Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents

Donna Gillies; John KH Sinn; Sagar S Lad; Matthew J Leach; Melissa J Ross

doi:10.1002/14651858.CD007986.pub2

. 2012 Jul 11;2012(7):CD007986. doi: 10.1002/14651858.CD007986.pub2

Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents

Donna Gillies ^1,^✉, John KH Sinn ², Sagar S Lad ³, Matthew J Leach ⁴, Melissa J Ross ⁵

PMCID: PMC6599878 PMID: 22786509

Abstract

Background

Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents, characterised by age‐inappropriate levels of inattention, hyperactivity and impulsivity, and is associated with long‐term social, academic and mental health problems. The stimulant medications methylphenidate and amphetamine are the most frequently used treatments for ADHD, but these are not always effective and can be associated with side effects. Clinical and biochemical evidence suggests that deficiencies of polyunsaturated fatty acids (PUFA) could be related to ADHD. Children and adolescents with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA and, in particular, lower levels of omega‐3 PUFA. These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD.

Objectives

To compare the efficacy of PUFA to other forms of treatment or placebo in treating the symptoms of ADHD in children and adolescents.

Search methods

We searched the following databases in August 2011: CENTRAL (The Cochrane Library 2011, Issue 2), MEDLINE (1948 to July Week 3, 2011), EMBASE (1980 to 2011 Week 29), PsycINFO (1806 to current), CINAHL (1937 to current), BIOSIS (1969 to 30 July 2011), Science Citation Index (1970 to 30 July 2011), Social Science Citation Index (1970 to 30 July 2011), Conference Proceedings Citation Index ‐ Science (1990 to 30 July 2011), Conference Proceedings Citation Index ‐ Social Science and Humanities (1990 to 30 July 2011), Cochrane Database of Systematic Reviews (2011, Issue 7), DARE (2011 Issue 2), Dissertation Abstracts (via Dissertation Express) and the metaRegister of Controlled Trials (mRCT). In addition, we searched the following repositories for theses on 2 August 2011: DART, NTLTD and TROVE. We also checked reference lists of relevant studies and reviews for additional references.

Selection criteria

Two review authors independently assessed the results of the database searches. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, by consultation with a third member of the review team.

Data collection and analysis

Two members of the review team independently extracted details of participants and setting, interventions, methodology and outcome data. If differences were identified, we resolved them by consensus or referral to a third member of the team. We made all reasonable attempts to contact the authors where further clarification or missing data were needed.

Main results

We included 13 trials with 1011 participants in the review. After screening 366 references, we considered 23 relevant and obtained the full text for consideration. We excluded five papers and included 18 papers describing the 13 trials.

Eight of the included trials had a parallel design: five compared an omega‐3 PUFA supplement to placebo; two compared a combined omega‐3 and omega‐6 supplement to placebo, and one compared an omega‐3 PUFA to a dietary supplement. Five of the included trials had a cross‐over design: two compared combined omega‐3/6 PUFA to placebo; two compared omega‐6 PUFA with placebo; one compared omega‐3 to omega‐6 PUFA, and one compared omega‐6 PUFA to dexamphetamine. Supplements were given for a period of between four and 16 weeks.

There was a significantly higher likelihood of improvement in the group receiving omega‐3/6 PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62). However, there were no statistically significant differences in parent‐rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) ‐0.17, 95% CI ‐0.38 to 0.03); inattention (six trials, 469 participants; SMD ‐0.04, 95% CI ‐0.29 to 0.21) or hyperactivity/impulsivity (five trials, 416 participants; SMD ‐0.04, 95% CI ‐0.25 to 0.16) when all participants receiving PUFA supplements were compared to those receiving placebo.

There were no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI ‐0.18 to 0.27); inattention (three trials, 260 participants; SMD 0.26, 95% CI ‐0.22 to 0.74) or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI ‐0.16 to 0.35).

There were also no differences between groups in behaviour, side effects or loss to follow‐up.

Overall, there were no other differences between groups for any other comparison.

Authors' conclusions

Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children and adolescents. The majority of data showed no benefit of PUFA supplementation, although there were some limited data that did show an improvement with combined omega‐3 and omega‐6 supplementation.

It is important that future research addresses current weaknesses in this area, which include small sample sizes, variability of selection criteria, variability of the type and dosage of supplementation, short follow‐up times and other methodological weaknesses.

