Chelation for autism spectrum disorder (ASD)

  • Review
  • Intervention

Authors


Abstract

Background

It has been suggested that the severity of autism spectrum disorder (ASD) symptoms is positively correlated with the level of circulating or stored toxic metals, and that excretion of these heavy metals, brought about by the use of pharmaceutical chelating agents, results in improved symptoms.

Objectives

To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms.

Search methods

We searched the following databases on 6 November 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and 15 other databases, including three trials registers. In addition we checked references lists and contacted experts.

Selection criteria

All randomised controlled trials of pharmaceutical chelating agents compared with placebo in individuals with ASD.

Data collection and analysis

Two review authors independently selected studies, assessed them for risk of bias and extracted relevant data. We did not conduct a meta-analysis, as only one study was included.

Main results

We excluded nine studies because they were non-randomised trials or were withdrawn before enrolment. We included one study, which was conducted in two phases. During the first phase of the study, 77 children with ASD were randomly assigned to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral dimercaptosuccinic acid (DMSA). Forty-nine children who were found to be high excreters of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times. The second phase thus assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who received a three-day course of oral DMSA. Overall, no evidence suggests that multiple rounds of oral DMSA had an effect on ASD symptoms.

Authors' conclusions

This review included data from only one study, which had methodological limitations. As such, no clinical trial evidence was found to suggest that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as hypocalcaemia, renal impairment and reported death, the risks of using chelation for ASD currently outweigh proven benefits. Before further trials are conducted, evidence that supports a causal link between heavy metals and autism and methods that ensure the safety of participants are needed.

Résumé scientifique

La chélation dans le traitement des troubles du spectre autistique (TSA)

Contexte

Il a été suggéré que la gravité des symptômes de troubles du spectre autistique (TSA) serait en corrélation positive avec le niveau de métaux toxiques en circulation ou stockés, et que l'excrétion de ces métaux lourds, induite par l'utilisation d'agents chélateurs pharmaceutiques, entraînerait l'amélioration des symptômes.

Objectifs

Évaluer les bénéfices et les effets indésirables des agents chélateurs pharmaceutiques (désignés sous le terme « chélation » dans cette revue) dans le traitement des symptômes de troubles du spectre autistique (TSA).

Stratégie de recherche documentaire

Nous avons effectué des recherches dans les bases de données suivantes le 6 novembre 2014 : CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature) et 15 autres bases de données, y compris trois registres d'essais. En outre, nous avons examiné des références bibliographiques et contacté des experts.

Critères de sélection

Tous les essais contrôlés randomisés comparant des agents chélateurs pharmaceutiques par rapport à un placebo chez les patients atteints de TSA.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les études, évalué leur risque de biais et extrait les données pertinentes. Nous n'avons pas réalisé de méta-analyse, car une seule étude a finalement été incluse.

Résultats principaux

Neuf études ont été exclues car il s'agissait d'essais non randomisés ou les études avaient été retirées avant le recrutement. Nous avons inclus dans la revue une étude, qui avait été réalisée en deux phases. Au cours de la première phase de l'étude, 77 enfants atteints de TSA ont été répartis de manière aléatoire pour recevoir pendant sept jours une lotion de glutathion ou une lotion placebo, suivis de trois jours d'acide dimercaptosuccinique (DMSA) par voie orale. Quarante-neuf enfants identifiés comme ayant excrété des métaux lourds à taux élevés pendant la première phase ont ensuite poursuivi dans la seconde phase, recevant pendant trois jours de la DMSA par voie orale ou un placebo, suivis de 11 jours d'arrêt, le cycle étant répété jusqu'à six fois. La seconde phase a donc évalué l'efficacité de multiples doses de DMSA en prise orale par rapport à un placebo chez des enfants excrétant des métaux lourds à taux élevés et ayant reçu un traitement sur trois jours par la DMSA en prise orale. Dans l'ensemble, aucune preuve ne suggère que plusieurs séries de DMSA en prise orale aient eu un effet sur les symptômes de TSA.

Conclusions des auteurs

Cette revue a inclus des données provenant d'une seule étude qui présentait des limitations méthodologiques. Par conséquent, aucune donnée probante issue d'essai clinique n'a été relevée suggéraient que la chélation pharmaceutique serait une intervention efficace dans les TSA. Compte tenu des rapports antérieurs d'événements indésirables graves, dont l'hypocalcémie, l'insuffisance rénale et les décès rapportés, les risques de l'utilisation de la chélation chez les patients atteints de TSA l'emportent actuellement sur les bénéfices avérés. Avant la réalisation d'essais supplémentaires, il est nécessaire d'obtenir des données corroborant un lien de causalité entre les métaux lourds et l'autisme et de mettre au point des méthodes garantissant la sécurité des participants.

Resumen

Quelación para el trastorno del espectro autista (TEA)

Antecedentes

Se ha indicado que la gravedad de los síntomas del trastorno del espectro autista (TEA) se correlaciona positivamente con el nivel de metales tóxicos circulantes o almacenados y que la excreción de estos metales pesados, lograda a través de la administración de agentes quelantes farmacológicos, da lugar a mejoría de los síntomas.

Objetivos

Evaluar los posibles efectos beneficiosos y adversos de los agentes quelantes farmacológicos (denominado tratamiento de quelación durante toda esta revisión) para los síntomas del trastorno del espectro autista (TEA).

Métodos de búsqueda

Se buscó en las siguientes bases de datos el 6 de noviembre de 2014: CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) y en otras 15 bases de datos, incluyendo tres registros de ensayos. Además, se verificaron las listas de referencias y se contactó con expertos.

Criterios de selección

Todos los ensayos controlados aleatorios de agentes quelantes farmacológicos comparados con placebo en pacientes con TEA.

Obtención y análisis de los datos

Dos autores de la revisión, de forma independiente, seleccionaron los estudios, evaluaron el riesgo de sesgo y extrajeron los datos relevantes. No se realizó un metanálisis porque solamente se incluyó un estudio.

Resultados principales

Se excluyeron nueve estudios porque fueron ensayos no aleatorios o se retiraron antes del reclutamiento. Se incluyó un estudio, que se realizó en dos fases. Durante la primera fase del estudio, se asignaron al azar 77 niños con TEA a recibir siete días de loción de glutatión o loción placebo, seguido de tres días de ácido dimercaptosuccínico (DMSA) oral. Cuarenta y nueve niños que se encontró que excretaron grandes cantidades de metales pesados durante la fase uno continuaron hacia la fase dos para recibir tres días de DMSA oral o placebo seguido de 11 días sin tratamiento, y el ciclo se repitió hasta seis veces. Por lo tanto, la segunda fase evaluó la efectividad de dosis múltiples de DMSA oral en comparación con placebo en los niños que excretaron grandes cantidades de metales pesados y que recibieron un ciclo de tres días de DMSA oral. En general, no hubo pruebas que indicaran que múltiples ciclos de DMSA oral tuvieran efecto sobre los síntomas del TEA.

Conclusiones de los autores

Esta revisión incluyó datos de un solo estudio, que tenía limitaciones metodológicas. Como tal, no se encontraron pruebas de ensayos clínicos que indicaran que la quelación farmacológica es una intervención eficaz para el TEA. Debido a los informes previos de eventos adversos graves como la hipocalcemia, el deterioro renal y la muerte informada, los riesgos de utilizar la quelación para el TEA actualmente superan los efectos beneficiosos comprobados. Antes de realizar ensayos adicionales se necesitan pruebas que apoyen una conexión causal entre los metales pesados y el autismo y métodos que aseguren la seguridad de los pacientes.

アブストラクト

自閉症スペクトラム障害(ASD)に対するキレーション療法

背景

自閉症スペクトラム障害(ASD)の症状の重症度は、血中または貯蔵有毒金属と正の相関関係にあることが示唆されており、医療用キレート剤を用いてこれらの重金属を排泄することで症状が改善する。

目的

自閉症スペクトラム障害(ASD)の症状に対する医療用キレート剤(本レビューではキレーション療法と呼ぶ)の有益性および有害作用を評価すること。

検索戦略

2014年11月6日にCENTRAL、Ovid MEDLINE、Ovid MEDLINE In-Process、Embase、PsycINFO、Cumulative Index to Nursing and Allied Health Literature(CINAHL)および試験レジストリ3件を含む15件のデータベースを検索した。さらに、参考文献一覧を確認し、専門家に問合せを行った。

選択基準

ASD患者を対象に医療用キレート剤をプラセボと比較したすべてのランダム化比較試験。

データ収集と分析

2名のレビュー著者がそれぞれ試験を選択し、バイアスのリスクを評価し、関連データを抽出した。1件の試験のみを組み入れたため、メタアナリシスは実施しなかった。

主な結果

9件の試験は、非ランダム化試験であるか、または組み入れ前に試験を中止したため、対象から除いた。2期構成の試験を1件組み入れた。試験の第1期ではASDの小児77名を、グルタチオンローションまたはプラセボローションの7日間投与にランダムに割り付けた後、ジメルカプトコハク酸(DMSA)を3日間経口投与した。第1期に重金属の排泄量が多かった49名の小児は引き続き第2期に移行し、DMSAまたはプラセボを3日間経口投与した後、11日間の休薬期間を設け、これを最大6サイクル繰り返した。したがって第2期では、重金属の排泄量が多く、DMSAを3日間経口投与した小児を対象に複数の用量レベルでDMSAを経口投与し、有効性をプラセボと比較評価した。総じて、DMSAを複数サイクル経口投与した場合、ASDの症状に有効であることを示唆するエビデンスは得られなかった。

著者の結論

本レビューでは、方法論に限界が認められる1試験のみのデータが対象であった。このため、医療用キレート剤の使用がASDに対して有効な介入であることを示唆する臨床試験のエビデンスは得られなかった。過去に低カルシウム血症、腎不全、死亡などの重篤な有害事象の報告があるため、現時点では立証された有益性よりASDにキレート剤を使用するリスクの方が大きい。今後さらに試験を実施するには、重金属と自閉症の因果関係を裏付けるエビデンスおよび参加者の安全が保証された方法が必要である。

Plain language summary

Chelation for autism spectrum disorder (ASD)

Background

Autism spectrum disorders (ASD) are types of disorders characterised by difficulties in social interaction and communication, and restricted and repetitive behaviours. It has been suggested that increased levels of toxic metals result in more severe symptoms of ASD, and that excretion of these heavy metals brought about by use of pharmaceutical chelating agents (chemicals that are injected into the blood stream to bind to and remove toxic heavy metals from the body) may lead to improvement of symptoms.

Review question

The purpose of this review was to assess the evidence for the effects of pharmaceutical chelating agents for symptoms of ASD.

Study characteristics

We searched multiple databases to find studies that examined pharmaceutical chelating agents as treatment for ASD symptoms. We found only one randomised controlled trial that evaluated oral dimercaptosuccinic acid (DMSA) for ASD, but this trial did not use ideal methods for answering our question. The evidence is current to November 2014.

The trial that we found was conducted in two phases. During the first phase, 77 children with ASD were assigned randomly to receive seven days of glutathione lotion or placebo lotion, followed by three days of oral DMSA. Forty-nine children who excreted high levels of heavy metals during phase one continued on to phase two to receive three days of oral DMSA or placebo followed by 11 days off, with the cycle repeated up to six times.

