biased our findings. Egger 1997 found that non-English studies tend to be negative, and so excluding them may have yielded an overestimation of treatment effects. On the other hand, other researchers have found that excluding trials reported in languages other than English do not significantly affect the results of a meta-analysis (Moher 2003).

Another limitation arises from the subgroup comparisons. It must be noted that these analyses are based on observational and not randomized comparisons, and therefore should not be interpreted as conclusive evidence.

Another potential bias of our review is that one of the authors, Dr. Catherine J Nikles, has published a study on amphetamines for ADHD; however, two independent authors assessed the eligibility of this study, which was subsequently excluded due to the nature of the design (Nikles 2006).

Agreements and disagreements with other studies or reviews

We identified two previously conducted systematic reviews prior to conducting ours (Charach 2011; Miller 1999). Charach 2011 only assessed the long-term (i.e. more than 12 months) efficacy and safety of amphetamines for pediatric ADHD, and included only one RCT that assessed amphetamines versus placebo, which was also included in our systematic review (Gillberg 1997). Miller 1999 also systematically assessed amphetamines for pediatric ADHD, however, reviewers only included studies that assessed the dexamphetamine derivative of amphetamines. Furthermore, this review was published in 1999, making it over 14 years old. As such, Miller 1999 included only three relevant RCTs in their review, which were also included in this review (Borcherding 1990; Donnelly 1989; Gillberg 1997). The majority of meta-analyses conducted in the Miller 1999 review included RCTs that assessed any stimulant medication (methylphenidate or amphetamine) versus placebo. The one meta-analysis that was restricted to the amphetamine versus placebo comparison showed that amphetamines improve total ADHD symptoms as rated by the Abbreviated Conners Teacher Rating Scale (ATRS; Conners 1990): MD -4.77; 95% CI -6.43 to -2.99. This is consistent with the results of our review for this outcome, which also showed improvement in this outcome in favour of amphetamine (SMD -0.55; 95% CI -0.83 to -0.27).

Authors' conclusions

Implications for practice

Although the results of this review demonstrate that amphetamines improve the core symptoms of ADHD in children and adolescents in the short term, they are also associated with higher risk of experiencing adverse events. Given the lack of available evidence as regards the effects of amphetamines on ADHD-subtypes, long-term effectiveness and safety data, and the effects of amphetamines on psychosocial outcomes, it is difficult to extrapolate the results from this research to the clinical population. As such, when making treatment decisions, clinicians must use their own judgement in weighing the benefits with the safety profile of the intervention, accounting for the patient’s responsiveness to other stimulant medications (for example, methylphenidate), and integrating patient/family preferences and values when making treatment decisions.

This review does not provide evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting formulations.

Implications for research

Future RCTs should be longer in duration in order to explore the long-term safety and efficacy of amphetamines. It would also be beneficial for future studies to subgroup their results based on important prognostic factors, such as age and gender, in order to yield more clinically relevant results. Furthermore, while it has been traditionally assumed that improvements in core ADHD symptoms result in improved overall functioning, including academic performance, peer relations and family functioning, there is a lack of data that supports these correlations. Initiatives such as COMET (Core Outcome Measures in Effectiveness Trials), which aims to develop standardized sets of research outcomes for various health conditions, will be pivotal to areas like ADHD in ensuring that future studies not only focus on symptom management as an outcome, but also on more global outcomes that focus on a child's overall functioning (Williamson 2012).

While there is evidence that shows industry funding has been associated with exaggerated treatment effects (Lundh 2012), the debate remains unresolved (Bero 2013; Sterne 2013). Future research should assess to what extent funding source, and author affiliation with the funding source, impact treatment effects, and recommendations on whether these factors should be included in the risk of bias assessment may be helpful.

Researchers should consult the Consolidated Standards of Reporting Trials (CONSORT) statement when designing their study and reporting their methods and results so that an appropriate risk of bias assessment can be made allowing for a more robust interpretation (Schulz 2010).

Acknowledgements

The authors wish to thank Soleil Surrette for her assistance in developing and reviewing the search strategy. We also want to thank Dr. Marek Varga for his help with translation.

We also wish to thank Geraldine McDonald (Co-ordinating Editor), Joanne Wilson (Managing Editor), and Margaret Anderson (Trials Search Co-ordinator) of the Cochrane Developmental, Psychosocial and Learning Problems Group for providing help and support.

We wish to thank those who peer reviewed this manuscript and providing their thoughtful feedback.

Data and analyses

Download statistical data

Comparison 1. Amphetamines versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total ADHD symptom score - parent ratings71247Std. Mean Difference (IV, Random, 95% CI)-0.57 [-0.86, -0.27]
2 Hyperactivity/impulsivity - parent ratings2132Std. Mean Difference (IV, Random, 95% CI)-0.54 [-0.89, -0.19]
3 Total ADHD symptom score - teacher ratings5745Std. Mean Difference (IV, Random, 95% CI)-0.55 [-0.83, -0.27]
4 Hyperactivity/impulsivity - teacher ratings1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
5 Inattention - teacher ratings1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
6 Total ADHD symptom score - clinician ratings3813Std. Mean Difference (IV, Random, 95% CI)-0.84 [-1.32, -0.36]
7 Hyperactivity/impulsivity - clinician ratings3813Std. Mean Difference (IV, Random, 95% CI)-0.75 [-1.28, -0.23]
8 Inattention - clinician ratings3813Std. Mean Difference (IV, Random, 95% CI)-0.78 [-1.26, -0.30]
9 Total ADHD symptom score - investigator/research personnel ratings3630Std. Mean Difference (IV, Random, 95% CI)-1.15 [-1.87, -0.44]
10 Hyperactivity/impulsivity - investigator/research personnel ratings2280Std. Mean Difference (IV, Random, 95% CI)-1.46 [-1.83, -1.08]
11 Inattention - investigator/research personnel ratings4634Std. Mean Difference (IV, Random, 95% CI)-0.73 [-1.42, -0.04]
12 Proportion of responders (Clinical Global Impression - Improvement; CGI - I)92207Risk Ratio (M-H, Random, 95% CI)3.36 [2.48, 4.55]
13 Clinical Global Impression - Severity (CGI - S) score286Std. Mean Difference (IV, Random, 95% CI)-0.86 [-1.72, -0.01]
14 Academic performance8826Std. Mean Difference (IV, Random, 95% CI)0.56 [0.39, 0.73]
15 Quality of life1 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
16 Retention: proportion of participants who completed the trial112381Risk Ratio (M-H, Random, 95% CI)1.03 [0.97, 1.10]
17 Proportion of participants experiencing decreased appetite112467Risk Ratio (M-H, Random, 95% CI)6.31 [2.58, 15.46]
18 Proportion of participants experiencing insomnia/trouble sleeping102429Risk Ratio (M-H, Random, 95% CI)3.80 [2.12, 6.83]
19 Proportion of participants experiencing abdominal pain102155Risk Ratio (M-H, Random, 95% CI)1.44 [1.03, 2.00]
20 Proportion of participants experiencing nausea/vomiting61579Risk Ratio (M-H, Random, 95% CI)1.63 [1.04, 2.56]
21 Proportion of participants experiencing headaches92091Risk Ratio (M-H, Random, 95% CI)0.93 [0.75, 1.16]
22 Proportion of participants experiencing anxiety/nervousness51088Risk Ratio (M-H, Random, 95% CI)1.22 [0.78, 1.93]
23 Proportion of participants who experienced at least one adverse event61742Risk Ratio (M-H, Random, 95% CI)1.30 [1.18, 1.44]
24 Proportion of participants who dropped out/withdrew due to an adverse event92160Risk Ratio (M-H, Random, 95% CI)1.60 [0.86, 2.98]
Analysis 1.1.

Comparison 1 Amphetamines versus placebo, Outcome 1 Total ADHD symptom score - parent ratings.

Analysis 1.2.

Comparison 1 Amphetamines versus placebo, Outcome 2 Hyperactivity/impulsivity - parent ratings.

Analysis 1.3.

Comparison 1 Amphetamines versus placebo, Outcome 3 Total ADHD symptom score - teacher ratings.

Analysis 1.4.

Comparison 1 Amphetamines versus placebo, Outcome 4 Hyperactivity/impulsivity - teacher ratings.

Analysis 1.5.

Comparison 1 Amphetamines versus placebo, Outcome 5 Inattention - teacher ratings.

Analysis 1.6.

Comparison 1 Amphetamines versus placebo, Outcome 6 Total ADHD symptom score - clinician ratings.

Analysis 1.7.

Comparison 1 Amphetamines versus placebo, Outcome 7 Hyperactivity/impulsivity - clinician ratings.

Analysis 1.8.

Comparison 1 Amphetamines versus placebo, Outcome 8 Inattention - clinician ratings.

Analysis 1.9.

Comparison 1 Amphetamines versus placebo, Outcome 9 Total ADHD symptom score - investigator/research personnel ratings.

Analysis 1.10.

Comparison 1 Amphetamines versus placebo, Outcome 10 Hyperactivity/impulsivity - investigator/research personnel ratings.

Analysis 1.11.

Comparison 1 Amphetamines versus placebo, Outcome 11 Inattention - investigator/research personnel ratings.

Analysis 1.12.

Comparison 1 Amphetamines versus placebo, Outcome 12 Proportion of responders (Clinical Global Impression - Improvement; CGI - I).

Analysis 1.13.

Comparison 1 Amphetamines versus placebo, Outcome 13 Clinical Global Impression - Severity (CGI - S) score.

Analysis 1.14.

Comparison 1 Amphetamines versus placebo, Outcome 14 Academic performance.

Analysis 1.15.

Comparison 1 Amphetamines versus placebo, Outcome 15 Quality of life.

Analysis 1.16.

Comparison 1 Amphetamines versus placebo, Outcome 16 Retention: proportion of participants who completed the trial.