Keywords: Adolescent; Child; Humans; Male; Dietary Supplements; Attention Deficit Disorder with Hyperactivity; Attention Deficit Disorder with Hyperactivity/drug therapy; Fatty Acids, Omega‐3; Fatty Acids, Omega‐3/administration & dosage; Fatty Acids, Omega‐6; Fatty Acids, Omega‐6/administration & dosage; Fatty Acids, Unsaturated; Fatty Acids, Unsaturated/administration & dosage

Polyunsaturated fatty acids (PUFA) supplements for attention deficit hyperactivity disorder (ADHD) in children and adolescents

Attention deficit hyperactivity disorder (ADHD) is a major problem in children and adolescents and can result in long‐term social, academic and mental health problems. Stimulant medications, such as methylphenidate and amphetamine, are the most frequently used treatments for ADHD but are not always effective and can be associated with side effects. There is evidence that ADHD could be related to deficiencies of polyunsaturated fatty acids (PUFA) and, in particular, omega‐3 PUFA; therefore, PUFA supplementation may improve ADHD symptoms and associated problems. The aim of this review was to evaluate whether PUFA supplements are an effective treatment for children and adolescents with ADHD. Although there were some limited data that did indicate there may be some improvement, overall there was little evidence that PUFA supplementation is beneficial. Further high‐quality research needs to be done.

Background

Description of the condition

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder characterised by age‐inappropriate levels of inattention, hyperactivity and impulsivity. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) (APA 1994) and the more recent text revision (DMS‐IV‐TR) (APA 2000), there are three categorical subtypes of ADHD: a predominantly inattentive subtype (ADHD‐Inattentive), a predominantly hyperactive‐impulsive subtype (ADHD‐Hyperactive‐Impulsive) and a combined inattentive and hyperactive‐impulsive subtype (ADHD‐Combined). The International Classification of Diseases (ICD‐10) definition of hyperkinetic disorders similarly includes developmentally inappropriate levels of inattention, hyperactivity and impulsivity (WHO 2010). However, the diagnosis for hyperkinetic disorders is more restrictive, which may explain why it is less prevalent than ADHD (Biederman 2005).

ADHD is a major public health problem (NIH 2000; Pelham 2007). The worldwide prevalence of ADHD is 5% (Polanczyk 2007) with 3% to 16% of children displaying symptoms of ADHD (Cantwell 1996; Faraone 2003). Boys are more commonly identified than girls (Cantwell 1996; Faraone 2003), with an approximate ratio of between two to nine boys to one girl, depending on the ADHD type (APA 2000) and whether prevalence is based on clinical or epidemiological populations (Cantwell 1996).

Children and adolescents with ADHD can have academic impairments, social dysfunction and poor self esteem (Cantwell 1996; Daley 2004; Furman 2005). ADHD is frequently comorbid with other mental health disorders, such as anxiety and depression (Cantwell 1996; Daley 2004), and is associated with a higher risk of negative effects such as substance abuse (Daley 2004). Between 50% to 75% of children with ADHD will continue to have symptoms into adulthood (Cantwell 1996; Daley 2004; Biederman 2005; Harpin 2005).

Aetiology

It is claimed that there are several factors that contribute to the onset and maintenance of ADHD symptoms, including: genetic factors (Goodman 1989; Gill 1997; Swanson 2000; Swanson 2007); neuroanatomical abnormalities (Raskin 1981; Barkley 1991; Biederman 2005); psychosocial factors (Morrell 2003; Biederman 2005); pregnancy and delivery complications (Zappitelli 2001; Biederman 2005) and environmental factors, such as prenatal cigarettes or alcohol (Linnet 2003; Langley 2005) and artificial food colouring (Schab 2004). However, the most significant factor associated with ADHD is heritability, which contributes approximately 75% to the aetiology of ADHD (Biederman 2005; Froehlich 2011).

There is good evidence that the neurotransmitter dopamine may be implicated in the pathogenesis of ADHD. Stimulant drugs that are used in the management of ADHD symptoms increase the availability of dopamine in the brain (Biederman 2005), and a number of genes related to the dopamine pathway have been implicated in ADHD, in particular, the dopamine D4 and D5 receptor, dopamine‐β‐hydroxylase and dopamine transporter genes (Faraone 2000; Li 2006). In addition, imaging studies have shown differences in the dopamine pathway in children and adults with ADHD (Krause 2003; Biederman 2005; Swanson 2007).

Diagnosis of ADHD

The diagnosis of ADHD in children and adolescents should be based on validated criteria such as DSM‐IV (APA 1994) or DSM‐IV‐TR (APA 2000) for ADHD or ICD‐10 for hyperkinetic disorder (WHO 2010). Assessment should be through diagnostic interviews and supported by behaviour rating scales, direct observations of behaviour and clinic‐based testing (Barkley 1998).