Key results

Results from the included study show that multiple rounds of oral DMSA did not have an effect on any of the ASD symptoms measured in children found to be high excreters who had already received three doses of a pharmaceutical chelating agent. Currently no clinical trial evidence suggests that pharmaceutical chelation is an effective intervention for ASD. Given prior reports of serious adverse events, such as changes to calcium levels in blood, kidney impairment and reported death, risks of using pharmaceutical chelating agents for ASD currently outweigh proven benefits.

Quality of the evidence

The quality of the evidence is poor, with only one study, which had methodological shortcomings, included in this review. These factors, when combined, preclude confidence in the findings. However, before further trials are conducted, more evidence is needed to show that heavy metals cause or worsen the severity of autism, and the safety of pharmaceutical chelating agents for participants must be established.

Laički sažetak

Kelacija za poremećaje autističnog spektra (PAS)

Dosadašnje spoznaje

Poremećaji autističnog spektra (ASD) su vrsta poremećaja obilježena poteškoćama s društvenim interakcijama i komunikacijom kao i ograničenim i ponavljanim ponašanjima. Pretpostavlja se da povišena razina toksičnih metala u organizmu dovodi do težih simptoma poremećaja iz autističnog spektra (PAS), te da bi uklanjanje teških metala pomoću lijekova koji djeluju kao kelirajuća sredstva moglo dovesti do poboljšanja (kelati su kemikalije koje se ubrizgaju u krvotok te na sebe vežu metale i na taj način se kelacijskom terapijom iz organizma uklanjaju metali).

Istraživačko pitanje

Cilj ovog Cochrane sustavnog pregleda je procijeniti dokaze o učincima kelacijske terapije na simptome poremećaja autističnog spektra.

Obilježja uključenih istraživanja

Pregledano je više baza podataka kako bi se pronašle studije koje su ispitale korištenje kelacijskih lijekova u terapiji simptoma PAS. Pronađen je samo jedan randomizirani kontrolirani pokus u kojem je istražena primjena dimerkaptosukcinilne kiseline (DMSA) (uzete na usta) kod PAS, ali metode korištene u pokusu nisu idealno odgovarale ovom istraživačkom pitanju. Dokazi se temelje na literaturi objavljenoj do studenog 2014.

Pokus koji je pronađen proveden je u dvije faze. U prvoj je fazi, 77 djece s PAS nasumično raspoređeno u dvije skupine od kojih jedna uzimala losion s glutationom, a druga placebo, nakon čega su ispitanici tri dana uzimali DMSA. Djeca koja su tijekom prve faze izlučila visoku razinu teških metala (49 djece), nastavila su s drugom fazom pokusa u kojoj su ispitanici na usta uzimali DMSA ili placebo, nakon čega je slijedilo 11 dana bez terapije. Ovakvi terapijski ciklusi su ponavljani do šest puta.

Ključni rezultati

Rezultati iz uključene studije pokazuju da višestruko davanje DMSA na usta nije imalo učinka ni na jedan od praćenih simptoma PAS, kod djece za koje je ustanovljeno da izlučuju velike količine teških metala i koja su već primila tri doze kelirajućeg lijeka. Trenutno ne postoji niti jedan klinički pokus koji bi pokazao da je farmaceutska kelacija učinkovita intervencija za PAS. S obzirom da postoje ranija izvješća o ozbiljnim neželjenim događajima, kao što su promjene u nivou kalcija, smanjena funkcija bubrega te smrt, rizik od korištenja kelacijske terapije za PAS trenutno premašuje dokazanu korist od te terapije.

Kvaliteta dokaza

Kvaliteta dokaza je loša, jer je u pregled uključena samo jedna studija koja je imala metodološke nedostatke. Kada se uzmu u obzir svi ti čimbenici, zaključci istraživanja se ne mogu smatrati pouzdanima. Međutim, prije nego se provedu novi pokusi, potrebni su dodatni dokazi da teški metali uzrokuju ili pogoršavaju težinu autizma, te je potrebno ustanoviti koliko je uzimanje kelacijske terapije za ispitanike sigurno.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Viljemka Bučević Popović
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

Résumé simplifié

La chélation dans le traitement des troubles du spectre autistique (TSA)

Contexte

Il a été suggéré qu'une augmentation des niveaux de métaux toxiques aggraverait les symptômes de troubles du spectre autistique (TSA), et que l'excrétion de ces métaux lourds induite par l'utilisation d'agents chélateurs pharmaceutiques pourrait conduire à une amélioration des symptômes.

Problématique de la revue

L'objectif de cette revue systématique était d'évaluer les éléments de preuve concernant les effets des agents chélateurs pharmaceutiques dans les symptômes de TSA.

Caractéristiques de l'étude

Nous avons interrogé plusieurs bases de données à la recherche d'études examinant des agents chélateurs pharmaceutiques à titre de traitement des symptômes de TSA. Nous n'avons trouvé qu'un seul essai contrôlé randomisé qui évaluait l'acide dimercaptosuccinique (DMSA) en prise orale dans les TSA, mais cet essai n'avait pas eu recours aux méthodes idéales permettant de répondre à notre question. Les données sont à jour en novembre 2014.

L'essai identifié a été mené en deux phases. Au cours de la première phase, 77 enfants atteints de TSA étaient assignés de façon aléatoire à l'application d'une lotion au glutathion ou d'une lotion placebo pendant sept jours, suivis par trois jours de DMSA par voie orale. Quarante-neuf enfants ayant excrété des métaux lourds à taux élevés pendant la première phase ont ensuite poursuivi dans la seconde phase, recevant pendant trois jours de la DMSA par voie orale ou un placebo, suivis de 11 jours d'arrêt, le cycle étant répété jusqu'à six fois.

Principaux résultats

Les résultats de l'étude incluse montrent que plusieurs séries de DMSA en prise orale n'ont eu d'effet sur aucun des symptômes de TSA mesurés chez les enfants ayant excrété des niveaux élevés de métaux et qui avaient déjà reçu trois doses d'un agent chélateur pharmaceutique. À l'heure actuelle, aucune preuve issue d'essais cliniques ne suggère que la chélation pharmaceutique soit une intervention efficace dans le traitement des TSA. Compte tenu des rapports antérieurs d'événements indésirables graves, tels que des changements dans les taux de calcium sanguins, des troubles du rein et des décès rapportés, les risques de l'utilisation d'agents chélateurs pharmaceutiques dans le traitement des TSA l'emportent actuellement sur les bénéfices avérés.

Qualité des preuves

La qualité des preuves est médiocre, car cette revue n'inclut qu'une seule étude comportant des lacunes méthodologiques. La combinaison de ces facteurs rend impossible d'accorder notre confiance à ces résultats. Cependant, avant de réaliser d'autres essais, davantage de preuves sont nécessaires pour démontrer que les métaux lourds provoquent de l'autisme ou l'aggravent, et l'innocuité des agents chélateurs pharmaceutiques pour les participants doit être établie.

Notes de traduction

Traduction réalisée par Cochrane France.

Streszczenie prostym językiem

Chelatacja w leczeniu zaburzeń ze spektrum autyzmu (ASD)

Wprowadzenie

Zaburzenia ze spektrum autyzmu (ASD) charakteryzują się trudnościami w kontaktach międzyludzkich i komunikacji oraz ograniczonymi i powtarzalnymi wzorcami zachowań. Sugeruje się, że zwiększone stężenia toksycznych metali skutkuje występowaniem bardziej nasilonych objawów ASD, a poprawę w tym zakresie można uzyskać, usuwając metale ciężkie z organizmu przy zastosowaniu farmaceutycznych środków chelatujących (związków chemicznych, które wprowadza się do krwi w celu związania i usunięcia toksycznych metali ciężkich z organizmu).

Pytanie badawcze

Celem niniejszego przeglądu jest ocena danych naukowych dotyczących wpływu stosowania farmaceutycznych środków chelatujących na nasilenie objawów ASD.

Charakterystyka badań

Przeszukaliśmy wiele baz danych, aby odnaleźć badania dotyczące skuteczności farmaceutycznych środków chelatujących w leczeniu objawów ASD. Odnaleźliśmy tylko jedno badanie z randomizacją, w którym oceniano doustne podawanie kwasu dimerkaptobursztynowego (DMSA) u chorych z ASD, ale w badaniu tym nie użyto idealnych metod, aby móc odpowiedzieć na pytanie badawcze przeglądu. Dane są aktualne do listopada 2014 r.

Badanie to przeprowadzono w dwóch etapach. Podczas pierwszej fazy, 77 dzieci z ASD przypisano losowo do grupy, w której otrzymywały przez 7 dni płyn glutationowy albo placebo, a następnie przez 3 dni DMSA doustnie. W grupie 49 dzieci, u których stwierdzono dużą ilość wydalanych metali ciężkich podczas pierwszej fazy badania, kontynuowano badanie w drugim etapie - podawano im przez 3 dni DMSA doustnie albo placebo, a następnie 11 dni przerwy, cykl powtarzano sześć razy.

Główne wyniki

Wyniki włączonego badania wskazują, że wielokrotne doustne podawanie DMSA nie wpływało na żaden z ocenianych objawów ASD u dzieci, które wydalały duże ilości metali ciężkich i które otrzymały już trzy dawki farmaceutycznego środka chelatującego. Obecnie nie ma badań klinicznych potwierdzających, że chelatacja farmaceutyczna jest skuteczną interwencją u chorych z ASD. Biorąc pod uwagę wcześniejsze doniesienia o poważnych działaniach niepożądanych (związanych ze stosowaniem środków chelatujących - przyp. tłum.), takich jak: zmiany stężenia wapnia we krwi, zaburzenia pracy nerek czy zgon, ryzyko stosowania farmaceutycznych środków chelatujących u chorych z ASD obecnie przewyższa dowiedzione korzyści.

Jakość danych naukowych

Jakość danych naukowych była niska, a jedyne właczone do przeglądu badanie miało niedociągnięcia metodologiczne. Taka sytuacja zmniejsza wiarygodność wyników. Zanim jednak przeprowadzi się dalsze badania, należy uzyskać więcej danych naukowych dotyczących tego, w jaki sposób metale ciężkie powodują autyzm lub wpływają na ciężkość jego przebiegu oraz zbadać bezpieczeństwo stosowania farmaceutycznych środków chelatujących.

Uwagi do tłumaczenia

Tłumaczenie: Dawid Storman Redakcja: Karolina Moćko, Małgorzata Kołcz

Resumen en términos sencillos

Quelación para el trastorno del espectro autista (TEA)

Antecedentes

Se ha indicado que el aumento de los niveles de metales tóxicos da lugar a síntomas más graves del trastorno del espectro autista (TEA), y que la excreción de estos metales pesados lograda a través de la administración de agentes quelantes farmacológicos puede dar lugar a la mejoría de los síntomas.

Pregunta de la revisión

El objetivo de esta revisión fue evaluar las pruebas de los efectos de los agentes quelantes farmacológicos en los síntomas del TEA.

Características de los estudios

Se buscó en múltiples bases de datos para encontrar estudios que examinaran los agentes quelantes farmacológicos como tratamiento para los síntomas del TEA. Solamente se encontró un ensayo controlado aleatorio que evaluó el ácido dimercaptosuccínico (DMSA) oral para el TEA, pero este ensayo no utilizó métodos ideales para responder la pregunta. Las pruebas están actualizadas hasta noviembre 2014.

El ensayo que se encontró se realizó en dos fases. Durante la primera fase, 77 niños con TEA se asignaron al azar a recibir siete días de loción de glutatión o loción placebo, seguido de tres días de DMSA oral. Cuarenta y nueve niños que excretaron niveles altos de metales pesados durante la fase uno continuaron hacia la fase dos para recibir tres días de DMSA oral o placebo, seguido de 11 días sin tratamiento, y el ciclo se repitió hasta seis veces.