Analysis 1.17.

Comparison 1 Amphetamines versus placebo, Outcome 17 Proportion of participants experiencing decreased appetite.

Analysis 1.18.

Comparison 1 Amphetamines versus placebo, Outcome 18 Proportion of participants experiencing insomnia/trouble sleeping.

Analysis 1.19.

Comparison 1 Amphetamines versus placebo, Outcome 19 Proportion of participants experiencing abdominal pain.

Analysis 1.20.

Comparison 1 Amphetamines versus placebo, Outcome 20 Proportion of participants experiencing nausea/vomiting.

Analysis 1.21.

Comparison 1 Amphetamines versus placebo, Outcome 21 Proportion of participants experiencing headaches.

Analysis 1.22.

Comparison 1 Amphetamines versus placebo, Outcome 22 Proportion of participants experiencing anxiety/nervousness.

Analysis 1.23.

Comparison 1 Amphetamines versus placebo, Outcome 23 Proportion of participants who experienced at least one adverse event.

Analysis 1.24.

Comparison 1 Amphetamines versus placebo, Outcome 24 Proportion of participants who dropped out/withdrew due to an adverse event.

Comparison 2. Subgroup analysis 1: Type of amphetamine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total ADHD symptom score - parent ratings71247Std. Mean Difference (IV, Random, 95% CI)-0.57 [-0.86, -0.27]
1.1 Dexamphetamine128Std. Mean Difference (IV, Random, 95% CI)-0.60 [-1.36, 0.16]
1.2 Lisdexamphetamine2486Std. Mean Difference (IV, Random, 95% CI)-0.72 [-1.59, 0.14]
1.3 Mixed amphetamine salts4733Std. Mean Difference (IV, Random, 95% CI)-0.44 [-0.63, -0.24]
2 Proportion of responders (CGI - I)92205Risk Ratio (M-H, Random, 95% CI)3.38 [2.51, 4.55]
2.1 Dexamphetamine164Risk Ratio (M-H, Random, 95% CI)5.4 [2.38, 12.25]
2.2 Lisdexamphetamine41065Risk Ratio (M-H, Random, 95% CI)3.62 [2.04, 6.41]
2.3 Mixed amphetamine salts41076Risk Ratio (M-H, Random, 95% CI)2.72 [2.14, 3.45]
3 Academic performance8826Std. Mean Difference (IV, Random, 95% CI)0.56 [0.39, 0.73]
3.1 Dexamphetamine4208Std. Mean Difference (IV, Random, 95% CI)0.40 [0.12, 0.67]
3.2 Lisdexamphetamine1226Std. Mean Difference (IV, Random, 95% CI)0.78 [0.51, 1.05]
3.3 Mixed amphetamine salts3392Std. Mean Difference (IV, Random, 95% CI)0.56 [0.29, 0.84]
4 Retention: proportion of participants who completed the trial102364Risk Ratio (M-H, Random, 95% CI)1.05 [0.99, 1.12]
4.1 Dexamphetamine164Risk Ratio (M-H, Random, 95% CI)1.03 [0.95, 1.12]
4.2 Lisdexamphetamine41084Risk Ratio (M-H, Random, 95% CI)1.14 [0.92, 1.42]
4.3 Mixed amphetamine salts51216Risk Ratio (M-H, Random, 95% CI)1.03 [0.96, 1.11]
5 Proportion of participants who dropped out/withdrew due to an adverse event92161Risk Ratio (M-H, Random, 95% CI)1.61 [0.86, 2.98]
5.1 Dexamphetamine192Risk Ratio (M-H, Random, 95% CI)3.0 [0.13, 71.78]
5.2 Lisdexamphetamine41085Risk Ratio (M-H, Random, 95% CI)2.03 [0.70, 5.91]
5.3 Mixed amphetamine salts4984Risk Ratio (M-H, Random, 95% CI)1.27 [0.53, 3.06]
6 Proportion of participants experiencing decreased appetite102273Risk Ratio (M-H, Random, 95% CI)6.20 [2.44, 15.71]
6.1 Dexamphetamine168Risk Ratio (M-H, Random, 95% CI)1.41 [0.95, 2.11]
6.2 Lisdexampheatmine41081Risk Ratio (M-H, Random, 95% CI)9.83 [5.08, 19.02]
6.3 Mixed amphetamine salts51124Risk Ratio (M-H, Random, 95% CI)6.42 [1.56, 26.52]
7 Proportion of participants experiencing insomnia/trouble sleeping102429Risk Ratio (M-H, Random, 95% CI)3.80 [2.12, 6.83]
7.1 Dexamphetamine168Risk Ratio (M-H, Random, 95% CI)2.14 [1.41, 3.26]
7.2 Lisdexamphetamine41081Risk Ratio (M-H, Random, 95% CI)5.91 [2.84, 12.29]
7.3 Mixed amphetamine salts51280Risk Ratio (M-H, Random, 95% CI)3.34 [1.25, 8.96]
8 Proportion of participants experiencing abdominal pain102155Risk Ratio (M-H, Random, 95% CI)1.44 [1.03, 2.00]
8.1 Dexamphetamine168Risk Ratio (M-H, Random, 95% CI)0.67 [0.27, 1.67]
8.2 Lisdexamphetamine3769Risk Ratio (M-H, Random, 95% CI)1.29 [0.76, 2.19]
8.3 Mixed amphetamine salts61318Risk Ratio (M-H, Random, 95% CI)1.69 [1.17, 2.45]
9 Proportion of participants experiencing headaches92063Risk Ratio (M-H, Random, 95% CI)0.93 [0.75, 1.16]
9.1 Dexamphetamine168Risk Ratio (M-H, Random, 95% CI)1.0 [0.42, 2.36]
9.2 Lisdexamphetamine51077Risk Ratio (M-H, Random, 95% CI)1.07 [0.73, 1.57]
9.3 Mixed amphetamine salts3918Risk Ratio (M-H, Random, 95% CI)0.85 [0.64, 1.14]
10 Proportion of participants experiencing nausea/vomiting61579Risk Ratio (M-H, Random, 95% CI)1.63 [1.04, 2.56]
10.1 Dexamphetamine168Risk Ratio (M-H, Random, 95% CI)1.67 [0.68, 4.07]
10.2 Lisdexamphetamine4927Risk Ratio (M-H, Random, 95% CI)1.48 [0.61, 3.61]
10.3 Mixed amphetamine salts1584Risk Ratio (M-H, Random, 95% CI)1.84 [1.04, 3.27]
Analysis 2.1.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 1 Total ADHD symptom score - parent ratings.

Analysis 2.2.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 2 Proportion of responders (CGI - I).

Analysis 2.3.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 3 Academic performance.

Analysis 2.4.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 4 Retention: proportion of participants who completed the trial.

Analysis 2.5.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 5 Proportion of participants who dropped out/withdrew due to an adverse event.

Analysis 2.6.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 6 Proportion of participants experiencing decreased appetite.

Analysis 2.7.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 7 Proportion of participants experiencing insomnia/trouble sleeping.

Analysis 2.8.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 8 Proportion of participants experiencing abdominal pain.

Analysis 2.9.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 9 Proportion of participants experiencing headaches.

Analysis 2.10.

Comparison 2 Subgroup analysis 1: Type of amphetamine, Outcome 10 Proportion of participants experiencing nausea/vomiting.

Comparison 3. Subgroup analysis 2: Type of amphetamine release formulation
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total ADHD symptom score - parent ratings71247Std. Mean Difference (IV, Random, 95% CI)-0.57 [-0.86, -0.27]
1.1 Long acting31049Std. Mean Difference (IV, Random, 95% CI)-0.61 [-1.08, -0.13]
1.2 Short acting4198Std. Mean Difference (IV, Random, 95% CI)-0.52 [-0.82, -0.23]
2 Proportion of responders (CGI - I)92105Risk Ratio (M-H, Random, 95% CI)3.31 [2.44, 4.49]
2.1 Long acting61662Risk Ratio (M-H, Random, 95% CI)3.55 [2.63, 4.79]
2.2 Short acting3443Risk Ratio (M-H, Random, 95% CI)2.89 [1.39, 6.02]
3 Academic performance8826Std. Mean Difference (IV, Random, 95% CI)0.56 [0.39, 0.73]
3.1 Long acting4494Std. Mean Difference (IV, Random, 95% CI)0.59 [0.36, 0.81]
3.2 Short acting4332Std. Mean Difference (IV, Random, 95% CI)0.48 [0.15, 0.81]
4 Retention: proportion of participants who completed the trial102364Risk Ratio (M-H, Random, 95% CI)1.05 [0.99, 1.12]
4.1 Long acting61756Risk Ratio (M-H, Random, 95% CI)1.11 [1.00, 1.24]
4.2 Short acting4608Risk Ratio (M-H, Random, 95% CI)0.98 [0.95, 1.01]
5 Proportion of participants experiencing decreased appetite102271Risk Ratio (M-H, Random, 95% CI)6.18 [2.44, 15.63]
5.1 Long acting82165Risk Ratio (M-H, Random, 95% CI)7.67 [3.33, 17.65]
5.2 Short acting2106Risk Ratio (M-H, Random, 95% CI)1.58 [0.69, 3.62]
6 Proportion of participants experiencing abdominal pain102155Risk Ratio (M-H, Random, 95% CI)1.44 [1.03, 2.00]
6.1 Long acting71855Risk Ratio (M-H, Random, 95% CI)1.49 [1.10, 2.02]
6.2 Short acting3300Risk Ratio (M-H, Random, 95% CI)2.54 [0.30, 21.39]
Analysis 3.1.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 1 Total ADHD symptom score - parent ratings.

Analysis 3.2.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 2 Proportion of responders (CGI - I).

Analysis 3.3.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 3 Academic performance.

Analysis 3.4.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 4 Retention: proportion of participants who completed the trial.