Treatment for ADHD

The most common approaches to the treatment of ADHD are medication and/or psychological or behavioural interventions. However, behavioural therapies do not appear to be effective in the absence of medication (Klassen 1999) and other psychological therapies have limited success (Shaywitz 1997). The most frequently used treatments for ADHD are the stimulant medications methylphenidate and amphetamine (Biederman 2005). Meta‐analyses of stimulant medications have shown them to be effective in improving inattention and behavioural symptoms, although their effectiveness for improving cognition and achievement is more modest (Swanson 1993; Klassen 1999; NIH 2000). However, the positive effects do not appear to last once stimulants are no longer used (Swanson 1993) and as many as 30% of children do not respond to stimulants (Banaschewski 2004). Stimulants are associated with side effects such as decreased appetite, weight loss, insomnia, stomachache, headache and irritability (Cantwell 1996; Biederman 2005), although most will dissipate with time (Simeon 1993; Findling 1998). There are also concerns that stimulants may cause longer‐term adverse effects such as decreased growth (Daley 2004), increased risk of substance abuse (Daley 2004; Wilens 2004) and worsening of comorbid symptoms such as tics (Daley 2004).

Non‐stimulant medications can be advantageous in the treatment of ADHD as they are longer acting than stimulants, have limited abuse potential and may be more effective in the treatment of comorbid symptoms such as depression and anxiety (Daley 2004); however, they are less likely to be effective in treating the core symptoms of ADHD (Biederman 2005). Non‐stimulants include: antidepressants (tricyclics such as imipramine and desipramine, and selective serotonin reuptake inhibitors such as fluoxetine); anti‐anxiety agents (such as clonidine and guanfacine); bupropion (which acts on noradrenaline pathways) and atomoxetine (which acts on dopamine and noradrenaline pathways) (Cantwell 1996; Daley 2004). Some of these non‐stimulant medications are also associated with severe side effects. The tricyclic antidepressant desipramine has been linked to sudden death (Findling 1998; Biederman 2005), and selective serotonin reuptake inhibitors such as fluoxetine have been associated with suicidality in some children and adolescents (Hammad 2006).

Description of the intervention

Use of polyunsaturated fatty acids (PUFA) in ADHD

The limitations associated with the available treatments for ADHD, particularly the stimulant medications, mean that families often look for alternative treatments (NIH 2000; Daley 2004). The use of PUFA is one such alternative (Brue 2001; Daley 2004). Clinical and biochemical evidence suggests that functional deficiency of certain PUFA could be related to ADHD (Richardson 2000; Haag 2003). There is growing evidence that behaviour and attention problems are related to omega‐3 deficiencies (Richardson 2000; Richardson 2004). Children with ADHD have been shown to have significantly lower plasma and blood concentrations of PUFA (Mitchell 1987; Stevens 1995; Chen 2004) and, in particular, lower levels of omega‐3 PUFA (Mitchell 1987; Stevens 1995; Burgess 2000; Chen 2004). These findings suggest that PUFA supplementation may reduce the attention and behaviour problems associated with ADHD. There is some evidence that PUFA supplementation can be effective in improving neurodevelopmental indices. Meta‐analyses of the literature have identified some evidence that PUFA formula supplementation improves neurodevelopmental outcomes in preterm infants (Simmer 2008a), although data for full‐term infants are limited (Simmer 2008b).

How the intervention might work

Physiology of polyunsaturated fatty acids (PUFA)

Human infants require omega‐6 and omega‐3 PUFA for neural development and to maintain neural integrity and function (Wainright 1992; Innis 2000; Haag 2003). The omega‐3 PUFA, which include alpha‐linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), are associated with brain development (Innis 2000; Richardson 2000; Haag 2003) and DHA is the major PUFA in the adult mammalian brain (Innis 2000). Arachidonic acid is the most abundant omega‐6 PUFA in the human brain (Agostoni 2008). The omega‐3 PUFA, ALA is found in green‐leaved plants while EPA and DHA are found in high concentrations in fish oil; the omega‐6 PUFA precursor linoleic acid is found in vegetable oils (Simopoulos 1991; Haag 2003; Assisi 2006). The ratio of omega‐3 to omega‐6 PUFA is also considered important to normal development and function of the human brain (Simopoulos 1991; Innis 2000; Haag 2003) with a ratio of 1:4 considered optimal (Assisi 2006; Borsonelo 2008).

Why it is important to do this review

Although there had been trials of PUFA supplementation in children and adolescents with ADHD or symptoms of ADHD (for example, Aman 1987; Voigt 2001; Richardson 2002; Stevens 2003; Hirayama 2004), there were no systematic reviews in this area when this review was undertaken.

Objectives

To compare the efficacy of polyunsaturated fatty acids in treating ADHD in children and adolescents compared to other treatments or no treatment.

Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi‐randomised controlled trials. Quasi‐randomised trials are trials that use allocation methods with no apparent association with participant characteristics; for example, allocation based on the last number of medical identifier numbers or last number of the date of birth.

Types of participants

Children or adolescents (up to and including 18 years of age) who have been diagnosed with ADHD using validated criteria such as the ICD‐10 or DSM‐IV TR or scores on related scales with high sensitivity and specificity for a diagnosis of ADHD. Children and adolescents with comorbidities were included.