Resultados clave

Los resultados del estudio incluido indican que los ciclos múltiples de DMSA oral no tuvieron efecto sobre ninguno de los síntomas del TEA medidos en los niños que se encontró que excretaron grandes cantidades de metales pesados y que ya habían recibido tres dosis de un agente quelante farmacológico. Actualmente no hay pruebas de ensayos clínicos que indiquen que la quelación farmacológica es una intervención eficaz para el TEA. Debido a informes de eventos adversos graves como cambios en los niveles de calcio en sangre, deterioro renal y muerte informada, los riesgos de utilizar agentes quelantes farmacológicos para el TEA actualmente superan los efectos beneficiosos comprobados.

Calidad de la evidencia

La calidad de las pruebas es baja; en esta revisión solamente se incluyó un estudio con deficiencias metodológicas. Estos factores, cuando se combinan, impiden la confianza en los resultados. Sin embargo, antes de realizar ensayos adicionales se necesitan más pruebas para mostrar que los metales pesados causan o empeoran la gravedad del autismo, y se debe establecer la seguridad de los agentes quelantes farmacológicos para los pacientes.

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.

Резюме на простом языке

Хелатирование при расстройствах аутистического спектра (РАС)

Актуальность

Расстройства аутистического спектра (РАС) – типы расстройств, характеризующиеся ограниченным и повторяющимся поведением, а также трудностями в социальном взаимодействии и коммуникации. Было предположено, что повышение уровня токсичных металлов в организме приводит к появлению более серьезных симптомов РАС и выведение этих тяжелых металлов с помощью фармацевтических хелатирующих агентов (химических веществ, которые вводят в кровь, чтобы связать и удалить токсичные тяжелые металлы из организма) может привести к уменьшению симптомов.

Вопрос обзора

Цель этого обзора заключалась в оценке доказательств влияния фармацевтических хелатирующих агентов на симптомы РАС.

Характеристика исследований

Мы изучили множество баз данных, чтобы найти исследования, в которых рассматривали использование хелатирующих агентов для лечения симптомов РАС. Мы нашли только одно рандомизированное контролируемое испытание, в котором оценивали влияние димеркаптосукциновой кислоты (DMSA) на симптомы РАС, но, к сожалению, в этом испытании не были использованы надлежащие методы для ответа на наш вопрос. Доказательства актуальны на ноябрь 2014 года.

Испытание, которое мы обнаружили, было проведено в два этапа. Во время первого этапа 77 детей с РАС в случайном порядке были распределены в группы для получения семидневного лечения глютатионом или плацебо, с последующим пероральным (внутрь) приёмом DMSA в течение трех дней. 49 детей, у которых выявили высокий уровень содержания тяжелых металлов во время первого этапа исследования, продолжили лечение и во время второго этапа в течение трех дней принимали димеркаптосукциновую кислоту или плацебо с последующим периодом отсутствия лечения в течение 11 дней, с циклом, повторяющимся до шести раз.

Основные результаты

Результаты исследования показали, что многократные циклы перорального применения DMSA не оказали влияния на симптомы РАС у детей с высокими показателями содержания тяжелых металлов, которые уже получили три дозы фармацевтического хелатирующего агента. В настоящее время нет доказательств из клинических испытаний, позволяющих предположить, что фармацевтические хелатирующие агенты являются эффективным вмешательством при РАС. Учитывая предыдущие данные о серьезных неблагоприятных событиях (изменение уровня кальция в крови, повреждение почек, сообщения о смерти), риски от использования фармацевтических хелатирующих агентов при РАС в настоящее время выше, чем доказанная польза.

Качество доказательств

Качество доказательств плохое, поскольку в этот обзор было включено только одно исследование, имеющее методологические недостатки. Эти факторы, в совокупности, мешают уверенности в результатах. Однако прежде, чем будут проведены дальнейшие испытания, необходимо больше доказательств, чтобы показать, что тяжелые металлы вызывают или ухудшают тяжесть аутизма, а также необходимо установить безопасность фармацевтических хелатирующих соединений для участников исследований.

Заметки по переводу

Перевод: Гумерова Эльвина Эльмеровна. Редактирование: Закиев Вадим Дмитриевич, Юдина Екатерина Викторовна. 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: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

平易な要約

自閉症スペクトラム障害(ASD)に対するキレーション療法

背景

自閉症スペクトラム障害(ASD)は、社会的交流およびコミュニケーションの障害ならびに限定的な反復行動が特徴の障害である。有毒金属濃度の増加がASDの症状を悪化させることが示唆されており、医療用キレート剤(血流に注射され、有毒な重金属と結合し体内から除去する ための化学物質)によるこれらの重金属の排泄が症状改善につながる可能性がある。

レビューの論点

本レビューの目的は、ASDの症状に対する医療用キレート剤の効果に関するエビデンスを評価することであった。

試験の特性

ASD症状の治療に医療用キレート剤を検討した試験を同定するため、複数のデータベースを検索した。ASDに対してジメルカプトコハク酸(DMSA)の経口投与を評価した1件のランダム化比較試験のみが同定されたが、この試験では我々の疑問に答えられる理想的な方法を採用していなかった。エビデンスは、2014年11月現在のものである。

同定した試験は2期構成であった。第1期にASDの小児77名をグルタチオンローションまたはプラセボローションの7日間投与にランダムに割り付けた後、DMSAを3日間投与した。第1期で重金属の排泄濃度が高かった小児49名は引き続き第2期に移行し、DMSAまたはプラセボを3日間経口投与した後、11日の休薬期間を設け、これを最大6サイクル反復した。

主な結果

対象試験の結果は、医療用キレート剤を3回投与後に金属排泄量が多かった小児にDMSAを複数サイクル経口投与してもASDの症状に対する効果は認められないことを示している。現時点では医療用キレート剤がASDに有効な介入であることを示唆する臨床試験のエビデンスは得られていない。血中カルシウム濃度の変化、腎不全、死亡などの重篤な有害事象が過去に報告されているため、現時点では立証された有益性よりもASDに医療用キレート剤を使用するリスクの方が大きい。

エビデンスの質

本レビューに組み入れた試験は1件のみで、エビデンスの質は低く、方法論的に不備が認められた。これらの要因を総合すると、結果の信頼性は低い。しかし、今後さらに試験を実施するには、重金属が自閉症の原因となる、または重症度を悪化させることを示すより多くのエビデンスが必要であり、患者に対する医療用キレート剤の安全性を確立しなければならない。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2018.3.14]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。
 CD010766 Pub2

Background

Description of the condition

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), autism spectrum disorder (ASD) is defined as a set of pervasive neurodevelopmental conditions that are characterised by difficulties in social interaction and communication, and by the presence of restricted, repetitive behaviours (i.e. stereotypies) (APA 2013). Historically, Asperger’s disorder, autistic disorder, atypical autism and pervasive developmental disorder not otherwise specified (PDD NOS) were considered separate, diagnosable conditions that fall within the autism spectrum. However, the latest edition of the DSM (DSM-5) (APA 2013) has replaced these diagnostic labels with one umbrella term: autism spectrum disorder (ASD).

The severity of ASD varies considerably from person to person, and great variability in symptoms and manifestations has been reported. Individuals with ASD have difficulty showing social-emotional reciprocity (e.g. participating in reciprocal conversations, maintaining eye gaze), communicating verbally and non-verbally, forming and maintaining relationships and understanding the social behaviour of others (Shattuck 2007; APA 2013). Individuals with ASD also exhibit preoccupations and restricted, repetitive patterns of interest and behaviours, which may include strong adherence to routines and stereotyped speech and motor movements (Lecavalier 2006; APA 2013). Some may present with behavioural symptoms (e.g. irritability, aggression, anxiety, self injury, hyperactivity); these features do not determine the diagnosis, rather they are co-occurring symptoms. Specific causes of ASD are currently unknown. However, genetic factors and prenatal and perhaps postnatal environmental factors are believed to contribute to the onset of ASD, although the role of environmental triggers remains uncertain (Hallmayer 2011). 

Many interventions are available for ASD, and although some, such as early intensive intervention, are effective in improving communication, social interaction and behaviours, none are capable of producing complete remission of all symptoms. Pharmacological interventions are often prescribed for individuals with ASD, primarily to target specific associated symptoms or co-occurring features. Currently, however, no pharmacological interventions target the core symptoms of ASD. Individuals with ASD often use complementary and alternative medicine (CAM) too; approximately 75% of children with ASD use CAM (Hanson 2007). Examples of CAM used for ASD include exclusion diets, essential fatty acids, multi-vitamins, acupuncture, auditory integration training and chelation therapy. To date, no consistent evidence indicates that CAM is an effective intervention for the core features and associated behaviours of ASD (Nye 2005; Millward 2008; Cheuk 2011; James 2011; Sinha 2011; Geretsegger 2014).

Description of the intervention

Chelation therapy involves administering a chelating substance that binds to heavy metals, such as lead and mercury, which then is excreted in urine. Pharmaceutical chelating substances (referred to as chelation therapy throughout this review) are approved for treating patients with heavy metal poisoning. However, they have also been used for unapproved reasons, including treatment of patients with Alzheimer’s disease, coronary heart disease and ASD (Ernst 2000; Dans 2002; Sinha 2006; Hedge 2009). See the section below for theories about the link between autism and heavy metals. Types of pharmaceutical chelating substances used to reduce heavy metal poisoning are outlined in Table 1. Chelation therapy is administered for approved uses in a highly controlled environment, which is different from the process followed by practitioners administering chelation for unapproved uses, such as for ASD.

Table 1. Examples of chelating agents
  1. From Osterloh 1986; Vamnes 2000; Drugs.com 2012.

    FDA: Food and Drug Administration.
    Tmx: time until maximum concentration.
    t1/2: time until maximum concentration drops in half.

Name Target heavy metals Route of administration FDA-approved indications Pharmacokinetics Pharmacodynamics Common adverse effects
Dimercaptosuccinic acid (DMSA)Lead; arsenic; mercury poisoningOralLead poisoning in adults and children > 12 months

Tmax 1 to 2 hours;

elimination t1/2

2 hours to 2 days;

primarily excreted renally

Forms water-soluble chelates with heavy metals, which are excreted renallyRash; gastrointestinal upset
Edetate disodium (EDTA)CalciumIntravenous (IV)

Hypercalcaemia (emergency treatment);

digitalis poisoning; ventricular arrhythmia in adults

Elimination t1/2

1.4 to 3 hours

Forms soluble chelate with calcium, resulting in a rapid decrease in plasma calcium concentrationsFatigue; hypocalcaemia; thrombophlebitis
Sodium 2, 3 dimercaptopropanesulphonate (DMPS)

Arsenic; bismuth subcitrate;

mercury; Wilson’s disease (copper)

Intravenous (IV) and oralNot approved for use in the United States of AmericaElimination t1/2 1.8 hours

Forms water-soluble chelates with many heavy metals, which are excreted renally

High affinity for mercury

Rash;

nausea; dysgeusia

Edetate calcium disodiumLeadIntravenous (IV) and intramuscular (IM)

Acute and chronic lead poisoning;

lead encephalopathy in adults and children

Elimination t1/2

20 to 60 minutes (IV), 1.4 to 3 hours (IM)

An effective chelator of extracellular lead, resulting in increased urine excretionFatigue; nephrotoxicity

Patients with heavy metal poisoning, such as acute lead poisoning, require urgent hospitalisation and administration of chelating substances intravenously or by deep intramuscular injection for four hours. During treatment of patients with acute lead poisoning, blood and urine are monitored constantly, as significant shifts in the heavy metal can occur between the blood and the central nervous system with dire consequences. Moreover, because minerals and metal ions are essential elements that serve important functions in multiple biological processes, excessive removal can lead to deleterious results, for example, a child with ASD recently experienced fatal myocardial necrosis resulting from hypocalcaemia after receiving chelation therapy (Brown 2006).