Analysis 3.5.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 5 Proportion of participants experiencing decreased appetite.

Analysis 3.6.

Comparison 3 Subgroup analysis 2: Type of amphetamine release formulation, Outcome 6 Proportion of participants experiencing abdominal pain.

Comparison 4. Subgroup analysis 3: Funding source
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total ADHD symptom score - parent ratings71247Std. Mean Difference (IV, Random, 95% CI)-0.57 [-0.86, -0.27]
1.1 Industry51135Std. Mean Difference (IV, Random, 95% CI)-0.53 [-0.89, -0.16]
1.2 Public184Std. Mean Difference (IV, Random, 95% CI)-0.75 [-1.20, -0.31]
1.3 Not reported128Std. Mean Difference (IV, Random, 95% CI)-0.60 [-1.36, 0.16]
2 Proportion of responders (CGI - I)92210Risk Ratio (M-H, Random, 95% CI)3.37 [2.50, 4.53]
2.1 Industry82146Risk Ratio (M-H, Random, 95% CI)3.24 [2.39, 4.40]
2.2 Not reported164Risk Ratio (M-H, Random, 95% CI)5.4 [2.38, 12.25]
3 Academic performance8826Std. Mean Difference (IV, Random, 95% CI)0.56 [0.39, 0.73]
3.1 Industry5688Std. Mean Difference (IV, Random, 95% CI)0.64 [0.46, 0.81]
3.2 Public144Std. Mean Difference (IV, Random, 95% CI)-0.01 [-0.60, 0.59]
3.3 Not reported294Std. Mean Difference (IV, Random, 95% CI)0.47 [0.06, 0.88]
Analysis 4.1.

Comparison 4 Subgroup analysis 3: Funding source, Outcome 1 Total ADHD symptom score - parent ratings.

Analysis 4.2.

Comparison 4 Subgroup analysis 3: Funding source, Outcome 2 Proportion of responders (CGI - I).

Analysis 4.3.

Comparison 4 Subgroup analysis 3: Funding source, Outcome 3 Academic performance.

Comparison 5. Sensitivity analysis 1: Fixed-effect model
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total ADHD symptom score - parent ratings71247Std. Mean Difference (IV, Fixed, 95% CI)-0.52 [-0.64, -0.40]
2 Hyperactivity/impulsivity - parent ratings2132Std. Mean Difference (IV, Fixed, 95% CI)-0.54 [-0.89, -0.19]
3 Total ADHD symptom score - teacher ratings5745Std. Mean Difference (IV, Fixed, 95% CI)-0.47 [-0.62, -0.32]
4 Hyperactivity/impulsivity - teacher ratings1 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
5 Inattention - teacher ratings1 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
6 Total ADHD symptom score - clinician ratings3813Std. Mean Difference (IV, Fixed, 95% CI)-0.84 [-1.01, -0.68]
7 Hyperactivity/impulsivity - clinician ratings3813Std. Mean Difference (IV, Fixed, 95% CI)-0.74 [-0.90, -0.58]
8 Inattention - clinician ratings3813Std. Mean Difference (IV, Fixed, 95% CI)-0.77 [-0.94, -0.61]
9 Total ADHD symptom score - investigator/research personnel ratings3630Std. Mean Difference (IV, Fixed, 95% CI)-1.08 [-1.25, -0.91]
10 Hyperactivity/impulsivity - Investigator/research personnel ratings2280Std. Mean Difference (IV, Fixed, 95% CI)-1.50 [-1.76, -1.23]
11 Inattention - investigator/research personnel ratings4634Std. Mean Difference (IV, Fixed, 95% CI)-0.76 [-0.93, -0.60]
12 Proportion of responders (CGI - I)92207Risk Ratio (M-H, Fixed, 95% CI)3.11 [2.68, 3.61]
13 CGI - S score286Std. Mean Difference (IV, Fixed, 95% CI)-0.71 [-1.15, -0.27]
14 Quality of life1 Std. Mean Difference (IV, Fixed, 95% CI)Subtotals only
15 Academic performance8826Std. Mean Difference (IV, Fixed, 95% CI)0.59 [0.45, 0.73]
16 Retention: proportion of participants who completed the trial102364Risk Ratio (M-H, Fixed, 95% CI)1.08 [1.04, 1.12]
17 Proportion of participants who experienced at least one adverse event61742Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.20, 1.47]
18 Proportion of participants who dropped out/withdrew due to an adverse event92160Risk Ratio (M-H, Fixed, 95% CI)1.95 [1.08, 3.51]
19 Proportion of participants experiencing decreased appetite112467Risk Ratio (M-H, Fixed, 95% CI)5.57 [4.03, 7.68]
20 Proportion of participants experiencing insomnia/trouble sleeping102429Risk Ratio (M-H, Fixed, 95% CI)3.91 [2.82, 5.41]
21 Proportion of participants experiencing abdominal pain102155Risk Ratio (M-H, Fixed, 95% CI)1.57 [1.18, 2.08]
22 Proportion of participants experiencing headaches92091Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.76, 1.18]
23 Proportion of participants experiencing anxiety/nervousness51088Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.94, 1.56]
24 Proportion of participants experiencing nausea/vomiting61579Risk Ratio (M-H, Fixed, 95% CI)1.72 [1.20, 2.46]
Analysis 5.1.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 1 Total ADHD symptom score - parent ratings.

Analysis 5.2.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 2 Hyperactivity/impulsivity - parent ratings.

Analysis 5.3.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 3 Total ADHD symptom score - teacher ratings.

Analysis 5.4.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 4 Hyperactivity/impulsivity - teacher ratings.

Analysis 5.5.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 5 Inattention - teacher ratings.

Analysis 5.6.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 6 Total ADHD symptom score - clinician ratings.

Analysis 5.7.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 7 Hyperactivity/impulsivity - clinician ratings.

Analysis 5.8.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 8 Inattention - clinician ratings.

Analysis 5.9.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 9 Total ADHD symptom score - investigator/research personnel ratings.

Analysis 5.10.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 10 Hyperactivity/impulsivity - Investigator/research personnel ratings.

Analysis 5.11.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 11 Inattention - investigator/research personnel ratings.

Analysis 5.12.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 12 Proportion of responders (CGI - I).

Analysis 5.13.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 13 CGI - S score.

Analysis 5.14.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 14 Quality of life.

Analysis 5.15.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 15 Academic performance.

Analysis 5.16.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 16 Retention: proportion of participants who completed the trial.

Analysis 5.17.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 17 Proportion of participants who experienced at least one adverse event.

Analysis 5.18.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 18 Proportion of participants who dropped out/withdrew due to an adverse event.

Analysis 5.19.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 19 Proportion of participants experiencing decreased appetite.

Analysis 5.20.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 20 Proportion of participants experiencing insomnia/trouble sleeping.

Analysis 5.21.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 21 Proportion of participants experiencing abdominal pain.

Analysis 5.22.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 22 Proportion of participants experiencing headaches.

Analysis 5.23.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 23 Proportion of participants experiencing anxiety/nervousness.

Analysis 5.24.

Comparison 5 Sensitivity analysis 1: Fixed-effect model, Outcome 24 Proportion of participants experiencing nausea/vomiting.

Appendices

Appendix 1. CENTRAL search strategy

1. exp Amphetamines/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. Central Nervous System Stimulants/
4. 1 or 2 or 3
5. exp Attention Deficit Disorder with Hyperactivity/
6. Child Behavior Disorders/
7. adhd.tw.
8. addh.tw.
9. adhs.tw.
10. "ad/hd".tw.
11. hyperactiv$.tw.
12. hyper-activ$.tw.
13. overactiv$.tw.
14. over-activ$.tw.
15. hyperkinesis/
16. hyperkin$.tw.
17. hyper-kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5-23
25. exp child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre-school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. Pediatrics/
30. p?ediatric$.tw.
31. or/25-30
32. 4 and 24 and 31

Appendix 2. Ovid MEDLINE search strategy

1. exp Amphetamines
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. Central Nervous System Stimulants/
4. 1 or 2 or 3
5. exp Attention Deficit Disorder with Hyperactivity/
6. Child Behavior Disorders/
7. adhd.tw.
8. addh.tw.
9. adhs.tw
10. "ad/hd".tw.
11. hyperactiv$.tw.
12. hyper-activ$.tw.
13. overactiv$.tw.
14. over-activ$.tw.
15. hyperkinesis/
16. hyperkin$.tw.
17. hyper-kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5-23
25. exp child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre-school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. Pediatrics/
30. p?ediatric$.tw.
31. or/25-30
32. 4 and 24 and 31
33. randomized controlled trial.pt.
34. controlled clinical trial.pt.
35. randomi#ed.ab.
36. placebo$.ab.
37. drug therapy.fs.
38. randomly.ab.
39. trial.ab.
40. groups.ab.
41. or/33-40
42. exp animals/ not humans.sh.
43. 41 not 42
44. 32 and 43

Lines 33 to 43 are the Cochrane highly sensitive search strategy for identifying randomized trials in MEDLINE (Ovid version) (Lefebvre 2011).