Types of interventions

The four main comparisons are:

PUFA versus placebo, no treatment or waiting list control;
PUFA + medication versus medication, for example, methylphenidate, amphetamine;
PUFA + behavioural therapy versus behavioural therapy*;
PUFA + psychotherapy versus psychotherapy*.

* We included trials that used medication in both groups.

Types of outcome measures

Primary outcomes

A change in ADHD symptoms measured by validated scales such as the Conners Rating Scales (Conners 1998) or Child Behavior Checklist (Achenbach 1983).

Secondary outcomes

Severity or incidence of behavioural problems, for example, oppositional behaviour or conduct disorder (measured by such scales as the Child Behavior Checklist (Achenbach 1983)).
Quality of life (for example, Pediatric Quality of Life Inventory Version 4.0 (Varni 2001)).
Severity or incidence of depressive symptoms (for example, Children's Depression Inventory (Kovacs 1992)).
Severity or incidence of anxiety symptoms (for example, State‐Trait Anxiety Inventory for Children (Spielberger 1973)).
Side effects, such as gastrointestinal symptoms, allergies, changes in weight, changes in appetite or sleep pattern.
Loss to follow‐up.
Cost.

We analysed data for parent, teacher, clinician and self reported outcomes separately.

Search methods for identification of studies

Electronic searches

The first searches for this review were run on the following databases in November 2008 by the Trials Search Co‐ordinator (TSC) of the Cochrane Developmental, Psychosocial and Learning Problems Group. The searches were re‐run to find new studies in September 2009 and again in August 2011.

Cochrane Central Register of Controlled Trials (CENTRAL) 2011, Issue 2, part of The Cochrane Library (last searched 1 August 2011)
Ovid MEDLINE (R) , 1948 to July Week 3 2011 (last searched 1 August 2011)
EMBASE (Ovid),1980 to 2011 Week 29 (last searched 1 August 2011)
PsycINFO (EBSCOhost) 1887 to current (last searched 1 August 2011)
PsycINFO (Ovid) 1806 to August Week 5 2009 (last searched 9 September 2009)
CINAHL, 1937 to current (last searched 1 August 2011)
BIOSIS, 1969 to 30 July 2011 (last searched 1 August 2011)
Science Citation Index, 1970 to 30 July 2011 (last searched 1 August 2011)
Social Science Citation Index, 1970 to 30 July 2011 (last searched 1 August 2011)
Dissertation Abstracts (via Dissertation Express) (last searched 1 August 2011)

The following databases were not listed at protocol stage but were added to improve the coverage of conference papers and theses literature, and to capture studies found by other systematic reviews:

Cochrane Database of Systematic Reviews, 2011, Issue 7 (last searched 1 August 2011)
Database of Abstracts of Review of Effects (DARE) 2011, Issue 2, part of the Cochrane Library (last searched 1 August 2011)
Conference Proceedings Citation Index ‐ Science ,1990 to 30 July 2011 (last searched 1 August 2011)
Conference Proceedings Citation Index ‐ Social Science and Humanities ,1990 to 30 July 2011 (last searched 1 August 2011)
NDLTD ‐ Networked Digital Library of Theses and Dissertations (last searched 2 August 2011)
DART ‐ Europe E‐theses portal (last searched 2 August 2011)
TROVE (limited to theses) ‐ National Library of Australia (last searched 2 August 2011)
metaRegister of Controlled Trials (mRCT), all databases selected, (last searched 1 August 2011)

We did not impose any date or language restrictions. Search strategies for each database are listed in Appendix 1

Searching other resources

We checked the reference lists of relevant studies and reviews for additional references to potentially relevant studies. We included trials in languages other than English.

Data collection and analysis

Selection of studies

Two review authors independently assessed the results of the database searches for eligibility to be included in the review. We resolved any disagreements regarding the selection of studies through consensus or, if necessary, we consulted a third member of the review team. If it was not clear from the abstract or title whether a reference met the inclusion criteria, we obtained and read the full article. Where further clarification was needed from trial authors in order to make a decision, we made all reasonable attempts to contact them.

Data extraction and management

All review authors developed and piloted a data extraction form for this review. Two members of the review team independently extracted details of participants, setting, interventions, methodology and outcome data from each trial. We then compared the data for any differences. If differences were identified, we resolved them by consensus or referral to a third member of the team when necessary. Where we needed further clarification or missing data from trial authors, we made all reasonable attempts to contact them.

We only included diagnostic outcome data (including improvement) in this review if the clinician making the diagnosis was blinded to the participant's treatment group membership or it was not clear whether the clinician was blinded. We only included outcome data that were measured using a scale or questionnaire if the scale or questionnaire had been reported to be valid and reliable in a peer‐reviewed journal.