Unapproved uses of chelation therapy, for example, when used as an intervention for ASD, may involve practitioners using various chelating substances and unlicensed routes of administration (such as through the rectum or the skin) to remove reported excess levels of mercury, other heavy metals or both (Semple 2011). Before treatment, individuals with ASD may undergo preliminary tests with the chelating substance to evoke a response, followed by timed urine collection to determine the levels of heavy metals in the body (Bradstreet 2003; Adams 2009). One of the more commonly used chelating substances, oral dimercaptosuccinic acid (DMSA; also called succimer), is given on a cyclical basis at doses of 10 mg/kg/d every eight hours for three days, followed by 11 days with no DMSA (Bradstreet 2003; Adams 2009). These two-weekly cycles are repeated up to six times, totalling approximately three months of treatment (Adams 2009).

Between 6% and 11% of families of children with ASD in various English-speaking countries, including the United States, Canada and Australia, have sought out and tried chelation therapy; most of these families perceived that chelation therapy improved symptoms (Green 2006; Goin-Kochel 2009; Christon 2010).

How the intervention might work

The theoretical basis for mercury or other heavy metals as a cause of ASD draws on a wide variety of hypotheses, none yet confirmed. One hypothesis is that mercury or other heavy metals are present in greater quantities in children with ASD, compared with their peers, as a result of intrauterine exposure to maternal stores or intake, increased intake from immunisations (thimerosal), oral ingestion (fish or medication), inhalation (airborne pollution), increased absorption, altered metabolism or decreased excretion (Bernard 2001; Goldman 2001; Holmes 2003; Levy 2003; Counter 2004; Kern 2007).

The excess of stored or circulating total body mercury or other heavy metals is thought to interfere with developmental processes implicated in ASD, and it has been suggested that symptoms of mercury poisoning and ASD share some characteristics (Bernard 2001). Mercury, through its ability to cross the blood-brain barrier and the placental barrier, can affect the nervous system and disrupt normal development of the foetus (Aschner 1990; Liu 2008). Prenatal mercury poisoning may result in neurological impairment, global developmental delay and intellectual disability, and postnatal exposure can result in memory loss, irritability, fatigue, intention tremor, skin discolouration and other organ involvement, including kidney dysfunction (e.g. nephrotic syndrome, tubular dysfunction, or both) (Bakir 1973; Amin-Zaki 1974; Grandjean 1997; Goldman 2001; Counter 2004).

Research has produced contradictory findings with regard to levels of heavy metals in individuals with ASD. Three studies (Cohen 1976; Cohen 1982; Adams 2013) (N = 34, N = 93 and N = 99, respectively), all from the USA, found higher levels of lead in individuals with ASD compared with individuals without ASD, with overlapping levels observed between diagnostic groups. One of these studies also reported elevated levels of heavy metals (lead, thallium and tungsten) in urine (Adams 2013). Two studies - one from the USA (N = 452) and one from Jamaica (N = 130) - exploring differences in mercury level in blood reported no association between ASD and higher levels of mercury when analyses were adjusted for fish eating and other relevant factors (Hertz-Picciotto 2010; Rahbar 2013). Another smaller study from Italy (N = 37) found no difference in mercury, or in other heavy metals, between individuals with ASD and a group recruited from a neuropsychiatric service who did not have ASD (Albizzati 2012).

An alternative hypothesis is that mercury or other heavy metals can cause ASD through altered cellular functioning, which does not require increased body stores or circulating mercury or other heavy metals. In this context, it is thought that individuals with ASD have an impaired capacity to excrete heavy metals, and that the severity of autism symptoms is inversely correlated with excretion ability (Holmes 2003; Kern 2007). This hypothesis is currently being explored (Deth 2008; Zecavati 2009; Garrecht 2011).

Why it is important to do this review

Novel therapies are used frequently by individuals with ASD (Hanson 2007). Despite their increasing use, most types of CAM for ASD lack a robust evidence base (Nye 2005; Millward 2008; Cheuk 2011; James 2011; Sinha 2011; Geretsegger 2014). Chelation therapy is one CAM that continues to be used and promoted as efficacious, despite reports of harm, withdrawal of a trial before recruitment because of safety concerns (Mitka 2008) and discouragement by physicians (Golnik 2009). Adverse effects commonly reported with the use of pharmaceutical chelating agents are listed in Table 1. Deaths have also been reported (Brown 2006). A systematic review that examines potential beneficial and harmful effects of chelation for symptoms of ASD is urgently needed. Results from this systematic review will help families with ASD make well-informed decisions about the use of chelation therapy and will assist relevant services and guide other organisations in making decisions about best practice.

Objectives

To assess the potential benefits and adverse effects of pharmaceutical chelating agents (referred to as chelation therapy throughout this review) for autism spectrum disorder (ASD) symptoms.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials.

Types of participants

Individuals of any age diagnosed with ASD using established diagnostic criteria (e.g. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)) or standardised diagnostic instruments (e.g. the Childhood Autism Rating Scale (CARS), the Autism Diagnostic Observation Scale (ADOS), the Autism Diagnostic Interview - Revised (ADI-R)) were eligible for inclusion in this review.

Types of interventions

Interventions were eligible for inclusion if they involved chelating substances of any type and dose, regardless of administration frequency or method, compared with placebo. Trials were also eligible for inclusion if the chelating substances were provided alone or as adjunctive treatment compared with placebo (e.g. chelation in combination with a behavioural intervention vs placebo in combination with a behavioural intervention).

Types of outcome measures

Primary outcomes
  1. Changes in the following core symptoms of ASD, using any measure (e.g. the Aberrant Behavior Checklist (ABC), CARS), as assessed separately.

    1. Social interaction.

    2. Communication.

    3. Stereotypy.

  2. Adverse events.

Secondary outcomes
  1. Changes in the following non-core behaviours, using any measure (e.g. ABC, CARS), as assessed separately.

    1. Irritability.

    2. Aggression.

    3. Hyperactivity.

    4. Insomnia.

    5. Self injury.

  2. Quality of life for individual or family.

  3. Heavy metal levels in blood or non-provoked urine. Provoked urine will be examined cautiously (as provocation testing elevates urine heavy metal levels).

Search methods for identification of studies

We first searched databases for this review in December 2013 and repeated the searches, beginning on 6 November 2014, to find new studies published in the intervening period.

Electronic searches

We searched the following databases with no language or date restrictions.

  1. Cochrane Central Register of Controlled Trials (CENTRAL) 2014, Issue 11, part of the Cochrane Library.

  2. Ovid MEDLINE, 1946 to October Week 5 2014.

  3. Ovid MEDLINE In-Process and Other Non-indexed Citations, 5 November 2014.

  4. Embase (Ovid), 1980 to Week 44.

  5. PsycINFO (Ovid), 1967 to November Week 1 2014.

  6. Science Citation Index (Web of Science), 1970 to 5 November 2014.

  7. Social Sciences Citation Index (Web of Science), 1970 to 5 November 2014.

  8. Conference Proceedings Citation Index – Science (Web of Science), 1990 to 5 November 2014.

  9. Conference Proceedings Citation Index – Social Science & Humanities (Web of Science), 1990 to 5 November 2014.

  10. Database of Abstracts of Reviews of Effects (DARE) 2014, Issue 4, part of the Cochrane Library.

  11. Cochrane Database of Systematic Reviews (CDSR) 2014, Issue 11, part of the Cochrane Library.

  12. Heatlh Technology Assessment Database 2014, Issue 4, part of the Cochrane Library.

  13. CINAHL Plus (Cumulative Index to Nursing and Allied Health Literature) (EBSCOhost), 1937 to current.

  14. Autism Data (www.autism.org.uk/autismdata).

  15. WorldCat (limited to theses and dissertations) (www.worldcat.org/)).

  16. metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com/mrct/search.html).

  17. ClinicalTrials.gov (clinicaltrials.gov/).

  18. International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).

  19. TOXNET (toxnet.nlm.nih.gov/).

  20. Latin American Caribbean Health Sciences Literature (LILACS) (search.bvsalud.org/portal/advanced/?lang=en).

  21. Scientific Electronic Library Online (SciELO) (scielo.br/cgi-bin/wxis.exe/iah/).

  22. Google Scholar (scholar.google.com/).

We reported the searches in detail in Appendix 1.

Searching other resources

We searched reference lists from the retrieved articles for studies not already identified, and we contacted known experts in the field to enquire about other sources of information. We also searched relevant websites, including Autism Speaks (www.autismspeaks.org/), Research Autism (http://researchautism.net/) and the US Department of Health and Human Services (www.hhs.gov/).

Data collection and analysis

Selection of studies

Two review authors (SJ and SS) independently screened the titles and abstracts of citations identified by the search. SJ and SS then obtained and reviewed the full text of studies that met, or seemed likely to meet, the inclusion criteria. In the event of uncertainties and differences of opinion, resolution was reached through discussions with the third and fourth review authors (NS and KW).

Data extraction and management

Two review authors (SJ and SS) independently extracted the following information from the included study using a data extraction form designed and piloted for this review.

  1. Study methods and setting, including study duration, design and location.

  2. Participant details, including age, gender, sample size and diagnosis.

  3. Intervention details.

  4. Outcomes.

No disagreements arose.

Assessment of risk of bias in included studies

Two review authors (SJ and SS) independently assessed risk of bias of the included study using the tool described in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011, section 8.5.a). For the included study, we judged the risk of bias to be low, high or unclear for each of the following domains.

  1. Sequence generation.

    1. Low risk: if a random component was used in the sequence generation process, such as coin-tossing, computer-generated random numbers or a table of random numbers.

    2. High risk: if a non-random component was used in the sequence generation process.

    3. Unclear risk: if the sequence generation process was not described.

  2. Allocation concealment.

    1. Low risk: if participants and trial investigators had no foreknowledge (i.e. before eligibility, decisions made and informed consent obtained) of intervention assignment through the use of, for example, central allocation or sequentially numbered envelopes that were opaque and sealed.

    2. High risk: if participants and trial investigators had foreknowledge of intervention assignment.

    3. Unclear risk: if the method of allocation concealment was not described.

  3. Blinding of participants and personnel.

    1. Low risk: if no blinding or incomplete blinding was reported but review authors judged the outcome as unlikely to have been influenced by lack of blinding, or if blinding of study participants and personnel was ensured and it is unlikely that blinding could have been broken.

    2. High risk: if no blinding or incomplete blinding was reported and the outcome was likely influenced by lack of blinding, or if blinding of study participants and personnel was attempted but it is likely that blinding could have been broken and the outcome influenced by lack of blinding.

    3. Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome.

  4. Blinding of outcome assessment.

    1. Low risk: if no blinding of outcome assessment was reported but review authors judged the outcome measurement as unlikely to have been influenced by lack of blinding, or if blinding of outcome assessment was ensured and it is unlikely that blinding could have been broken.

    2. High risk: if no blinding of outcome assessment was reported and the outcome measurement was likely influenced by lack of blinding, or if blinding of outcome assessment was reported but it is likely that blinding could have been broken and the outcome measurement influenced by lack of blinding.