Appendix 3. Embase search strategy

1. exp amphetamine/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. central stimulant agent/
4. 1 or 2 or 3
5. exp attention deficit disorder/
6. behavior disorder/
7. adhd.tw.
8. addh.tw.
9. adhs.tw.
10. "ad/hd".tw.
11. hyper-activ$.tw.
12. hyperactiv$.tw.
13. overactiv$.tw.
14. over-activ$.tw.
15. hyperkinesia/
16. hyperkin$.tw.
17. hyper-kin$.tw.
18. hkd.tw.
19. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
20. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
21. (behav$ adj3 (dysfunc$ or disorder$)).tw.
22. (impulsiv$ or inattentiv$ or inattention$).tw.
23. disruptiv$.tw.
24. or/5-23
25. child/
26. adolescent/
27. (adoles$ or teen$ or youth$ or young people or young person$).tw.
28. (child$ or toddler$ or preschool$ or pre-school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
29. pediatrics/
30. p?ediatric$.tw.
31. or/25-30
32. 4 and 24 and 31
33. randomized controlled trial/
34. controlled clinical trial/
35. randomi#ed.ab.
36. placebo$.ab.
37. drug therapy/
38. randomly.ab.
39. trial.ab.
40. single blind procedure/
41. double blind procedure/
42. or/33-41
43. exp animal/ not human.sh.
44. 42 not 43

Appendix 4. PsycINFO search strategy

1. exp amphetamine/
2. (amphetamine$ or dexamphetamine$ or methamphetamine$ or dextroamphetamine$ or lisdexamphetamine$ or vyvanase$ or Dexedrin3 or desoxyn$ or adderall$).mp.
3. exp attention deficit disorder/
4. behavior disorder/
5. adhd.tw.
6. addh.tw.
7. adhs.tw.
8. "ad/hd".tw.
9. hyper-activ$.tw.
10. hyperactiv$.tw.
11. overactiv$.tw.
12. over-activ$.tw.
13. hyperkin$.tw.
14. hyper-kin$.tw.
15. hkd.tw.
16. (minimal adj3 brain$ adj3 (damag$ or disorder$ or dysfunc$)).tw.
17. (attention$ adj3 (deficit$ or disorder$ or dysfunc$)).tw.
18. (behav$ adj3 (dysfunc$ or disorder$)).tw.
19. (impulsiv$ or inattentiv$ or inattention$).tw.
20. disruptiv$.tw.
21. (adoles$ or teen$ or youth$ or young people or young person$).tw.
22. (child$ or toddler$ or preschool$ or pre-school or schoolchild$ or schoolgirl$ or schoolboy$ or girl$ or boy$).tw.
23. pediatrics/
24. p?ediatric$.tw.
25. randomi#ed.ab.
26. placebo$.ab.
27. drug therapy/
28. randomly.ab.
29. trial.ab.
30. (doubl$ adj blind$).mp.
31. (singl$ adj blind$).mp.
32. 1 or 2
33. or/3-20
34. or/21-24
35. 32 and 33 and 34
36. or/25-31
37. exp animals/ not humans.sh.
38. 36 not 37
39. 35 and 38

Appendix 5. Proquest Dissertations and Theses search strategy

Advanced search
(attention deficit disorder OR attention deficit hyperactivity disorder OR hyperactivity) AND all(amphetamine OR adderall) AND all(children OR youth OR adolescent)

Appendix 6. Networked Digital Library of Theses and Dissertations search strategy

Attention Deficit Hyperactivity Disorder AND amphetamine AND (child OR youth OR adolescent)

Appendix 7. ClinicalTrials.gov search strategy

Advanced search
Conditions: Attention Deficit Hyperactivity Disorder OR ADHD OR Attention Deficit Disorder OR ADD
Interventions: amphetamine OR dexamphetamine OR methamphetamine OR dextroamphetamine OR lisdexamphetamine OR vyvanase OR dexedrine OR adderall
Study results: All studies
Age group: Child

Appendix 8. Risk of bias domains

DomainDescriptionJudgement
Random sequence generationThe method used to generate the allocation sequence is described in sufficient detail so as to assess whether it should have produced comparable groups.What is the risk of selection bias due to inadequate generation of a randomized sequence?
Allocation concealmentThe method used to conceal the allocation sequence is described in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.What is the risk of selection bias due to inadequate concealment of allocations prior to assignment?
Blinding of participants and personnelThe measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received and any information relating to whether the intended blinding was effective.What is the risk of performance bias due to knowledge of the allocated interventions by participants and personnel during the study?
Blinding of outcome assessmentThe measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received and any information relating to whether the intended blinding was effective.What is the risk of detection bias due to knowledge of the allocated interventions by outcome assessors?
Incomplete outcome dataAssessment of the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis.What is the risk of attrition bias due to amount, nature, or handling of incomplete outcome data?
Selective outcome reportingAttempts made to assess the possibility of selective outcome reporting by investigators.What is the risk of reporting bias due to selective outcome reporting?
Other sources of biasAssessment of other sources of bias in other domains not covered by the tool, including validity of outcome measures utilized.What is the risk of bias due to problems not covered elsewhere in the table?

Contributions of authors

SP and SV conceived this review and share overall responsibility for this review.
SP led the design and ongoing co-ordination of this review with oversight from LS, LH, LU, BV, CJN, and SV.
SP developed the additional search strategies and carried out the searches for this review.
SP and BV developed the analysis plan.
SP retrieved the papers for this review.
SP and LS independently assessed the retrieved papers against the eligibility criteria for this review.
SP and LS independently appraised the risk of bias in the papers for this review.
SP and LS independently extracted the data from the papers for this review.
SP wrote to authors of included studies for additional information for this review.
SP managed the data for this review, including entering data into RevMan and analysing the data under the guidance of BV.
SP interpreted the data for this review with input from all authors.
SP wrote the review.
All authors critically read and edited the review.

Declarations of interest

Salima Punja - none known.
Larissa Shamseer - none known.
Lisa Hartling - none known.
Liana Urichuk - received salary support from the Addiction & Mental Health Program of Alberta Health Services - Edmonton Zone during the course of this review. Dr Urichuk also received a grant for a research project entitled "Neurofeedback for children with Attention Deficit Hyperactivity Disorder" from the Sick Kids Hospital Foundation and John and Lotte Hecht Memorial Foundation.
Ben Vandermeer - none known.
Catherine Jane Nikles - published a paper in the area of amphetamines for ADHD (Nikles 2006). The study was excluded due to the nature of the design. Dr Nikles was not involved in assessing the eligibility of this study, which was performed by two independent authors.
Sunita Vohra - is the recipient of an Alberta Innovates - Health Scholar salary award. Dr Vohra's institution receives funds from Alberta Innovates - Health Solutions and protects 75% of her time for research. Other funders include Health Canada, Canadian Institutes of Health Research, Women & Children’s Health Research Institute and National Health, Medical Research Council (Australia) and SERIN-ETD Acupuncture Research Fund. SERIN is a commercial entity who provided acupuncture needles for a trial. The population is not pediatric ADHD. None of these companies pose a conflict of interest as regards this review.

Sources of support

Internal sources

  • None, Other.

External sources

  • Alberta Innovates - Health Solutions, Canada.

    Salary support for Dr. Sunita Vohra

Differences between protocol and review

Please refer to Table 1 for a summary of protocol decisions not used in this review.

Methods. Data collection and analysis. Assessment of risk of bias in included studies.

In our protocol, we had included funding source in the risk of bias assessment. However, given the ongoing debate of the influence of funding source on treatment effect estimates, we removed this from the assessment. Instead, we explored the influence of industry on treatment effects by performing a subgroup analysis on funding source (industry versus publicly funded versus not reported).

Methods. Data collection and analysis. Unit of analysis issues.

Studies with multiple comparisons

For dichotomous outcomes of cross-over studies, we randomly dropped one arm and used the other in the meta-analysis.

Methods. Data collection and analysis. Assessment of heterogeneity

We added that we assessed statistical heterogeneity by examining "Chi² (P value less than 0.10 as evidence of heterogeneity)", and "Tau² estimates for each random-effects meta-analysis".

Methods. Data collection and analysis. 'Summary of findings'.

We added a description of what was included in the 'Summary of findings' table beneath the subsection on 'Data synthesis'.

Methods. Data collection and analysis. Subgroup analysis and investigation of heterogeneity.

We had planned to perform a subgroup analysis based on type of questionnaire used (teacher, parent, clinician, investigator). However, given the importance of each of these informants individually in the overall assessment of ADHD, these were separated in our primary analysis.

Methods. Data collection and analysis. Sensitivity analysis.

We did not conduct a sensitivity analysis according to study design (parallel-group versus cross-over trial) as planned, since all included cross-over studies were treated as if they were parallel-group studies.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Barkley 2000

Methods

Randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants Sample size: 46* children/adolescents with an ADHD diagnosis according to the DSM-IV criteria
Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 12 years to 17 years
Mean age (SD): 14 (NR) years
Sex: 30 (86%) males
ADHD subtype: NR
Interventions

Five interventions (all 46 children/adolescents participated in each of the five interventions):

  1. Mixed amphetamine salts (short acting), 5 mg, twice a day, (n = 46)

  2. Mixed amphetamine salts (short acting), 10 mg, twice a day, (n = 46)

  3. Methylphenidate, 5 mg, twice a day, (n = 46)

  4. Methylphenidate, 10 mg, twice a day, (n = 46)

  5. Placebo (n = 46)

Duration: 35 days (5 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (parents and teachers)

  2. Clinical impression, assessed with Clinical Global Impressions - Improvement scale

  3. Adverse events

Other outcomes:

  1. Oppositional defiant disorder symptom severity, assessed with an oppositional defiant disorder rating scale (not specified)

  2. Assessment attention and impulsivity, as measured by the Conners' Continuous Performance Test

  3. Response inhibition and interference control, assessed with the Stroop Word - Color Association Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: pharmaceutical industry
*Clinical characteristics were only reported on children/adolescents who started the trial (n = 35)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly data for completers included in analysis. For one of the primary outcomes, only 37% of randomized children/adolescents included in analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not adequately described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Biederman 2002

Methods

Multi-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States
Number of study sites: 47

Statistical methods: modified ITT (last observation carried forward)

Participants Sample size: 584* children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: 75
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 8.6 (1.7) years
Sex: 434 (77%) males
ADHD subtype: 28 (5%) hyperactive - impulsive; 12 (2%) inattentive; 523 (93%) combined
Interventions

Four interventions (584 children/adolescents participated in one of four interventions):