Assessment of risk of bias in included studies

Using the Cochrane Collaboration’s tool for assessing the risk of bias (Higgins 2011), two review authors independently assessed trials on the following five criteria: 1) the adequacy of sequence generation; 2) allocation concealment; 3) the blinding of participants and personnel; 4) the blinding of outcome assessors; 5) incomplete outcome data; and 6) selective outcome reporting. We rated these criteria as 'low risk of bias', 'high risk of bias' or 'unclear risk of bias'. We also collected information on any other sources of bias (for example, baseline imbalance, cross‐over design, differential loss to follow‐up, inappropriate administration of an intervention or co‐intervention, early stopping and selective reporting of subgroups).

We collected details on how each of these criteria were addressed from the trial report. If there was any disagreement regarding risk of bias criteria, we resolved these differences by consensus or by referral to a third member of the review team.

Measures of treatment effect

Binary data

For binary outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI) using a fixed‐effect model, or a random‐effects model where there was significant heterogeneity.

Continuous data

For continuous outcomes, we used endpoint data in preference to change data if both were available. We calculated the standardised mean difference (SMD) between groups and 95% CI using a fixed‐effect model, or a random‐effects model where there was significant heterogeneity. We used SMDs because more than one scale was used for each of these continuous outcomes.

Unit of analysis issues

As the length of any effect of essential fatty acids is unknown, we only used first‐period data from any cross‐over trials that fitted the inclusion criteria. As first‐period data may increase the risk of bias (Higgins 2011), we reported this under 'other possible sources of bias' in the 'Risk of bias' tables. In all other cross‐over studies, the data from both periods were combined and were therefore not included in a meta‐analysis.

If cluster‐randomised trials that otherwise fit the inclusion criteria had been identified, they would not have been used because using this design for trials of essential fatty acid supplementation may have resulted in biased data (Higgins 2011).

Dealing with missing data

We used intention‐to‐treat data where available. We also collected information on how the intention‐to‐treat analysis was calculated and reported this in Characteristics of included studies. Where the reporting of data appeared to be incomplete, we made all reasonable efforts to contact trial authors to request missing data.

We reported the loss to follow‐up and reasons for missing data where available. If outcome data were reported as a median or range, or as a mean without a variance, we reported it in additional tables.

We considered the potential impact of missing data on the results in the interpretation of the results of the review.

Assessment of heterogeneity

We used a Chi² test and I² statistic to evaluate heterogeneity. We interpreted a P value of less than 0.10 for the Chi² test of heterogeneity and/or an I² value of greater than 50% as significant heterogeneity. If heterogeneity was significant, we used a random‐effects model for meta‐analysis. It had been proposed that a sensitivity analysis would be done to try and identify the source of heterogeneity; however, due to the low number of included trials, this was not possible.

Assessment of reporting biases

Publication bias

If data from at least 10 trials were available, we had planned to enter primary outcome data into a funnel plot because asymmetry of the plots may indicate publication bias (Higgins 2011). However, we could not do this due to the low number of identified trials.

Data synthesis

Where data were available, we synthesised similar interventions and outcomes in a meta‐analysis.

Data collection intervals

We planned to collect data for all follow‐up periods. It had been proposed that data would be analysed as short‐term (up to three months following completion of the therapy), medium‐term (from three months to one year following completion) and long‐term (greater than one year); however, we could not do this due to the paucity of data.

Skewed data

As a meta‐analysis is based on assumptions of normality, we checked all continuous data for skew before inclusion. We considered data to be skewed if the standard deviation was greater than half the mean (Altman 1996). It was not possible to check change data as this can include positive and negative values. We found no endpoint data to be skewed.

Subgroup analysis and investigation of heterogeneity

If data were available, subgroup analyses had been planned to assess the differential impact of gender, age group (under five years, five to 12 years and 13 to 18 years) and length of treatment. However, we were not able to do these analyses because of the low number of identified trials.

We carried out subgroup analyses for the type of PUFA supplement that was used that is, omega‐3 only, omega‐6 only, or a combination of omega‐3 and omega‐6.

Sensitivity analysis

We had proposed sensitivity analyses for the risk of selection, detection and attrition bias as these are associated with biased estimates of effect size (Moher 1998). However, there were only enough available data to perform sensitivity analysis for selection bias as described in the Results.

The inclusion criteria of some studies were based on scale cut‐off scores, therefore we conducted an additional sensitivity analyses to evaluate whether there was any difference compared to studies which used a clinician diagnosis of ADHD.

Results

Description of studies

Results of the search

We have included 13 trials with 1011 participants in this review. From the database searches, we identified 366 references. We thought 22 of these were potentially relevant and obtained them to read in full. We identified an additional reference when the authors of the trial contacted one of the authors of this review. Therefore, we obtained 23 papers. We included 18 papers describing 13 trials and excluded five papers (Figure 1). Our search of a trials register clinical trials and recent review of the literature by Sinn 2010 identified eight trials currently in progress, which we have detailed in Characteristics of ongoing studies.