    3. Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome.

  5. Incomplete outcome data.

    1. Low risk: if no missing data were reported or if appropriate methods were used to impute missing data, or if the reason for missing data is unlikely to be related to the true outcome.

    2. High risk: if missing data were reported and no appropriate methods were used to impute missing data, or if the reason for missing data is likely to be related to the true outcome.

    3. Unclear risk: if lack of information prohibits judgement of low or high risk of bias, or if the study did not address this outcome.

  6. Selective reporting.

    1. Low risk: if a study has a protocol and all prespecified outcomes were reported in the prespecified manner, or if a study has no protocol but all expected outcomes have been reported.

    2. High risk: if a study has a protocol and one or more prespecified outcomes were not reported or were reported in a manner that was not prespecified, or if a study has no protocol and all expected outcomes have not been reported.

    3. Unclear risk: if lack of information prohibits judgement of low or high risk of bias.

  7. Other bias.

    1. Low risk: if other sources of bias (e.g. contamination, recruitment bias) do not appear to exist.

    2. High risk: if other sources of bias exist.

    3. Unclear risk: if lack of information permits judgement of whether other sources of bias exist.

No differences of opinions arose.

Measures of treatment effect

We did not conduct a meta-analysis, given that only one study was included in this review. Analysis methods that we will use in updates of this review can be found in Table 2 and in our protocol (James 2013).

Table 2. Analysis methods planned in our protocol that will be used in updates of this review
Measures of treatment effectWe will analyse dichotomous outcomes by calculating the risk ratio (RR) and the corresponding 95% confidence interval (CI). For continuous data, we will calculate mean difference (MD) and corresponding 95% CI if studies used the same rating scales. As recommended by Higgins 2011, we will focus on final values unless change scores are used in some of the studies. We will combine in the same meta-analysis studies that reported final values with studies that reported only change scores, provided the studies used the same rating scale (Higgins 2011). A potential problem associated with including change scores is that the standard deviation of changes may not be reported in the original study (Higgins 2011). We will contact trial authors and will attempt to estimate the standard deviation of changes if not reported. We will calculate the standardised mean difference (SMD) with 95% CIs if studies used different scales to measure the same outcomes
Multiple outcomesIf studies provided multiple, interchangeable measures of the same construct at the same point in time, we will calculate the average SMD across outcomes and the average estimated variances (Higgins 2011)
Unit of analysis issuesWhen possible, we will obtain mean treatment differences and standard errors for cross-over trials, and will enter these into RevMan under the generic inverse variance outcome type (Higgins 2011). We will create a single pair-wise comparison for each identified multi-arm study by combining all relevant experimental groups into a single group, and by combining all relevant control groups into a single group (Higgins 2011)
Dealing with missing dataWe will attempt to contact trial investigators to request missing data. If missing data are provided by the trialists, we will conduct meta-analysis according to intention-to-treat principles using all data and keeping participants in the treatment group to which they were originally randomly assigned, regardless of the treatment that they actually received (Higgins 2011). If missing data are not provided, we will analyse only available data, and we will not impute missing data given that symptoms of autism spectrum disorder (ASD) vary greatly. We will document missing data and attrition in the ’Risk of bias’ table, and we will discuss how missing data may affect interpretation of the results
Assessment of heterogeneity

We will assess clinical heterogeneity by comparing the between-trials distribution of participant characteristics (e.g. children vs adults), trial characteristics (e.g. cross-over vs parallel design) and intervention characteristics (e.g. treatment type, dose). We will evaluate statistical heterogeneity using the I² statistic and the Chi² test of heterogeneity, with statistical significance set at P value < 0.10. We will consider I² values as follows.

  1. 0% to 29% might not be important

  2. 30% to 49% may represent moderate heterogeneity

  3. 50% to 74% may represent substantial heterogeneity

  4. 75% to 100% represents considerable heterogeneity (Higgins 2011)

Assessment of reporting biasesIf 10 or more studies are found, we will use funnel plots to investigate the relationship between intervention effect and study size. Asymmetry of a funnel plot may indicate, among other things, publication bias or poor methodological quality (Egger 1997). We will explore possible reasons for any asymmetry found
Data synthesisWe will synthesise results in a meta-analysis using a fixed-effect model when studies are similar enough with regard to the intervention, population and methods to assume that the same treatment effect is estimated. We will synthesise results in a meta-analysis using a random-effects model when statistical heterogeneity is found, or when studies differ enough with regard to the intervention, population and methods to assume that different yet related treatment effects are estimated, and when it is deemed to be clinically relevant (Higgins 2011)
Subgroup analysis and investigation of heterogeneity

We will conduct the following subgroup analyses

  1. Type of ASD (e.g. autistic disorder vs Asperger’s disorder)

  2. Participant age (e.g. adult vs child, preschool vs school-age)

  3. Treatment type (e.g. dimercaptosuccinic acid (DMSA) vs other agents)

  4. Treatment dosage (e.g. DMSA dose of 10 mg/kg body weight administered 3 times per day vs higher doses)

  5. Length of follow-up (e.g. ≤ 3 months vs > 3 months)

Sensitivity analysis

We will conduct sensitivity analyses to investigate the effect on overall results of excluding trials when

  1. Allocation concealment or sequence generation was inadequate (selection bias)

  2. Blinding was not done (performance bias)

  3. Outcome data were incomplete (attrition bias)

Dealing with missing data

We assessed and reported missing data and dropouts for the included study (see Characteristics of included studies). Based on our judgement that missing data and dropouts in the included study were unlikely related to the outcomes (and missing data appeared balanced across intervention groups, with similar reasons for missing data across groups), we did not contact the trial investigators for further information.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

Our search strategy identified 846 citations, of which 12 were deemed to be potentially eligible on the basis of title or abstract (see Figure 1). We obtained full-text copies of these 12 reports and inspected them. After all full-text copies had been reviewed, we included three reports of one study (Adams 2009) and excluded nine reports (Eppright 1996; Lonsdale 2002; Geier 2006a; Geier 2006b; Nataf 2006; Geier 2007; Patel 2007; Blaucok-Busch 2012; NCT00376194).

Figure 1.

Study flow diagram.

Included studies

The study included in this review was reported to be randomised and double-blind (Adams 2009). Although it fulfilled criteria for inclusion, the methods, which we have outlined here, are not appropriate to allow testing of the hypothesis of interest in this review. Instead, the included study was conducted in two phases: During the first phase, participants were randomly assigned to receive seven days of glutathione lotion (experimental group) or placebo lotion (control group) followed by three days of oral dimercaptosuccinic acid (DMSA) (for all children). This phase tested whether topical glutathione was absorbed and whether topical glutathione was effective for increasing the effectiveness of oral DMSA. During the second phase, a subset of participants - high heavy metal excreters - from phase one were randomly assigned to receive three days of oral DMSA (experimental group) or placebo (control group) followed by 11 days off, with this cycle repeated up to six times. This phase assessed the effectiveness of multiple doses of oral DMSA compared with placebo in children who were high excreters of heavy metals and who had received a three-day course of oral DMSA.

We discussed at length whether the study should be included, as all children entering phase two had already received a chelating agent. Ultimately, however, we believed that we would not be deviating from protocol by including the study, because the second phase of the study was a randomised placebo-controlled trial.

Participants

A total of 82 children, aged three to eight years, enrolled in the included study, of whom 77 completed the required initial blood collection (to assess baseline liver and kidney function, red blood cell (RBC) glutathione, and complete blood count (CBC)). Although the total number of children randomly assigned (and the number randomly assigned to each group) is not explicitly stated, it appears as though randomisation occurred after the initial blood collection (i.e. for the 77 children). All children (69 male and eight female; mean age 6.3 years) were Arizona residents who had been diagnosed with autism spectrum disorder (autism 95%, pervasive developmental disorder not otherwise specified (PDD NOS) 3%, Asperger's 3%) by a psychiatrist, a psychologist or a developmental paediatrician. Only 65 participants completed phase one, and 49 heavy metal excreting participants were included in phase two.

Interventions

For the first phase of the included study, children in the experimental group initially received glutathione lotion, which was administered once per day for seven days. Each daily dosage contained ˜ 180 mg of “reduced 1-glutathione in a lotion of isopropyl myristate, mineral oil, caprylic/capric triglyceride, and vitamin E acetate” (Adams 2009, p 5). Children in the control group received a placebo lotion that was identical in packaging and contained a similar formulation (with the exception of glutathione). After receiving the glutathione or placebo lotion for seven days, all children received one round of oral DMSA, administered in a 10 mg/kg dose, three times per day for three days. All children were given one round of oral DMSA for screening purposes to ensure that only high heavy metal excreters continued on to the second phase.

For the second phase of the included study, all children had received a three-day course of oral DMSA before randomisation. The experimental group received up to six more rounds of oral DMSA. Each round consisted of a 10 mg/kg dose, administered three times per day for three days, followed by 11 days of no DMSA. Children in the control group received up to six rounds of placebo (methyl cellulose), which was similar to DMSA in appearance and was packaged in identical bottles. Each round consisted of three days on placebo, followed by 11 days off.

Outcomes

Blood was collected to assess CBC and RBC glutathione. Blood was collected at the beginning of phase one, at the beginning of phase two, after the third round of oral DMSA/placebo in phase two and after the sixth round of oral DMSA/placebo in phase two. Urine was collected to assess excretion of toxic metals and essential minerals. Urine was collected at the beginning of phase one, after the first dose of oral DMSA in phase one, after the ninth dose in phase one and at the end of the second round in phase two. Severity of autism symptoms was assessed using the Pervasive Developmental Disorder Behavior Inventory (PDD-BI), the Autism Treatment Evaluation Checklist (ATEC), the Severity of Autism Scale (SAS) and the Autism Diagnostic Observation Schedule (ADOS). The ATEC was administered at the beginning of phase one and at the end of phase two. The PDD-BI, SAS and ADOS were administered at the beginning of phase two and at the end of phase two. Changes in autism symptoms were assessed at the end of phase two using the Parental Global Impressions (PGI) questionnaire.

As such, the included trial was able to answer only the following question.

Do repeated doses of oral DMSA decrease core features of ASD in children who have previously received a three-day course of oral DMSA and are known to be high excreters?

Only outcomes that were available at the beginning of phase one and at the completion of phase two, or were available at the beginning and end of phase two, could assist with answering this question.

See also the Characteristics of included studies table.

Excluded studies

We excluded nine studies - eight studies because they were non-randomised (Eppright 1996; Lonsdale 2002; Geier 2006a; Geier 2006b; Nataf 2006; Geier 2007; Patel 2007; Blaucok-Busch 2012) and one study because it was withdrawn before enrolment (NCT00376194). See the Characteristics of excluded studies table for more information.

Risk of bias in included studies

An overview of risk of bias is illustrated in Figure 2. See below for more detailed information on risk of bias.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Participants in the included study (Adams 2009) were reported to be randomly assigned, but no details were available on sequence generation or allocation concealment. As such, we rated risk of bias in these domains as unclear.

Blinding

Participants, caregivers and investigators in the included study were reported to be blinded to the treatment condition; however, it is unclear whether all lab technicians and ADOS evaluators were blinded. It is also uncertain whether parents knew that all children would receive at least one round of oral DMSA during the first phase, and that only high excreters would continue on to the second phase. Knowledge that all children received at least one round of chelation or awareness of who was in the high excreter group would likely yield high risk of bias in the second phase. Therefore, we rated risk of performance bias and risk of detection bias as unclear.