  1. Mixed amphetamine salts (long acting), 10 mg/day, (n = 129)

  2. Mixed amphetamine salts (long acting), 20 mg/day (10 mg/day for week 1 with forced dose escalation to 20 mg/day in weeks 2 to 3), (n = 121)

  3. Mixed amphetamine salts (long acting), 30 mg/day (10 mg/day in week 1, 20 mg/day in week 2, 30 mg/day in week 3), (n = 124)

  4. Placebo (n = 210)

Duration: 21 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners Global Index, teacher- and parent-rated

  2. Clinician impression, assessed with Clinical Global Impressions - Improvement scale

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who experienced at least one adverse event

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliations: university
Study funding: pharmaceutical industry

*Clinical characteristics are only provided on those children included in the primary efficacy analysis (n = 563)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate attrition (13%). Reasons for attrition reported and 96% of randomized children/adolescents included in primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Biederman 2007a

MethodsMulti-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States
Number of study sites: 4
Statistical methods: modified ITT (all randomized children/adolescents who had at least one post-randomization score on primary outcome measure)
Participants Sample size: 52 children/adolescents with an ADHD diagnosis according to the DSM-IV-TR criteria
Dropouts: 2
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.1 (1.7) years
Sex: 33 (64%) males
ADHD subtypes: 52 (100%) combined
Interventions

Three interventions (all 52 children/adolescents participated in each of the three interventions):

  1. Mixed amphetamine salts (long acting), either 10 mg/day, 20 mg/day or 30 mg/day (determined by dose optimisation period), (n = 52)*

  2. Lisdexamphetamine (long acting), either 30 mg/day, 50 mg/day or 70 mg/day (determined by dose optimisation period), (n = 52)

  3. Placebo (n = 52)

Duration: 21 days (3 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (investigator) of the Swanson, Kotkin, Agler, M-Flynn and Pelham scale

  2. Academic performance, assessed with Permanent Product Measure of Performance scale

  3. Clinical impression, assessed with Clinical Global Impressions - Severity and Clinical Global Impressions - Improvement scales

  4. Retention: number of participants who completed the study

  5. Adverse events

Other outcomes:

  1. Conduct problems, assessed with deportment subscale of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

  2. Vital signs (blood pressure, pulse)

Notes ClinicalTrials.gov identifier: NCT00557011
Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Mixed amphetamine salts - extended release was randomly chosen to represent the amphetamine group in this study for binary outcomes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Low riskMethod of allocation concealment involved pre-packaged, serially-numbered drug kits, in which the next participant enrolled received the next available drug kit. Drug kits prepared by a third party
Incomplete outcome data (attrition bias)
All outcomes
Low riskAlthough the primary analysis only included trial completers, attrition was low at 4%
Selective reporting (reporting bias)Low riskData provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Biederman 2007b

MethodsMulti-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States
Number of study sites: 40
Statistical methods: modified ITT (children/adolescents who had baseline and at least one post-randomization primary efficacy measure, last observation carried forward)
Participants Sample size: 290 children/adolescents with an ADHD diagnosis according to the DSM-IV-TR criteria
Dropouts: 60
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9 (1.8) years
Sex: 201 (69%) males
ADHD subtype: 12 (4%) hyperactive - impulsive; 278 (96%) combined
Interventions

Four interventions (290 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 71)

  2. Lisdexamphetamine (long acting), 50 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for weeks 2 to 4), (n = 74)

  3. Lisdexamphetamine (long acting), 70 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for week 2 and 70 mg/day for weeks 3 to 4), (n = 73)

  4. Placebo (n = 72)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version, and the Conners' Parent Rating Scale-Revised: Short Form

  2. Clinical impression, assessed with Clinical Global Impression - Severity and Clinical Global Impressions - Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who experienced at least one adverse event

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: pharmaceutical industry
*The authors reported their results of parent ratings of hyperactivity/impulsivity and inattention on the ADHD Rating Scale, Fourth Version, as well as total ADHD symptom scores on the Conners' Parent Rating Scale - Revised as bar graphs. We sought to extract relevant data using graphic digitizer software but this gave implausible results. Consequently, this data could not be included in the meta-analysis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generated by a computer program
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate attrition (21%). However, 98% of randomized children/adolescents included in primary analysis. Reasons for dropouts provided
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Borcherding 1990

MethodsSingle-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States
Number of study sites: 1
Statistical methods: ITT (all randomized children/adolescents are included in the analysis, with any missing data imputed with the group mean value)
Participants Sample size: 46 children/adolescents with an ADHD diagnosis according to DSM-III criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, reading developmental disorder, arithmetic disorder, dysthymic disorder
Age range: 6 years to 12 years
Mean age (SD): 8.6 (1.7) years
Sex: 46 (100%) males
ADHD subtype: NR
Interventions

Three interventions (all 46 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight-based dosing increasing each week (children < 30 kg (66 lbs) received 10, 25, and 40 mg/day, twice a day; children/adolescents > 30 kg (66 lbs) received 15, 30, and 45 mg/day, twice a day), (n = 46)

  2. Methylphenidate hydrochloride, weight-based dosing increasing each week (children < 30 kg (66 lbs) received 25, 40, and 70 mg/day, twice a day; children/adolescents > 30 kg (66 lbs) received 30, 50, and 90 mg/day, twice a day), (n = 46)

  3. Placebo (n = 46)

Duration: 63 days (3 x 21-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale - Short Form* and Conners' Parent Rating Scale - Long Form

  2. Clinical impression, assessed with Clinical Global Impressions - Improvement scale

  3. Academic performance, assessed with: the Barnell Loft, Ltd, Developing Key Concepts in Math test

  4. Retention: proportion of participants who completed the trial

  5. Adverse events

Other outcomes:

  1. Nervous habits/mannerisms, compulsive acts and obsessive thinking assessed with Children's Psychiatric Rating Scale

  2. Urine biochemistry

  3. Plasma biochemistry

  4. Renal clearance

  5. Cognitive ratings, assessed with Conners' Continuous Performance Test

Notes

ClinicalTrials.gov identifier: not available
Authors' affiliation: National Institute of Mental Health
Study funding: NR

Outcomes were presented across four publications with varying sample sizes
*Unpublished data on the ADHD symptoms as rated by the Conners' Teacher Rating Scale - Short Form were sought on three separate occasions but were not obtained

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
High riskThis study has four associated publications, and all reports have varying numbers of participants. Upon communication with the corresponding author of these reports, it was confirmed that the numbers of participants vary in the four publications due to missing data and dropouts. Reasons for missing data not provided
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasUnclear riskNo information on the validity of the primary outcome measure provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Childress 2015

MethodsMulti-center, randomized, double-blinded, placebo-controlled, cross-over trial
Countries: United States
Number of study sites: 7
Statistical methods: modified ITT (all randomized children/adolescents who took at least one dose of the study medication, and had at least one post-randomization score on primary outcome measure)
Participants Sample size: 97 children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 2
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.6 (1.86) years
Sex: 59 (60.8%) males
ADHD subtype: 0 (0%) hyperactive - impulsive; 18 (18.6%) inattentive; 79 (81.4%) combined
Interventions

Two interventions (all 97 children/adolescents participated in both interventions):

  1. Mixed amphetamine salts (short acting), dose determined by dose optimisation period (mean (SD) dose: 23.4 (8.18) mg/day), (n = 97)

  2. Placebo (n = 97)

Duration: 14 days (2 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the combined (investigator/research personnel) and attention subscales of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Retention: proportion of participants who completed the trial

  4. Adverse events

Notes ClinicalTrials.gov identifier: NCT01986062
Authors' affiliation: pharmaceutical industry
Study funding: pharmaceutical industry
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generated using an interactive web-based response system
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskVery low attrition (2%)
Selective reporting (reporting bias)Low riskData provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Coghill 2013

MethodsMulti-center, randomized, double-blind, placebo-controlled, parallel-group trial
Countries: Belgium, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, UK
Number of study sites: 48
Statistical methods: modified ITT (last observation carried forward)
Participants Sample size: 336* children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 140
Psychiatric comorbid conditions: ODD
Age range: 6 years to 17 years
Mean age (SD): 10.9 (2.8)
Sex: 268 (81%) male
ADHD subtype: 10 (3%) hyperactive-impulsive; 53 (16%) inattentive; 268 (80.7%) combined; 1 (0.3%) NR
Interventions

Three interventions (336 children/adolescents participated in one of three interventions):

  1. Lisdexampehtamine (long acting), varying doses at either 30, 50, or 70 mg/day, (n = 113)

    1. Mean (SD) dose across participants: 53.8 (15.6) mg/day

  2. Osmotic release oral system methylphenidate, varying doses at either 18, 36, or 59 mg/day, (n = 112)

    1. Mean (SD) dose across participants: 45.4 (12.7) mg/day

  3. Placebo (n = 111)

Duration: 49 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (investigator), and Conners' Parent Rating Scale - Revised

  2. Clinical impression, assessed with Clinical Global Impression - Severity and Clinical Global Impression - Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to lack of efficacy

  5. Number of participants who dropped out due to any adverse event

  6. Adverse events

Notes

ClinicalTrials.gov identifier: NCT00763971
Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
Outcomes were presented across three publications

*Clinical characteristics were only reported on those who received at least one dose of the intervention to which they were randomized (n = 332)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Low riskStudy utilized an interactive voice/web response system, which automatically generated a unique randomization number for each child/adolescent
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh attrition (58%). 14 (4%) children/adolescents excluded from the efficacy analysis with no reasons provided
Selective reporting (reporting bias)High riskOutcomes listed in the registered protocol are not reported in any of the three publications
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment is not described

Donnelly 1989

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: ITT

Participants Sample size: 20 children/adolescents with an ADHD diagnosis according to DSM-III criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, mental learning disorder, language disorder
Age range: NR
Mean age (SD): 8 (2) years
Sex: 20 (100%) males
ADHD subtype: NR
Interventions