Included studies

Five trials (seven references) were of a cross‐over design (Aman 1987; Arnold 1989; Sinn 2007; Belanger 2009; Johnson 2009). Two compared omega‐6 PUFA with a placebo (Aman 1987; Arnold 1989), and one of these also compared omega‐6 PUFA with dexamphetamine (Arnold 1989). One study compared omega‐3 to omega‐6 PUFA (Belanger 2009). Sinn 2007 and Johnson 2009 both compared omega‐3/6 PUFA to placebo in the first phase, followed by PUFA supplement for all, but because first‐phase data were reported, this was integrated with data from parallel trials. We reported data from all other cross‐over trials separately. The eight remaining trials (11 references) were all of a parallel design. Five compared an omega‐3 PUFA supplement to placebo (Voigt 2001; Hirayama 2004; Vaisman 2008; Gustafsson 2010; Manor 2011); two compared a combined omega‐3 and omega‐6 supplement to placebo (Stevens 2003; Raz 2009), and one compared an omega‐3 PUFA to a dietary supplement (Brue 2001).

The omega‐3 PUFA used in supplements were DHA (median dose 187 mg/day, range 2.7 to 1035 mg/day), EPA (median dose 500 mg/day, range 80 to 1000 mg/day) and ALA (120 mg/day). The omega‐6 PUFA were arachidonic acid (40 mg/day), linoleic acid (median dose 1400 mg/day, range 480 to 2800 mg/day) and gamma‐linoleic acid (median dose 96 mg/day, range 60 to 320 mg/day). Supplements were given for a period of between four and 16 weeks.

The number of participants ranged from 18 to 147 and their ages were between six and 18 years. Four trials were done in the US, three in Israel, two in Sweden and one in each of Australia, Canada, Japan and New Zealand. In most trials the diagnosis of ADHD was made by a clinician except for the studies by Aman 1987, Arnold 1989 and Sinn 2007, which used scale cut‐offs with high sensitivity for a diagnosis of ADHD. Only one study (Stevens 2003) used inclusion criteria that could be indicative of PUFA deficiency, that is, thirst or skin symptoms.

We could not include data from Aman 1987 and Belanger 2009, both cross‐over studies, in a meta‐analysis because variances were not reported. We could not include data from two parallel trials in a meta‐analysis because the sample numbers were not clear (Brue 2001), the median number of symptoms were reported (Hirayama 2004). Not all outcomes in Sinn 2007 could be included in meta‐analyses as data for anxiety, oppositional behaviour and social problems were skewed.

Excluded studies

We excluded five references. Two were excluded because they were found to be literature reviews once the full papers were obtained (Doebel 2005; Anon 2009) and two were excluded because they were not randomly allocated trials (Harding 2003; Joshi 2006). Richardson 2002 was excluded because it was not clear which cut‐off scores were used as inclusion criteria despite attempts to contact the authors.

Risk of bias in included studies

See Figure 2 for 'Risk of bias' graph.

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

Allocation

Random sequence generation

In the majority of trials, the methods used to generate a random sequence were not described (Aman 1987; Arnold 1989; Brue 2001; Belanger 2009) or were not described in sufficient detail (Stevens 2003; Sinn 2007; Johnson 2009; Raz 2009) and we therefore rated them as at unclear risk of bias. In the remaining trials (Voigt 2001; Hirayama 2004; Vaisman 2008; Gustafsson 2010; Manor 2011) there was a low risk of bias in the generation of a random sequence.

Allocation concealment

The method of allocation concealment was also unclear in the majority of trials, although there was a low risk of bias in four trials (Hirayama 2004; Sinn 2007; Johnson 2009; Manor 2011).

Blinding

Participants and personnel

The majority (10) of the included trials described methods used to blind participants and personnel and we therefore rated them as at a low risk of performance bias. However, we rated three as at an unclear risk of performance bias. Two of these did not detail how blinding was done (Arnold 1989; Belanger 2009) and in Raz 2009 it may have been possible to detect which intervention was the PUFA.

Outcome assessors

Brue 2001, Raz 2009 and Manor 2011 were the only trials that described how outcome assessment was blinded. However, as the majority of trials described the intervention and placebo as identical, and because parent and/or teacher‐rated measures were used, we also rated these as at a low risk of bias. We rated the remaining two trials (Belanger 2009; Johnson 2009) as at an unclear risk of detection bias because of insufficient information.