Incomplete outcome data

In phase two, two children (one in each treatment group) withdrew because of perceived lack of benefit, and four children dropped out as the result of adverse effects (two children in the control group for worsening of behaviours, and two children in the experimental group - one for sleep problems and one for worsening of behaviours and skills). Additionally in phase two, one child dropped out as a result of elevated liver enzymes (reported to be due to psychiatric medication) and one child withdrew because of the death of a family member. Trialists did not report if these two children were included in the experimental group or in the control group. We rated risk of attrition bias as low, given that the reason for missing data was deemed unlikely to be related to the true outcome.

Selective reporting

The level of urinary excretion of toxic metals was not reported for participants in the control group during or after phase two, and no results were reported with regard to potential differences between the experimental group and the control group in excretion levels of toxic metals during or after phase two. As such, we rated risk of reporting bias as high.

Other potential sources of bias

Given that both the experimental group and the control group received an initial round of oral DMSA in phase one, carry-over effects may have occurred. Trialists acknowledged that the effect of the phase one oral DMSA carried over into phase two: "...the single screening round of DMSA [in phase one] had an unexpectedly dramatic effect on improving abnormal glutathione and platelet levels, and the effect lasted until the end of phase two, so that phase two was not a placebo-control-led investigation" (Adams 2009, p 3).

The included study also appears to have biases related to the validity of the statistical conclusions. It is perplexing that the trialists would use an unconventional and atheoretical regression approach without the critical step of including a cross-validation sample, and given the relatively small sample size and the apparently large set of variables (the number of tested variables was not revealed). Furthermore, use of adjusted R² instead of R² appears to be a less-than-satisfactory approach to the handling of sample uniqueness, which likely artificially inflated model effect size.

Finally, trialists downplayed the variability of heavy metal levels and the severity of ASD, stating, “Since the toxic metal excretions exhibit considerable correlation amongst themselves, one should refrain from reading too much into the relationships between specific metals and severity of autism" (p 6). This attempt to persuade readers to disregard differences across heavy metals, however, is undermined by the presented regression analyses, which show inconsistencies in the direction of the effects that metal excretion has on various change indices. For example, the unstandardised b-weight signs suggest that increased excretion of As9 is associated with differential change patterns in PDD-BI, ADOS and ATEC scores (although it is unclear how trialists created the change scores). Similar inconsistencies are evident upon examination of Pb9 with PDD-BI and SAS. Incidentally, trialists did not report the b-weight for SAS regressed on T19, although they reported on its statistical significance.

Given these factors, we rated other bias as high.

Effects of interventions

For the current version of this review, meta-analysis was not possible, as only one study was included. In the included study, 77 children completed the required blood collection at the beginning of the trial. Of these, 65 children completed phase one, 49 high heavy metal excreters continued to phase two and 41 completed phase two.

Primary outcome: social interaction

ATEC sociability subscale

For children in the experimental group who completed phase two of the trial, the mean (standard deviation (SD)) score on the ATEC sociability subscale decreased from 16.6 (8.5) at the beginning of phase one, to 12.1 (6.5) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the ATEC sociability subscale decreased from 14.9 (6.8) at the beginning of phase one, to 11.2 (6.5) at the end of phase two. The between-group difference was reported to be non-significant.

PDD-BI social pragmatic problems subscale

For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD-BI social pragmatic problems subscale decreased from 16.9 (9.2) at the beginning of phase two, to 14.5 (9.2) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD-BI social pragmatic problems subscale decreased from 13.9 (7.5) at the beginning of phase two, to 9.9 (7.5) at the end of phase two. The significance of the between-group difference was not reported.

PDD-BI social approach behaviours subscale

For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD-BI social approach behaviours subscale increased from 63.8 (20.6) at the beginning of phase two, to 70.8 (23.6) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD-BI social approach behaviours subscale increased from 68.2 (25.4) at the beginning of phase two, to 72.6 (20.2) at the end of phase two. The significance of the between-group difference was not reported.

ADOS sociability subscale

For children in the experimental group who completed phase two of the trial, the mean score on the ADOS sociability subscale decreased from 9.3 at the beginning of phase two, to 8.3 at the end of phase two. For children in the control group who completed phase two of the trial, the mean score on the ADOS sociability subscale decreased from 8.1 at the beginning of phase two, to 7.9 at the end of phase two. The between-group difference was reported to be non-significant.

Primary outcome: communication

ATEC speech/language communication subscale

For children in the experimental group who completed phase two of the trial, the mean (SD) score on the ATEC speech/language communication subscale decreased from 13.4 (7.7) at the beginning of phase one, to 10.6 (7.0) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the ATEC speech/language communication subscale decreased from 12.0 (8.4) at the beginning of phase one, to 10.5 (8.9) at the end of phase two. The between-group difference was reported to be non-significant.

ADOS communication subscale

For children in the experimental group who completed phase two of the trial, the mean score on the ADOS communication subscale decreased from 7.8 at the beginning of phase two, to 7.1 at the end of phase two. For children in the control group who completed phase two of the trial, the mean score on the ADOS communication subscale decreased from 6.7 at the beginning of phase two, to 5.9 at the end of phase two. The between-group difference was reported to be non-significant.

Primary outcome: stereotypy

PDD-BI ritualism/resistance to change subscale

For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD-BI ritualism/resistance to change subscale decreased from 13.9 (10.5) at the beginning of phase two, to 10.0 (7.8) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD-BI ritualism/resistance to change subscale decreased from 15.0 (8.5) at the beginning of phase two, to 11.5 (8.2) at the end of phase two. The significance of the between-group difference was not reported.

ADOS stereotyped behaviours and restricted interests subscale

For children in the experimental group who completed phase two of the trial, the mean score on the ADOS stereotyped behaviours and restricted interests subscale decreased from 3.9 at the beginning of phase two, to 3.5 at the end of phase two. For children in the control group who completed phase two of the trial, the mean score on the ADOS stereotyped behaviours and restricted interests subscale was 3.5 at the beginning of phase two and 3.5 at the end of phase two. The between-group difference was reported to be non-significant.

Primary outcome: adverse events

During phase one, one child experienced an adverse event (lethargy and diminished appetite), causing the child to withdraw from the study (treatment group not specified). During phase two, four children dropped out after experiencing adverse events, including sleep problems (n = 1; experimental group), worsening of behaviours and skills (n = 1; experimental group), increased self stimulatory behaviour (n = 1; control group) and regression of behaviour (n = 1; control group). Two additional children in the experimental group withdrew from the study as the result of low excretion of metals and worsening of symptoms, including sleep problems (n = 1) and sleep problems plus increased tantrums (n = 1).

Secondary outcome: aggression

PDD-BI aggressiveness subscale

For children in the experimental group who completed phase two of the trial, the mean (SD) score on the PDD-BI aggressiveness subscale decreased from 13.4 (9.8) at the beginning of phase two, to 9.8 (6.7) at the end of phase two. For children in the control group who completed phase two of the trial, the mean (SD) score on the PDD-BI aggressiveness subscale decreased from 11.4 (8.1) at the beginning of phase two, to 8.4 (7.2) at the end of phase two. The significance of the between-group difference was not reported.

Secondary outcome: heavy metal levels

No results were reported with regard to potential differences between the experimental group and the control group in excretion levels of toxic metals during or after phase two.

Discussion

Summary of main results

Few studies have examined the effectiveness of chelation for ASD, and no true randomised placebo-controlled trials were identified for this review. This review included only one study, which compared children who received one round of oral dimercaptosuccinic acid (DMSA) versus children who received multiple rounds of oral DMSA, and found no significant differences with regard to autism spectrum disorder (ASD) symptoms.

Overall completeness and applicability of evidence

One trial, which had methodological issues and a relatively small sample size, is insufficient to provide robust evidence on chelation for ASD. The included study compared one round of oral DMSA versus multiple rounds of oral DMSA. Although this study sheds light on the impact of using different quantities of DMSA rounds, it does not address completely the question of whether DMSA is effective in the first place. Moreover, external validity is limited, given that the included study involved children from only one state (Arizona) in the United States of America, and given that only one chelating agent (DMSA) was assessed. Finally, most of the secondary outcomes presented in the protocol of this review (James 2013) were not investigated in the included study.

Quality of the evidence

The quality of the evidence is poor. Only one trial was included in this review, and we judged it to have high or uncertain risk of bias and methodological problems that limited the interpretation of outcomes presented. Of particular concern are the trialists’ questionable data analytical approach and interpretation of findings. It is interesting that trialists found differential directions of heavy metal excretion and change in ASD indices, yet they attempted to convince the reader not to read too much into these differences. Given the deleterious effects of chelation, misinterpretation and misuse of the study of Adams et al to justify the use of chelation for ASD is unethical and potentially places children unnecessarily in harm’s way. Moreover, if these findings are in fact valid, they actually undermine the heavy metal toxicity theory and the rationale for chelation treatment, suggesting that it should not be used in the first place.

The inclusion of only one study, which had a relatively small sample size and a high likelihood of carry-over effects and other biases, precludes confidence in the findings. Further well-designed studies from multiple locations and using larger numbers of participants are needed to better ascertain the effects of chelation for ASD.

Potential biases in the review process

We attempted to minimise bias by having two review authors independently screen studies for inclusion, extract and manage data and assess risk of bias in included studies. Although we attempted to minimise publication bias by using a comprehensive search strategy and by searching multiple sources, we may have failed to identify relevant trials.

Agreements and disagreements with other studies or reviews

A systematic review evaluating the effectiveness of chelation for ASD (Davis 2013) was published after the title for this review was registered. The Davis 2013 review did not limit inclusion criteria to randomised controlled trials; whereas we included one trial, Davis 2013 included five trials. Nonetheless, all of the trials included in the Davis 2013 review were reported to have substantial methodological limitations, and the results of our review support the findings reported by Davis 2013; we agree that no available evidence supports the use of chelation to treat individuals with ASD symptoms.

Authors' conclusions

Implications for practice

This review found no high-quality evidence to suggest that chelation is an effective treatment for improving ASD symptoms. Cochrane reviews typically avoid making recommendations for practice; however, given that harm resulting from the use of chelation therapy has been reported, and that no proven benefits have been found, it seems reasonable to conclude that use of chelation for the treatment of individuals with ASD symptoms should not be recommended.

Implications for research

At the present time, the theory that heavy metals may cause autism or might worsen symptoms has not been established. This underlying theory needs to be tested and confirmed before future trials that assess chelation for ASD symptoms are implemented. However, the numerous side effects of chelation therapy, including hypocalcaemia, renal impairment, musculoskeletal and gastrointestinal symptoms and even death (Morgan 2002; Brown 2006; Kosnett 2010), have led to the withdrawal of at least one planned study. It is therefore unlikely that institutional review boards will approve future trials for chelation for ASD unless safety in children can be assured through the current approach to research.

If evidence emerges that supports a causal link between heavy metals and autism, further trials with methods suitable to ensure safety and to demonstrate that chelation removes heavy metals, improves social communication and reduces restricted repetitive behaviours seen in autism will be needed.