Three interventions (all 20 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight-based dose, 0.5 mg/kg/day, twice a day, (n = 20)

  2. Fenfluramine hydrochloride, weight-based dosing increasing each week (0.6 mg/kg/day, 1.3 mg/kg/day, 2.0 mg/kg/day), twice a day, (n = 20)

  3. Placebo (n = 20)

Duration: 63 days (3 x 21-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale - Short Form

  2. Clinical impression, assessed with Clinical Global Impression scale*

  3. Adverse events

Other outcomes:

  1. Vigiliance/attention and impulsivity, assessed with Conners' Continuous Performance Test

  2. Motor activity, assessed with activity monitor

  3. Biochemical and platelet measures (urine and plasma)

  4. Measures of prolactin

Notes

ClinicalTrials identifier: not available

Authors' affiliation: university and National Institute of Mental Health
Study funding: NR

Donnelly 1986 is a pilot study of Donnelly 1989 and therefore have overlapping data

*Unpublished data on the Clinical Global Impression scale sought on three separate occasions but not obtained

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll recruited children/adolescents included in analyses. Only one dropout, with reasons provided
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasUnclear riskNo information on the validity of the primary outcome measure provided
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Findling 2011

MethodsMulti-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States
Number of study sites: 45
Statistical methods: modified ITT (last observation carried forward)
Participants Sample size: 314 children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 52
Psychiatric comorbid conditions: NR
Age range: 13 years to 17 years
Mean age (SD): 14.6 (1.31) years
Sex: 249 (79%) males
ADHD subtype: 203 (65%) combined
Interventions

Four interventions (312 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 78*)

  2. Lisdexamphetamine (long acting), 50 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for weeks 2 to 4), (n = 77*)

  3. Lisdexamphetamine, long acting, 70 mg/day (30 mg/day for week 1 with forced dose escalation to 50 mg/day for week 2 and 70 mg/day for weeks 3 to 4), (n = 78*)

  4. Placebo (n = 79)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Clinical impression, assessed with Clinical Global Impression - Severity and Clinical Global Impression - Improvement scales

  3. Quality of life, assessed with Youth Quality of Life - Research Version (YQOL-R)

  4. Retention: proportion of participants who completed the trial

  5. Number of participants who dropped out due to lack of efficacy

  6. Number of participants who experienced at least one adverse event

  7. Number of participants who dropped out due to any adverse event

  8. Adverse events

Notes

ClinicalTrials.gov identifier: NCT00735371

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Numbers are based on participants included in the safety analysis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence generated by a web-based computer system
Allocation concealment (selection bias)Low riskAllocation concealment ensured using the web-based computer system and third party, which serially numbered treatment bottles for each participant
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate attrition (16%). However, 98% of randomized children/adolescents included in primary efficacy analysis. Reasons for dropouts provided
Selective reporting (reporting bias)Low riskData provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Giblin 2011

Methods

Single-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States

Number of study sites: 1
Statistical methods: modified ITT (all randomized children/adolescents who had both a baseline and a post-randomization primary outcome assessment)

Participants Sample size: 24 children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 0
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.65 (2.2) years
Sex: 10 (42%) males
ADHD subtype: NR
Interventions

Four interventions (24 children/adolescents participated in one of four interventions):

  1. Lisdexamphetamine (long acting), 30 mg/day, (n = 3)

  2. Lisdexamphetamine, (long acting), 50 mg/day, (n = 11)

  3. Lisdexamphetamine, (long acting), 70 mg/day, (n = 2)

  4. Placebo (n = 8)

Duration: 28 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (investigator) and Conners' Parent Rating Scale - Revised: Short Form*

  2. Clinical impression, assessed with Clinical Global Impression - Severity scale

  3. Adverse events

Other outcomes:

  1. Sleep onset latency, assessed with polysomnography

  2. Wake time after sleep onset, assessed with polysomnography and actigraphy

  3. Number awakenings after sleep onset, assessed with polysomnography

  4. Total sleep time, assessed with polysomnography and actigraphy

  5. Sleep efficiency, assessed with actigraphy

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: private organization and pharmaceutical industry
Study funding: pharmaceutical industry
*Unpublished data sought on both outcome measures on three separate occasions but not obtained

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskIncomplete outcome data not addressed; number of completers not reported
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Gillberg 1997

MethodsMulti-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: Sweden
Number of sites: 4
Statistical methods: modified ITT (for inclusion into the analysis at least two measurements had to be available, with the last observation carried forward)
Participants Sample size: 62 children/adolescents with an ADHD diagnosis according to DSM-III-R criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, conduct disorder, anxiety, autistic disorder, pervasive development disorder, motor tic disorder, Tourette syndrome, mild mental retardation
Age range: 6 years to 11 years
Mean age (SD): 9 (1.6) years
Sex: 52 (84%) males
ADHD subtype: NR
Interventions

Two interventions (62 children/adolescents participated in one of two interventions):

  1. Mixed amphetamine salts (short acting), dosage was titrated from 10 mg/day, twice a day, to a maximum of 60 mg/day, twice a day, (n = 32)

  2. Placebo (n = 30)

Duration: 365 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale and Conners' Parent Rating Scale

  2. Adverse events

Other outcomes:

  1. Depression, assessed with the Birleson Depression Self-Rating Scale

  2. Mood, assessed with the McGrath Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry and public funds

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate attrition (14%). However, all dropouts occurred prior to randomization. Reasons for dropout provided. All randomized children/adolescents included in primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

James 2001

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants Sample size: 35 children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, anxiety, enuresis, dysthymic disorder, learning disorder
Age range: 6.9 years to 12.2 years
Mean age (SD): 9.1 (1.5) years
Sex: 21 (60%) males
ADHD subtype: 35 (100%) combined
Interventions

4 interventions:*

  1. Dextroamphetamine (short acting)*

  2. Dextroamphetamine spansules (long acting)*

  3. Mixed amphetamine salts (long acting)*

  4. Placebo

Duration: 56 days (4 x 14-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Teacher Rating Scale and Conners' Parent Rating Scale

  2. Academic performance, assessed with a 5-minute timed math task

  3. Adverse events

Other outcomes:

  1. Motor activity, assessed with an actometer

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliation: National Insitute of Mental Health
Study funding: NR
*Doses were individualized and based on age, weight, prior medication experience and symptom severity (overall mean dose range: 7.8 mg/day to 12.8 mg/day)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (7%), and reasons provided. All dropouts occurred prior to randomization. All randomized children/adolescents completed the trial and included in primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Manos 1999

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: unclear

Participants Sample size: 84 children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: NR
Psychiatric comorbid conditions: oppositional defiant disorder, anxiety, mood disorder, learning disability
Age range: 5 years to 17 years
Mean age (SD): 10.1 (NR) years
Sex: 66 (79%) males
ADHD subtypes: 38 (45%) inattentive; 46 (55%) combined
Interventions

Two conditions (84 children/adolescents participated in one of two conditions):

  1. Mixed amphetamine salts (short acting), (42 children/adolescents participated in each of the following four interventions):

    1. 5 mg/day, once daily

    2. 10 mg/day, once daily

    3. 15 mg/day, once daily

    4. Placebo

  2. 2. Methylphenidate (42 children/adolescents participated in each of the following four interventions):

    1. 5 mg/day, twice a day

    2. 10 mg/day, twice a day

    3. 15 mg/day, twice a day

    4. Placebo

Children/adolescents received either the four mixed amphetamine salt OR methylphenidate conditions (determined by his or her physician) in a randomly assigned sequence
Duration: 28 days (4 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Abbreviated Symptoms Questionnaire - Parent Version and Conners' Abbreviated Symptoms Questionnaire - Teacher Version

  2. Adverse events

Other outcomes:

  1. Concentration in school, assessed with School Situations Questionnaire - Revised

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliations: university
Study funding: public funds

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Low riskA third party pharmacist prepared individually sealed bottles dated by week
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskStudy did not describe if any children/adolescents dropped out from the trial
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Low riskClinician, teacher and parent (outcome assessors) were blinded to treatment order

McCracken 2003

MethodsMulti-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States
Number of study sites: 4
Statistical methods: modified ITT
Participants Sample size: 51 children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: 4
Psychiatric comorbid conditions: NR
Age range: 6 years to 12 years
Mean age (SD): 9.5 (1.9) years
Sex: 44 (86%) males
ADHD subtypes: 1 (2%) hyperactive - impulsive; 50 (98%) combined
Interventions

Five interventions (all 51 children/adolescents participated in each of the five interventions):

  1. Mixed amphetamine salts (short acting), 10 mg, once a day, (n = 51)

  2. Mixed amphetamine salts (long acting), 10 mg, once a day, (n = 51)

  3. Mixed amphetamine salts (long acting), 20 mg, once a day*, (n = 51)

  4. Mixed amphetamine salts (long acting), 30 mg, once a day, (n = 51)

  5. Placebo (n = 51)

Duration: 35 days (5 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (investigator ratings) of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to any adverse event

  5. Adverse events

Other outcomes:

  1. Conduct problems, assessed with the deportment subscale of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

Notes ClinicalTrial.gov identifier: not available
Authors' affiliation: university
Study funding: pharmaceutical industry
*We randomly chose mixed amphetamine salts (long acting), given at 20 mg/day, to represent the amphetamine group in this study for binary outcomes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (4%) and reasons provided. All randomized children/adolescents included in primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Nemzer 1986

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: NR

Participants

Sample size: 14 children/adolescents with an ADHD diagnosis according to DSM-III criteria

Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 7 years to 12 years
Mean age (SD): 9.36 (NR) years
Sex: 11 (79%) males
ADHD subtype: NR

Interventions

Four interventions (all 14 children/adolescents participated in each of the four interventions):

  1. Dextroamphetamine (short acting), weight-based dosing (children < 32 kg (70.5 lbs) received 5 mg/day, twice a day; children/adolescents > 32 kg (70.5 lbs) received 10 mg/day), twice a day, (n = 14)