Incomplete outcome data

There was a high risk of bias due to attrition in eight included trials (Voigt 2001; Brue 2001; Stevens 2003; Sinn 2007; Vaisman 2008; Belanger 2009; Raz 2009; Manor 2011) because data were only reported for participants who were not lost to follow‐up. In the remainder of trials, we rated the level of bias as unclear. Sinn 2007 also reported that baseline scores for ADHD symptoms were significantly higher in the group lost to follow‐up. The number of participants enrolled and lost to follow‐up was not clear in the trials reported by Arnold 1989 and Johnson 2009. There was only one of 31 participants lost to follow‐up in the trial by Aman 1987, and although Gustafsson 2010 reported that intention‐to‐treat (ITT) analysis was done on 92 participants, this did seem to include "17 dropouts". We rated only one trial (Hirayama 2004) as having a low risk of attrition bias.

Selective reporting

There was a high risk of reporting bias in nine trials (Arnold 1989; Voigt 2001; Sinn 2007; Vaisman 2008; Belanger 2009; Raz 2009; Manor 2011) because the result of at least one outcome was not reported. We rated the risk of bias as unclear in the trial by Johnson 2009 as the authors referred to outcomes that would be published in "future publications". We rated the remaining trials as at a low risk of reporting bias as all outcomes appear to have been reported.

Other potential sources of bias

In the majority of trials (12), there was an unclear risk of other biases. Eight trials were sponsored by the companies that produced the PUFA supplement under investigation (Aman 1987; Arnold 1989; Voigt 2001; Vaisman 2008; Belanger 2009; Johnson 2009; Gustafsson 2010; Manor 2011). In addition, there were potential confounding variables in five studies. In Aman 1987 it was not clear whether the additional five children included in the trial would have met the original inclusion criteria. The PUFA group in Brue 2001 had received an additional 12 weeks of dietary supplementation before the PUFA trial was started. There were fewer children with Asperger's syndrome and more with a learning disorder in the PUFA group in the trial reported by Hirayama 2004, although this was not significant. More than half of the children in the PUFA group in Sinn 2007 also received a multivitamin. Although both groups were comparable over a large range of variables in Stevens 2003, the Conners Parent score and Reaction time were significantly lower in the PUFA group. We rated one trial (Raz 2009) as a low risk of other bias because the authors had comprehensively reported the possibility of confounding variables. Three trials did not report baseline characteristics of each group (Aman 1987; Arnold 1989; Brue 2001).

Effects of interventions

PUFA versus placebo ‐ parallel trials

ADHD symptoms

Two trials reported improvement. Both trials compared omega‐3/6 PUFA to placebo. There was a significantly higher likelihood of improvement in the group receiving PUFA compared to placebo (two trials, 97 participants; risk ratio (RR) 2.19, 95% confidence interval (CI) 1.04 to 4.62, Analysis 1.1).

Analysis 1.1 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 1 Improvement.

There were no statistically significant differences between groups in parent‐rated ADHD symptoms (five trials, 413 participants; standardised mean difference (SMD) ‐0.17, 95% CI ‐0.38 to 0.03, Analysis 1.2); inattention (six trials, 469 participants; SMD ‐0.04, 95% CI ‐0.29 to 0.21, Analysis 1.3) or hyperactivity/impulsivity (five trials, 416 participants; SMD ‐0.04, 95% CI ‐0.25 to 0.16, Analysis 1.4). However, there was a significant improvement in parent‐rated ADHD symptoms in the subgroup of studies that compared omega‐3/6 PUFA to placebo (two trials, 120 participants; SMD ‐0.48, 95% CI ‐0.88 to ‐0.08, Analysis 1.2).

Analysis 1.2 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 2 ADHD symptoms: total ‐ parent.

Analysis 1.3 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 3 ADHD symptoms: inattention ‐ parent.

Analysis 1.4 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 4 ADHD symptoms: hyperactivity/impulsivity ‐ parent.

There were also no statistically significant differences in teacher ratings of overall ADHD symptoms (four trials, 324 participants; SMD 0.05, 95% CI ‐0.18 to 0.27, Analysis 1.5); inattention (three trials, 260 participants; SMD 0.26, 95% CI ‐0.22 to 0.74, Analysis 1.6), or hyperactivity/impulsivity (three trials, 259 participants; SMD 0.10, 95% CI ‐0.16 to 0.35, Analysis 1.7).

Analysis 1.5 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 5 ADHD symptoms: total ‐ teacher.

Analysis 1.6 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 6 ADHD symptoms: inattention ‐ teacher.

Analysis 1.7 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 7 ADHD symptoms: hyperactivity/impulsivity ‐ teacher.

Only one trial reported clinician ratings of overall ADHD symptoms (64 participants; mean difference (MD) ‐0.30, 95% CI ‐0.80 to 0.19, Analysis 1.8); inattention (64 participants; MD ‐1.01, 95% CI ‐2.59 to 0.57, Analysis 1.9), and hyperactivity/impulsivity (64 participants; MD ‐1.15, 95% CI ‐3.06 to 0.76, Analysis 1.10). There were no differences between groups for any of these measures.