Acknowledgements

We would like to thank Laura MacDonald, Geraldine Macdonald and Joanne Wilson for feedback and guidance, and Margaret Anderson for assistance with the development of our search strategy. We would also like to thank Dr. Yashwant Sinha for pharmacological advice about topical glutathione and dimercaptosuccinic acid (DMSA). Finally, we are extremely grateful for invaluable feedback provided by external reviewers and statisticians.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Search strategy

Cochrane Central Register of Controlled Trials (CENTRAL), part of theCochrane Library

2013 (Issue 11), searched 5 December 2013 (2 records)
2014 (Issue 11), searched 6 November 2014. Limited to year=2013 to 2014 (no records)

ID Search
#1 [mh ^"child development disorders, pervasive"]
#2 [mh "Developmental Disabilities"]
#3 pervasive next development* next disorder*
#4 (pervasive near/3 child*)
#5 (PDD or PDDs or PDD next NOS or ASD or ASDs)
#6 autis*
#7 asperger*
#8 kanner*
#9 childhood next schizophreni*
#10 Rett*
#11 {or #1-#10}
#12 [mh "Chelation Therapy"]
#13 MeSH descriptor: [Chelating Agents] explode all trees
#14 [mh "Iron Chelating Agents"]
#15 [mh siderophores]
#16 [mh ferrozine] or [mh "pentetic acid"] or [mh deferoxamine] or [mh enterobactin] or [mh Fursultiamin]
#17 (Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide")
#18 complexon*
#19 (chelation or chelating or chelator*)
#20 (metal near/3 antagonist*)
#21 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown next (compound or ether)) or cyclodextrin or cyclophane or cuprizone)
#22 (dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb)
#23 (edetate or Edetic Acid or Egtazic Acid or "Fura-2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide)
#24 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin)
#25 {or #12-#24}
#26 #11 and #25

Ovid MEDLINE

1946 to November Week 3 2013, searched 5 December 2014 (130 records)
1946 to October Week 5 2014, searced 6 November 2014. Limited to ed=20131101-20141106 (6 records)

1 exp child development disorders, pervasive/
2 Developmental Disabilities/
3 pervasive development$ disorder$.tw.
4 (pervasive adj3 child$).tw.
5 (PDD or PDDs or PDD-NOS or ASD or ASDs).tw.
6 autis$.tw.
7 asperger$.tw.
8 kanner$.tw.
9 childhood schizophrenia.tw.
10 Rett$.tw.
11 or/1-10
12 Chelation Therapy/
13 Chelating Agents/
14 2,2'-dipyridyl/ or caseins/ or chitosan/ or citric acid/ or cuprizone/ or dimercaprol/ or dithizone/ or ditiocarb/ or edetic acid/ or egtazic acid/ or fura-2/ or humic substances/ or nitrilotriacetic acid/ or penicillamine/ or pentetic acid/ or phytochelatins/ or razoxane/ or succimer/ or technetium tc 99m pentetate/ or thenoyltrifluoroacetone/ or trientine/ or unithiol/
15 Iron Chelating Agents/
16 siderophores/
17 ferrozine/ or pentetic acid/ or deferoxamine/ or enterobactin/
18 Fursultiamin/ or (Fursultiamin$ or TTFD or thiamine tetrahydrofurfuryl disulfide).tw.
19 complexon$.tw.
20 (chelation or chelating or chelator$).tw.
21 (metal adj3 antagonist$).tw.
22 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).mp.
23 (dimercaprol or dimercapto succinic acid or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp.
24 (edetate or Edetic Acid or Egtazic Acid or Fura-2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp. (77430)
25 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp.
26 or/12-25
27 11 and 26
28 exp animals/ not humans.sh.
29 27 not 28
30 remove duplicates from 29

Ovid MEDLINE In-Process & other Non-indexed Citations

Database content last updated 4 December 2014. Searched 6 December 2013 (9 records)
Database content last updated 5 November 2014. Searched 6 November 2014 (12 records)

1 pervasive development$ disorder$.tw.
2 (pervasive adj3 child$).tw.
3 (PDD or PDDs or PDD-NOS or ASD or ASDs).tw.
4 autis$.tw.
5 asperger$.tw.
6 kanner$.tw.
7 childhood schizophrenia.tw.
8 Rett$.tw.
9 complexon$.tw.
10 (chelation or chelating or chelator$).tw.
11 (metal adj3 antagonist$).tw.
12 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).mp.
13 (dimercaprol or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp. )
14 (edetate or Edetic Acid or Egtazic Acid or Fura-2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp.
15 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp.
16 or/1-8
17 or/9-15
18 16 and 17

Embase (Ovid)

1980 to Week 48, searched 5 December 2013 (252 records)
1980 to Week 44, searched 6 November 2014. Limited to em=201349-201444 (35 records)

1 exp autism/
2 pervasive development$ disorder$.tw.
3 (PDD or PDDs or ASD or ASDs).tw.
4 autis$.tw.
5 asperger$.tw.
6 kanner$.tw.
7 childhood schizophreni$.tw.
8 Rett$.tw.
9 (pervasive adj3 child$).tw.
10 or/1-9
11 exp chelation/
12 chelation therapy/
13 exp chelating agent/
14 enterochelin/
15 (Fursultiamin$ or TTFD or thiamine tetrahydrofurfuryl disulfide).tw.
16 complexon$.tw.
17 (chelation or chelating or chelator$).tw.
18 (metal adj3 antagonist$).tw.
19 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).mp.
20 (dimercaprol or dimercaptosuccinic acid or dimercapto succinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).mp.
21 (edetate or Edetic Acid or Egtazic Acid or Fura-2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).mp.
22 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).mp. (21516)
23 or/11-22
24 10 and 23
25 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
26 human/ or normal human/ or human cell/
27 25 and 26
28 25 not 27
29 24 not 28

PsycINFO (Ovid)

1967 to November Week 4 2013, searched 5 December 2013 (143 records)
1967 to November Week 1 2014, searched 6 November 2014. Limited to up=20131125-20141103 (23 records)

1 exp pervasive developmental disorders/
2 Developmental disabilities/
3 pervasive development$ disorder$.tw.
4 (pervasive adj3 child$).tw.
5 autis$.tw.
6 asperger$.tw.
7 (ASD or ASDs or PDD or PDDs).tw.
8 Rett$.tw.
9 Kanner$.tw.
10 or/1-9
11 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or caloxetic acid or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or choline tetrathiomolybdate or citric acid or clathrin$ or (crown adj (compound or ether)) or cyclodextrin or cyclophane or cuprizone).af.
12 (dimercaprol or dimercapto succinic acid or dimercaptosuccinic acid or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb).af.
13 (edetate or Edetic Acid or Egtazic Acid or Fura-2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine$ or tropantiol or Unithiol or versetamide).af.
14 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin).af.
15 (chelation or chelating or chelator$).af.
16 (metal adj3 antagonist$).af.
17 complexon$.af.
18 alternative medicine/
19 or/11-18
20 10 and 19
21 remove duplicates from 20

Web of Science databases

Science Citation Index - expanded: 1970 to 4 December 2013, searched 5 December 2013 (18 records)
Science Citation Index - expanded: 1970 to 5 November 2014, searched 6 November 2014. Limited to year= 2013 to 2014 (2 records)
Social Sciences Citation Index: 1970 to 4 December 2013, searched 5 December 2013 (18 records)
Social Sciences Citation Index: 1970 to 5 November 2014, searched 6 November 2014. Limited to year= 2013 to 2014 (2 records)
Conference Proceedings Citation Index - Science and Conference Proceedings Citation Index - Social Science & Humanities, 1990 to 4 December 2013, searched 5 December 2013 (3 records)
Conference Proceedings Citation Index - Science and Conference Proceedings Citation Index - Social Science & Humanities, 1990 to 5 November 2014, searched 6 November 2014. Limited to year= 2013 to 2014 (no records)

#13 #4 AND #3
DocType=All document types; Language=All languages;
#12 #11 AND #3
DocType=All document types; Language=All languages;
#11 #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4
DocType=All document types; Language=All languages;
#10 Ts=(siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin)
DocType=All document types; Language=All languages;
#9 TS= (edetate or Edetic Acid or Egtazic Acid or "Fura-2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide)
DocType=All document types; Language=All languages;
#8 TS=(dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb)
DocType=All document types; Language=All languages;
#7 TS= ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown NEAR/1(compound or ether)) or cyclodextrin or cyclophane or cuprizone)
DocType=All document types; Language=All languages;
#6 TS =(metal near/3 antagonist*)
DocType=All document types; Language=All languages;
#5 TS= (complexon* or Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide")
DocType=All document types; Language=All languages;
#4 TS=(chelation or chelating or chelator*)
DocType=All document types; Language=All languages;
#3 #2 OR #1
DocType=All document types; Language=All languages;
#2 Ts=("childhood schizophren*")
DocType=All document types; Language=All languages;
#1 TS=(autis* or asperger* or ASD or ASDs or PDD or PDDs or Pdd-NOS or ("pervasiv* development* disorder*" ) or kanner* or Rett*)
DocType=All document types; Language=All languages;

CINAHL Plus (EBSCOhost)

1937 to current, searched 5 December 2013 (57 records)
1937 to current, searched 6 November 2014. Limited to EM>=2013120 (1 record)

# Query Limiters/Expanders Last Run Via Results Action
S20 S9 AND S19
S19 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18
S18 (siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin)
S17 (edetate or Edetic Acid or Egtazic Acid or Fura-2 or Humic Substances or Nitrilotriacetic Acid or Penicillamine or Pentetic Acid or phytic acid or Phytochelatins or Razoxane or salicylhydroxamic acid or
sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide)
S16 (dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb)
S15 ("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown N1 (compoundor ether)) or cyclodextrin or cyclophane or cuprizone)
S14 (chelation or chelating or chelator*)
S13 complexon*
S12 (MH "Chelating Agents+")
S11 (MH "Detoxification, Alternative Therapy")
S10 (MH "Chelation Therapy")
S9 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8
S8 Rett*
S7 childhood schizophren*
S6 kanner*
S5 (PDD or PDDs or PDD-NOS or ASD or ASDs)
S4 (pervasive N3 child*)
S3 pervasive development* disorder*
S2 autis* or asperger*
S1 (MH "Child Development Disorders, Pervasive+")

Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) databases (all part of theCochrane Library)

CDSR 2013, Issue 12, searched 5 December 2013 (no records)
CDSR 2014, Issue 11, searched 6 november 2014. Limited to 2013 to 2014 (no records)
DARE 2013, Issue 4 , searched 5 December 2013 (no records)
DARE 2014, Issue 4, searched 6 November 2014. Limited to 2013 to 2014 (no records)
HTA 2013, Issue 4, searched 5 December 2013 (no records)
HTA 2014, Issue 4, searched 6 November 2014. Limited to 2013 to 2014 (no records)

#1[mh ^"child development disorders, pervasive"]
#2[mh "Developmental Disabilities"]
#3(pervasive next development* next disorder*):ti,ab
#4(pervasive near/3 child*):ti,ab
#5(PDD or PDDs or PDD next NOS or ASD or ASDs):ti,ab
#6autis*:ti,ab
#7asperger*:ti,ab
#8kanner*:ti,ab
#9childhood next schizophreni*:ti,ab
#10Rett*:ti,ab
#11{or #1-#10}
#12[mh "Chelation Therapy"]
#13MeSH descriptor: [Chelating Agents] explode all trees
#14[mh "Iron Chelating Agents"]
#15[mh siderophores]
#16[mh ferrozine] or [mh "pentetic acid"] or [mh deferoxamine] or [mh enterobactin] or [mh Fursultiamin]
#17(Fursultiamin* or TTFD or "thiamine tetrahydrofurfuryl disulfide"):ti,ab
#18complexon*:ti,ab
#19(chelation or chelating or chelator*):ti,ab
#20(metal next/3 antagonist*):ti,ab
#21("2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin* or (crown next (compound or ether)) or cyclodextrin or cyclophane or cuprizone):ti,ab
#22(dimercaprol or "dimercapto succinic acid" or "dimercaptosuccinic acid" or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb):ti,ab
#23(edetate or Edetic Acid or Egtazic Acid or "Fura-2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide):ti,ab
#24(siderophores or ferrozine or pentetic acid or deferoxamine or enterobactin):ti,ab
#25{or #12-#24}
#26#11 and #25