  2. Tyrosine supplement, 140 mg/kg/day, (n = 14)

  3. Tryptophan supplement, 100 mg/kg/day, (n = 14)

  4. Placebo (n = 14)

Duration: 28 days (4 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale and Conners' Teacher Rating Scale

  2. Academic performance, assessed with Wechsler Intelligence Scale for Children - Revised

  3. Adverse events

Other outcomes:

  1. Tyrosine serum levels

  2. Tryptophan serum levels

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: NR

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDropouts not discussed
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Pliszka 2000

Methods

Single-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States

Number of study sites: 1
Statistical methods: modified ITT (last observation carried forward)

Participants Sample size: 59* children/adolescents with an ADHD diagnosis according to the Diagnostic Interview Schedule for Children
Dropouts: 5
Psychiatric comorbid disorders: oppositional defiant disorder, conduct disorder, anxiety
Age range: 6 years to 10 years
Mean age (SD): 8.2 (1.6) years
Sex: NR
ADHD subtype: NR
Interventions

Three interventions (58 children/adolescents participated in one of three interventions):

  1. Mixed amphetamine salts (short acting), weight-based, titrated dosing (maximum dose for children < 27.2 kg (60 lbs) was 15 mg/day; maximum daily dose for children/adolescents > 27.2 kg (60 lbs) was 30 mg/day), (n = 20)

  2. Methylpehnidate, weight-based, titrated dosing (maximum dose for children < 27.2 kg (60 lbs) was 25 mg/day; maximum daily dose for children/adolescent > 27.2 kg (60 lbs) was 50 mg/day), (n = 20)

  3. Placebo (n = 18)

Duration: 21 days

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with IOWA (inattention/overactivity with aggression) Conners' Teacher Rating Scale and Conners' Parent Global Index

  2. Clinical impression, assessed with Clinical Global Impressions - Improvement scale

  3. Number of participants who dropped out due to any adverse event

  4. Adverse events

Other outcomes:

  1. Agression/defiance, assessed with Conners' Teacher Rating Scale

Notes

ClinicalTrials.gov identifier: not available

Author's affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*1 participant dropped out before the end of the study, and was not accounted for in the participant characteristic description (data only provided on 58 participants)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (10%), and reasons provided. All randomized children/adolescents included in primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Ramtvedt 2013

MethodsMulti-center, randomized, placebo-controlled, cross-over trial
Country: Norway
Number of study sites: 4
Statistical methods: unclear
Participants Sample size: 36* children/adolescents with an ADHD diagnosis according to DMS-IV-TR criteria
Dropouts: 0
Psychiatric comorbid disorders: oppositional defiant disorder, anxiety/depression, learning disability
Age range: 9 years to 14 years
Mean age (SD): 11.4 (1.4) years
Sex: 29 (81%) males
ADHD subtype: 10 (28%) inattentive; 1 (3%) hyperactive - impulsive; 25 (69%) combined
Interventions

Three interventions (all 36 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), 5 mg twice a day in week 1; 10 mg twice a week in week 2, (n = 36)

  2. Methylphenidate (short acting): 10 mg three times a day in week 1; 15 mg twice a day, 10 mg once daily in week 2, (n = 36)

  3. Placebo (n = 36)

Duration: 42 days (3 x 14-day treatment periods)

Outcomes

Relevant outcomes:

  1. Improvement of ADHD symptoms, assessed with a 21-item ADHD questionnaire developed for the study by parents and teachers**

  2. Adverse events

Other outcomes:

  1. Inattention, assessed with Conners' Continuous Performance Test

  2. Motor activity, assessed with Conners' Continuous Performance Test

Notes

ClinicalTrials.gov identifier: NCT01220440
Authors' affiliation: university and hospital
Study funding: public funds
Outcomes were presented across two publications

*Data only provided on those children/adolescents who completed the trial; no information provided regarding number of children/adolescents randomized
**Data is presented as an aggregate score of parent and teacher ratings and therefore could not be incorporated into the meta-analysis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
High riskPrimary analysis only included a subset of completers without any reason provided. No information on non-completers provided
Selective reporting (reporting bias)High riskAlthough the registered protocol stated that they would collect adverse events using the Side-Effects Rating Scale, this was not reported in the published manuscript
Other biasUnclear riskNo information on the validity of the primary outcome measure provided
Blinding of participants and personnel (performance bias)
All outcomes
High riskInterventions and placebo were not identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Sharp 1999

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: ITT (missing data were imputed using group means)

Participants Sample size: 32* children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: 1
Psychiatric comorbid disorders: oppositional defiant disorder, conduct disorder, depression, separation anxiety, specific phobias, tic disorder, enuresis, reading disorder
Age range: 6.2 years to 12.7 years
Mean age (SD): 8.9 (1.7) years
Sex: 0 (0%) males
ADHD subtype: 32 (100%) combined
Interventions

Three interventions (all 32 children/adolescents participated in each of the three interventions):

  1. Dextroamphetamine (short acting), weight-based dosing and increasing over time (mean doses of 0.23 mg/kg/day, 0.43 mg/kg/day, and 0.64 mg/kg/day, twice a day for weeks 1, 2, and 3 respectively), (n = 32)

  2. Methylphenidate, weight-based dosing and increasing over time (mean doses of 0.45 mg/kg/day, 0.85 mg/kg/day, and 1.28 mg/kg/day, once daily for weeks 1, 2, and 3 respectively), (n = 32)

  3. Placebo (n = 32)

Duration: 63 days (3 x 21-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale and Conners' Teacher Rating Scale**

  2. Clinician impression, assessed with Clinical Global Impressions - Severity and Clinical Global Impressions - Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Adverse events

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliation: university and National Institute for Mental Health
Study funding: NR

*Clinical characteristics were presented on 42 children/adolescents, 10 of whom participated in a separate pilot program
**Unpublished data on the ADHD core symptoms sought on three separate occasions but not obtained

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskModerate attrition (14%), with reasons provided
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo are described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Shekim 1986

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: NR

Participants Sample size: 22 children/adolescents with an ADHD diagnosis according to DSM-III criteria
Dropouts: NR
Psychiatric comorbid disorders: 0
Age range: 6 years to 12 years
Mean age (SD): 9.75 (2.08) years
Sex: 22 (100%) males
ADHD subtype: NR
Interventions

Two interventions (all 22 children/adolescents participated in both interventions):

  1. Dextroamphetamine (short acting), weight-based at 0.3 mg/kg twice a day, and titrated upwards during trial period, (n = 22)

  2. Placebo (n = 22)

Duration: 28 days (2 x 14-day treatment periods)

Outcomes

Relevant outcomes:

  1. Academic performance, assessed with Wide Range Achievement Test - math subset

Other outcomes:

  1. Wide Range Achievement Test - spelling and reading subsets

  2. Monoamine oxidase activity

  3. Attention and impulsivity, assessed with Conners' Contininuous Performance Test

Notes

ClinicalTrials.gov identifier: not available

Authors' affiliation: university
Study funding: public funds

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
High riskReasons for exclusions from the analysis not provided. Methods of analysis not described. Number of individuals included in the analyses not reported
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Short 2004

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: per protocol

Participants Sample size: 34* children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: NR
Psychiatric comorbid conditions: NR
Age range: 3 years to 5.9 years
Mean age (SD): 5.3 (NR) years
Sex: 24 (85%) males
ADHD subtype: 5 (17%) inattentive; 23 (83%) hyperactive - impulsive or combined
Interventions

Two conditions (28 children/adolescents participated in one of two conditions)*:

  1. Amphetamine:

    1. Mixed amphetamine salts (short acting), 5 mg/day, once daily

    2. Mixed amphetamine salts (short acting), 10 mg/day, once daily

    3. Mixed amphetamine salts (short acting), 15 mg/day, once daily

    4. Placebo

  2. Methylphenidate:

    1. Methylphenidate, 5 mg/day, twice a day

    2. Methylphenidate, 10 mg/day, twice a day

    3. Methylphenidate, 15 mg/day, twice a day

    4. Placebo

Amphetamine or methylphenidate determined by a physician
Duration: 28 days (4 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with Conners' Parent Rating Scale-short form and Conners' Teacher Rating Scale-short form**

  2. Adverse events

Notes

ClinicalTrial.gov identifier: not available

Authors' affiliations: university
Study funding: public funds
*Clinical characteristics only presented on children/adolescents included in analysis (n = 28)
**The authors did not separate the two active interventions (amphetamine and methylphenidate) in their analysis. We contacted the authors on three occasions to obtain the data on amphetamines only, but we received no response, and therefore outcomes could not be included in the meta-analysis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not sufficiently described
Incomplete outcome data (attrition bias)
All outcomes
High riskReasons for attrition not described. In addition, six participants were dropped from the analysis, and their last data point was not carried forward
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors blinded to order of trial interventions

Spencer 2006a

MethodsMulti-center, randomized, double-blind, placebo-controlled, parallel-group trial
Country: United States
Number of study sites: NR
Statistical methods: modified ITT (those with at least one post-baseline primary efficacy assessment)
Participants Sample size: 287* children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 52
Psychiatric comorbid conditions: NR
Age range: 13 years to 16 years
Mean age (SD): 14.2 (1.2) years
Sex: 182 (66%) males
ADHD subtypes: 114 (41%) inattentive; 7 (2.5%) hyperactive-impulsive; 157 (56.5%) combined
Interventions

Five interventions (287 children/adolescents participated in one of five interventions):

  1. Mixed amphetamine salts (long acting), 10 mg/day, once daily, (n = 56)

  2. Mixed amphetamine salts (long acting), 20 mg/day, once daily (10 mg/day for week 1 with forced dose escalation to 20 mg/day for weeks 2 to 4), (n = 56)

  3. Mixed amphetamine salts (long acting), 30 mg/day, once daily (10 mg/day for week 1, with forced dose escalation to 20 mg/day for week 2, and 30 mg/day for weeks 3 to 4), (n = 58)

  4. Mixed amphetamine salts (long-acting), 40 mg/day, once daily (10 mg/day for week 1, with forced dose escalation to 20 mg/day for week 2, 30 mg/day for week 3, and 40 mg/day for week 4), (n = 63)

  5. Placebo (n = 54)

Duration: 28 days (4 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Clinical impression, assessed with Clinical Global Impression - Severity and Clinical Global Impression - Improvement scales

  3. Retention: proportion of participants who completed the trial

  4. Number of participants who dropped out due to any adverse event

  5. Adverse events

Other outcomes:

  1. Vital signs

  2. Body weight

Notes

ClinicalTrials.gov Identifier: NCT00507065

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Clinical characteristics only provided on the study's ITT population (n = 278)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (10%), and reasons provided. Only 3% of children/adolescents excluded from analysis due to no post-baseline primary efficacy assessment
Selective reporting (reporting bias)Low riskData provided on all outcomes listed in the registered protocol. Study appears to be free of selective reporting
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of participants and personnel not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Swanson 1998a

Methods

Single-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States

Number of study sites: 1
Statistical methods: unclear

Participants Sample size: 33 children/adolescents with an ADHD diagnosis according to DSM-IV criteria
Dropouts: 3
Psychiatric comorbid conditions: NR
Age range: 7 years to 14 years
Mean age (SD): 10.58 (1.81) years
Sex: 26 (79%) males
ADHD subtypes: NR
Interventions

Six interventions (all 33 children/adolescents participated in each of the six interventions):

  1. Mixed amphetamine salts (short acting), 5 mg/day, once daily, (n = 33)

  2. Mixed amphetamine salts (short acting), 10 mg/day, once daily, (n = 33)

  3. Mixed amphetamine salts (short acting), 15 mg/day, once daily, (n = 33)

  4. Mixed amphetamine salts (short acting), 20 mg/day, once daily, (n = 33)

  5. Methylphenidate (dose determined by physician), (n = 33)

  6. Placebo (n = 33)

Duration: 49 days (6 x 7-day treatment periods defined by the six medication conditions above, plus an extra seven-day period to provide an opportunity to make-up any missed weeks)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with the attention subscale (teacher ratings)* of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

  2. Academic performance, assessed with Permanent Product Measure of Performance*

  3. Retention: proportion of randomized participants who completed the trial

Other outcomes:

  1. Conduct problems, assessed with the deportment subscale of the Swanson, Kotkin, Agler, M-Flynn and Pelham (SKAMP) scale

Notes

ClinicalTrials identifier: not available

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry
*Unpublished data on outcomes sought on three separate occasions but not obtained

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
High riskLow attrition (8%), but reasons for dropout not provided, and only 88% of children/adolescents contributed to primary analysis
Selective reporting (reporting bias)Unclear riskStudy protocol not available and the possibility of reporting bias could not be assessed
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Wigal 2009a

  1. a

    ADHD: attention deficit hyperactivity disorder.
    DSM-III: Diagnostic and Statistical Manual of Mental Disorders, Third Edition.
    DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised.
    DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.
    DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision.
    ITT: intention-to-treat.
    NR: not reported.

MethodsMulti-center, randomized, double-blind, placebo-controlled, cross-over trial
Country: United States
Number of study sites: 7
Statistical methods: modified ITT (children/adolescents who received at least one dose of study medication, with at least one post-randomization measurement of the primary efficacy variable - last observation carried forward)
Participants Sample size: 117* children/adolescents with an ADHD diagnosis according to DSM-IV-TR criteria
Dropouts: 6
Psychiatric comorbid disorders: NR
Age range: 6 years to 12 years
Mean age (SD): 10.1 (1.5) years
Sex: 98 (76%) males
ADHD subtypes: NR
Interventions

Two interventions (all 117 children/adolescents participated in both interventions):

  1. Lisdexamphetamine (long acting), either 30 mg/day, 50 mg/day or 70 mg/day (determined by dose optimisation period), (n = 117)

  2. Placebo (n = 117)

Duration: 14 days (2 x 7-day treatment periods)

Outcomes

Relevant outcomes:

  1. ADHD core symptom severity, assessed with ADHD Rating Scale, Fourth Version (clinician ratings)

  2. Academic performance, assessed with Permanent Product Measure of Performance

  3. Clinical impression, assessed with Clinical Global Impression - Severity and Clinical Global Impressions - Improvement scales

  4. Retention: number of participants who completed the study

  5. Number of participants who experienced at least one adverse event

  6. Number of participants who dropped out due to an adverse event

  7. Adverse events

Notes

ClinicalTrials.gov Identifier: NCT00500149

Authors' affiliation: university and pharmaceutical industry
Study funding: pharmaceutical industry

*Clinical characteristics provided on 129 children/adolescents first enrolled into an open-label dose-optimisation phase. Of these, 117 children/adolescents randomized to the double-blind phase

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (9%), and reasons provided; 97% of randomized children/adolescents included in primary analysis. Four individuals not included due to no post-baseline efficacy measure
Selective reporting (reporting bias)Unclear riskData provided on all outcomes listed in the registered protocol. However, also reported on additional outcomes not listed in protocol
Other biasLow riskStudy appears to be free of other biases
Blinding of participants and personnel (performance bias)
All outcomes
Low riskIntervention and placebo described as identical
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskBlinding of outcome assessment not described

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    ADHD: attention deficit hyperactivity disorder.

Akhondzadeh 2003No placebo comparison assessed
Alexandris 1968ADHD diagnosis not confirmed using formal diagnostic criteria
Arnold 2011No direct amphetamine - placebo comparison
Biederman 2006Not a randomized controlled trial
Biederman 2008Not a randomized controlled trial
Boellner 2010Not a randomized controlled trial
Brown 2010Not a randomized controlled trial
Denhoff 1971ADHD diagnosis not confirmed using formal diagnostic criteria
Donner 2007Not a randomized controlled trial
Efron 1997No placebo comparison assessed
Findling 2009Not a randomized controlled trial
Greenhill 2003No placebo comparison assessed
Kamien 1998Study design was a series of multiple, cross-over, randomized controlled trials; our review included only single, cross-over, randomized controlled trials
Lopez 2008Not a randomized controlled trial
McGough 2005Not a randomized controlled trial
Najib 2009Not a randomized controlled trial
Nikles 2006Study design was a series of multiple, cross-over, randomized controlled trials; our review included only single, cross-over, randomized controlled trials
Quintana 2007Not a randomized controlled trial
Scheffer 2005Included children/adolescents who had comorbid bipolar disorder and were treated with mood stabilizers (divalproex sodium)
Sleator 1974Not a randomized controlled trial
Spencer 2005Not a randomized controlled trial
Spencer 2006bADHD diagnosis not confirmed using formal diagnostic criteria
Turgay 2010Not a randomized controlled trial
Wigal 2009bNot a randomized controlled trial
Wigal 2010aNot a randomized controlled trial
Wigal 2010bStudy participants were adults with ADHD

Characteristics of studies awaiting assessment [ordered by study ID]

Glos 1973

MethodsDouble-blind, controlled trial*
Participants Sample size: 20 hyperactive children**
Mean age: 9.4 years
InterventionsAmphetamine and placebo
Outcomes 
Notes*Information on whether or not the trial was randomized is necessary for inclusion into this review
**Information on whether participants were diagnosed with ADHD and according to formal diagnostic criteria is necessary for inclusion into this review. Since we were unable to contact the author due to lack of contact information, we are unable to classify this study as either included or excluded

Itil 1974

  1. a

    ADHD: attention deficit hyperactivity disorder.

MethodsDouble-blind, three-way study design
ParticipantsChildren with hyperactivity
InterventionsThioridazine, dextroamphetamine and placebo
OutcomesGlobal behavior evaluation
Notes

Only abstract available. Detailed outcome data not in abstract. Unsure:

  1. If treatments were randomized

  2. If participants had a formal diagnosis of ADHD

  3. Of the ages of the participants included

Author has been contacted three times but no response received as yet

Characteristics of ongoing studies [ordered by study ID]

Fanton 2009

Trial name or titleEffectiveness of an extended-release stimulant medication in treating preschool children with attention deficit hyperactivity disorder
MethodsSix-week, placebo-controlled, cross-over trial
ParticipantsChildren aged 3 years to 6 years with ADHD
InterventionsMixed amphetamine salts (long acting) and placebo
Outcomes

Primary

  1. Composite parent and teacher Conners' Rating Scale score

  2. Tolerance of extended-release mixed amphetamine salts

Secondary

  1. Clinical Global Impression - Improvement Scale score

Starting dateJune 2008
Contact informationDr. John Fanton, Baystate Medical Center
Notes Clinicaltrials.gov identifier: NCT00712699. States that recruitment period ended in August 2010. However, no results have been published as yet. Currently, only abstract available

NCT01711021

  1. a

    ADHD: attention deficit hyperactivity disorder.

Trial name or titleA randomized, double-blind, placebo-controlled, cross-over, laboratory, classroom study to evaluate the safety and efficacy of d-amphetamine transdermal drug delivery system (d-ATS) compared to placebo in children and adolescents with ADHD
MethodsTwo-week, double-blind, randomized cross-over trial
ParticipantsChildren and adolescents aged 6 years to 17 years with ADHD
InterventionsD-Amphetamine Transdermal System and placebo patch
Outcomes

Primary

  1. Change in ADHD symptoms using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale

Starting dateOctober 2012
Contact informationDr. James Waxmonsky (affiliation not stated)
Notes ClinicalTrials.gov identifier: NCT01711021. States that recruitment period ended in March 2013. However, no results have been published as yet. No abstract available

Ancillary