LILACS

(search.bvsalud.org/portal/advanced/?lang=en)
Searched 9 December 2013 (no records)
Searched 7 November 2014. Limited to year=2013 to 2014 (7 records)

(tw:(autis* OR asperger* OR "pdd-nos" OR asd OR asds) OR mh:("Autistic Disorder" OR "Asperger Syndrome" OR "Child Development Disorders, Pervasive")) AND (mh:("Chelating Agents" OR "Chelation Therapy" OR "Iron Chelating Agents" OR "Siderophores") OR tw:(chelating OR chelate* OR chelator* OR complexon* or DMSA))

TOXNET

(toxnet.nlm.nih.gov/)
Searched 20 November 2014

Autism and chelation

Google Scholar

(scholar.google.com/)
Searched 20 November 2014

Autism and chelation

SciELO

(scielo.br/cgi-bin/wxis.exe/iah/)
Searched 9 December 2013 (no records)
Searched 7 November 2014 (no records)

Database : article
Search on : autism OR autistic OR asperger OR ASD OR pervasive [All indexes] and chelation OR chelating OR DMSA [All indexes]

Worldcat (limited to theses/dissertations)

(www.worldcat.org)
Searched 9 December 2013 (2 records)
Searched 7 November 2014. Limited to 2013 to 2014 (no records)

(kw:autis* OR kw:asperger* OR kw:ASD OR kw:ASDs) AND (kw:chelation OR kw:chelator OR kw:DMSA)

metaRegister of Controlled Trials (mRCT)

(www.controlled-trials.com/mrct/search.html)
Searched 10 December 2013 (9 records)
Searched 7 November 2014 (no new records)

Autis* AND (chelat* OR DMSA)

ClinicalTrials.gov (CT.gov)

clinicaltrials.gov

Seached 9 December 2013 ( 5 records)

Searched 7 November 2014 (1 record)

Advanced search: autism OR aspergers OR ASD OR pervasive | chelation OR chelating OR chelator OR DMSA

World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)

(www.who.int/ictrp/en/)
Searched 9 December 2013 (12 records)
Searched 7 November 2014. Limited to Date of registration, between: 01/12/2013 and 7/11/2014 (no new records)

Search 1

autism AND chleation

Search 2

Condition autis% or asperger% or PDD% or ASD% or pervasive AND Intervention "2,2'-Dipyridyl" or alcaligin or antipyrylazo or arsenazo or bixalomer or cabiotraxetan or calcobutrol or caldiamide or calixarene or calteridol or "caloxetic acid" or "carboxymethyl beta cyclodextrincaseins" or catenane or chitson or "choline tetrathiomolybdate" or "citric acid" or clathrin*

Search 3

Condition autis% or asperger% or PDD% or ASD% or pervasive AND Intervention dimercaprol or “dimercapto succinic acid” or “dimercaptosuccinic acid” or DMSA or deferasirox or deferiprone or deferitrin or deferoxamine or deferriferrithiocin or diglycine or dimercaprol or dimethyldithiocarbamate or dithizone or ditiocarb

Search 4

Condition autis% or asperger% or PDD% or ASD% or pervasive AND Intervention edetate or Edetic Acid or Egtazic Acid or "Fura-2" or "Humic Substances" or "Nitrilotriacetic Acid" or Penicillamine or "Pentetic Acid" or "phytic acid" or Phytochelatins or Razoxane or "salicylhydroxamic acid" or sugammadex or Succimer or "Technetium Tc 99m Pentetate " or Thenoyltrifluoroacetone or Trientine or triethylenetetramine* or tropantiol or Unithiol or versetamide

What's new

DateEventDescription
7 October 2016AmendedSlight amendments have been made to the 'Background' section of the Plain Language Summary, to clarify details of both intervention and condition.

Contributions of authors

Stephen James: wrote the protocol and the review, screened records, reviewed the included study, assessed risk of bias and managed production of the review.

Shawn W Stevenson: contributed to the write-up of the protocol and the review, screened records, reviewed the included study and assessed risk of bias.

Natalie Silove: contributed to the write-up of the protocol and the review and reviewed the included study.

Katrina Williams: contributed to the write-up of the protocol and the review, reviewed the included study and assessed risk of bias.

Declarations of interest

Stephen James is employed by Southwest Autism Research and Resource Center. His work is not related to chelation, and he receives no personal funds.

Shawn W Stevenson was employed by Autism Victoria at the time of this review. He was an unpaid Board Member of Support and Advocacy for Autism Spectrum Individuals and Families. Shawn is currently employed by the University of Melbourne and has received no personal funds.

Natalie Silove works at the Children's Hospital Westmead, which is enrolling up to eight participants in a phase two drug trial in adolescents with fragile X syndrome. It is not related to autism or to chelation. Natalie receives no personal funds.

Katrina Williams gave a talk about treatments for autism at a symposium organised by Janssen-Cilag Pty Ltd. Janssen-Cilag had no control over the contents of the talk, and the speaker's fee was paid to the University that employs her. She does not have an ongoing relationship with Janssen-Cilag. She is not involved in any funded work relevant to chelation therapy.

Sources of support

Internal sources

  • University of Melbourne, Australia.

    Shawn Stevenson received a salary through support of the Williams Collie Trust, University of Melbourne, for autism research during the time of this protocol. Katrina Williams received a salary through support of the APEX Australia Chair of Developmental Medicine, University of Melbourne. The University provided IT, office and library facilities during the time of this protocol.

  • NSW Health Service, Australia.

    Natalie Silove's salary is paid by NSW Health Service - The Sydney Children's Hospital Network

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adams 2009

  1. a

    ADOS: Autism Diagnostic Observation Schedule.
    ATEC: Autism Treatment Evaluation Checklist.
    CBC: complete blood count.
    DMSA: dimercaptosuccinic acid.
    PDD-BI: Pervasive Developmental Disorder Behavior Inventory.
    PGI: Parental Global Impressions.
    RBC: red blood cell.
    SAS: Severity of Autism Scale.

Methods

Randomised controlled trial. Phase 1 involved 7 days of glutathione lotion (experimental group) or placebo lotion (control group), followed by 3 days of oral DMSA. Phase 2 involved 3 days on oral DMSA (experimental group) or placebo (control group), followed by 11 days off, with the cycle repeated up to 6 times

Duration: 4 months

Participants

Setting: Arizona residents

Diagnosis of autism spectrum disorder made by a psychologist, a psychiatrist or a developmental paediatrician

Of the 82 children enrolled in the study, 77 (69 male, 8 female) completed the initial blood draw and 65 completed phase 1. 1 child was excluded as the result of elevated liver enzymes, 4 children dropped out after their physical examination, 11 children dropped out after the initial blood draw and an additional child did not submit urine for analysis after taking DMSA. 49 of the 65 children who completed phase 1 continued into phase 2 - 8 children did not meet phase 2 inclusion criteria (i.e. they did not have high urinary excretion of toxic metals), 1 child had exceedingly high levels of lead excretion (and this child was referred to a physician for potential acute lead exposure), 7 families discontinued for personal reasons and 1 family discontinued because of a mild adverse effect (lethargy, diminished appetite). Of the 49 children who began phase 2, 41 finished - 1 child dropped out because of elevated liver enzymes resulting from psychiatric medication, 1 child discontinued because of the death of a family member, 2 children dropped out because of perceived lack of benefit (1 child in the experimental group and 1 child in the control group) and 4 children discontinued as the result of adverse effects (2 children in the experimental group (sleep problems, worsening of behaviours and skills) and 2 children in the control group (worsening of behaviours))

Age range: 3 to 8 years (M 6.3 years for the 77 children who completed the initial blood draw)

Interventions

Experimental group: glutathione lotion, followed by 1 round of oral DMSA (phase 1), followed by up to 6 more rounds of oral DMSA (phase 2)

  1. Phase 1 - glutathione lotion: administered 1 ×/d for 7 days. Each daily dosage contained ˜ 180 mg of “reduced 1-glutathione in a lotion of isopropyl myristate, mineral oil, caprylic/capric triglyceride, and vitamin E acetate” (p 5)

  2. Phase 1 - 1 round of oral DMSA: 10 mg/kg dose, 3 ×/d, for 3 days

  3. Phase 2 - up to 6 more rounds of oral DMSA: Each round consisted of 10 mg/kg dose, 3 ×/d, for 3 days, followed by 11 days of no DMSA. Repeated up to 6 times

Control group: placebo lotion, followed by 1 round of oral DMSA (phase 1), followed by up to 6 rounds of placebo (phase 2)

  1. Phase 1 - placebo lotion: administered 1 ×/d for 7 days: “The placebo was identical in packaging and formulation except it did not contain glutathione” (p 5)

  2. Phase 1 - 1 round of oral DMSA: 10 mg/kg dose, 3 ×/d, for 3 days

  3. Phase 2 - up to 6 rounds of placebo: methyl cellulose "packed in identical pills and bottles as the DMSA. Since oral DMSA has a strong smell, each bottle included a small slotted container that contained oral DMSA, so that the medication smell was present in the container” (p 5). Each round consisted of 3 days on placebo, followed by 11 days off

Outcomes
  1. Complete blood count (CBC)

  2. Red blood cell (RBC) glutathione

  3. Urinary excretion of toxic metals and essential minerals

  4. Severity of autism symptoms (Pervasive Developmental Disorder Behavior Inventory (PDD-BI); Autism Treatment Evaluation Checklist (ATEC); Severity of Autism Scale (SAS); Autism Diagnostic Observation Schedule (ADOS))

  5. Changes in autism symptoms (Parental Global Impressions (PGI))

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAlthough each of the 3 reports stated randomised, no details were given
Allocation concealment (selection bias)Unclear riskNo details were given
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk ClinicalTrials.gov indicates that participants, caregivers and investigators were blinded, and efforts were made to make the placebo comparable with oral DMSA in appearance and smell: "It [the placebo] was packed in identical pills and bottles as the DMSA. Since DMSA has a strong smell, each bottle included a small slotted container that contained DMSA, so that the medication smell was present in the container" (p 5). However, it is uncertain whether parents knew that all children would receive at least 1 round of oral DMSA during the first phase, and that only high excreters would continue on to the second phase
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAlthough ClinicalTrials.gov indicates that caregivers (who assessed certain behavioural outcomes) were blind, no details were given about whether all lab technicians and ADOS evaluators were blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskThe reason for missing data is unlikely to be related to the true outcome
Selective reporting (reporting bias)High riskLevel of urinary excretion of toxic metals was reported for all combined participants after phase 1, and for participants in the experimental group after phase 2, but not for participants in the control group after phase 2
Other biasHigh riskGiven that both groups received an initial round of oral DMSA in phase 1, it is likely that a carry-over effect occurred

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Blaucok-Busch 2012Not a randomised controlled trial
Eppright 1996Not a randomised controlled trial
Geier 2006aNot a randomised controlled trial
Geier 2006bNot a randomised controlled trial
Geier 2007Not a randomised controlled trial
Lonsdale 2002Not a randomised controlled trial
Nataf 2006Not a randomised controlled trial
NCT00376194Study withdrawn before enrolment
Patel 2007Not a randomised controlled trial