Analysis 1.9 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 9 ADHD symptoms: inattention ‐ clinician.

Analysis 1.10 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 10 ADHD symptoms: hyperactivity/impulsivity ‐ clinician.

Behaviour

There were no differences between groups in the one trial that reported parent‐rated internalising behaviour (53 participants; MD 1.90, 95% CI ‐3.16 to 6.96, Analysis 1.11) and externalising behaviour (53 participants; MD 2.20, 95% CI ‐3.76 to 8.16, Analysis 1.12). There were no differences in parent ratings of socialisation (one trial, 53 participants; MD 0.40, 95% CI ‐3.90 to 4.70, Analysis 1.13); conduct (one trial, 33 participants; MD 1.30, 95% CI ‐1.54 to 4.14, Analysis 1.14), and oppositional behaviour (three trials, 266 participants; SMD 0.10, 95% CI ‐0.15 to 0.35, Analysis 1.15) and no differences in teacher ratings of conduct (one trial, 33 participants; MD 0.20, 95% CI ‐2.43 to 2.83, Analysis 1.16) and oppositional behaviour (three trials, 257 participants; SMD 0.11, 95% CI ‐0.15 to 0.36, Analysis 1.17).

Analysis 1.11 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 11 Behaviour: internalising ‐ parent.

Analysis 1.12 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 12 Behaviour: externalising ‐ parent.

Analysis 1.13 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 13 Behaviour: socialisation ‐ parent.

Analysis 1.14 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 14 Behaviour: conduct ‐ parent.

Analysis 1.15 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 15 Behaviour: oppositional ‐ parent.

Analysis 1.16 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 16 Behaviour: conduct ‐ teacher.

Analysis 1.17 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 17 Behaviour: oppositional ‐ teacher.

Quality of life

There was no difference between participants receiving omega‐3 PUFA and those receiving placebo in the one study that reported a quality of life measure (138 participants; MD ‐0.12, 95% CI ‐3.71 to 3.47, Analysis 1.18).

Analysis 1.18 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 18 Quality of life.

Side effects

There were no differences between groups in the incidence of dermatitis (one trial, 147 participants; RR 1.43, 95% CI 0.06 to 34.36), diarrhoea (one trial, 85 participants; RR 0.73, 95% CI 0.17 to 3.08), gastrointestinal discomfort (one trial, 147 participants; RR 0.70, 95% CI 0.21 to 2.38), headache (one trial, 147 participants; RR 0.16, 95% CI 0.01 to 3.82), hyperactivity (one trial, 147 participants; RR 1.43, 95% CI 0.06 to 34.36), nausea (three trials, 306 participants; RR 1.02, 95% CI 0.39 to 2.70), nose bleed (one trial, 88 participants; RR 0.32, 95% CI 0.03 to 2.95), tics (one trial, 147 participants; RR 1.43, 95% CI 0.06 to 34.36) or general side effects (one trial, 63 participants; RR 2.91, 95% CI 0.87 to 9.74) (Analysis 1.19).

Analysis 1.19 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 19 Side effects.

Loss to follow‐up

Loss to follow‐up in the PUFA and placebo groups was not significantly different (seven trials, 589 participants; RR 0.95, 95% CI 0.69 to 1.31, Analysis 1.20)

Analysis 1.20 — Comparison 1 PUFA versus placebo ‐ parallel trials, Outcome 20 Loss to follow‐up.

PUFA versus placebo ‐ cross‐over trials

Only one trial that compared PUFA with placebo provided enough data for meta‐analysis. In this one trial, which compared an omega‐6 PUFA to placebo, there was no difference in teacher ratings of overall ADHD symptoms (36 participants; MD ‐0.20, 95% CI ‐0.52 to 0.12, Analysis 2.1) or hyperactivity/impulsivity (36 participants; MD 0.29, 95% CI ‐0.17 to 0.75, Analysis 2.2).

Analysis 2.1 — Comparison 2 PUFA versus placebo ‐ cross‐over trials, Outcome 1 ADHD symptoms: total ‐ teacher.

Analysis 2.2 — Comparison 2 PUFA versus placebo ‐ cross‐over trials, Outcome 2 ADHD symptoms: hyperactivity/impulsivity ‐ teacher.

Data from the cross‐over trial by Aman 1987 reported that mean scores for parent‐rated inattention and hyperactivity were significantly decreased in the omega‐6 PUFA group compared to the placebo group, but there were no significant differences in teacher ratings of inattention and hyperactivity, and parent‐ or teacher‐rated scores for conduct problems or anxiety (Table 5).

Table 1.

Other data

Study	Comparison	ADHD symptoms: total	ADHD: inattention	ADHD: hyperactivity	Behaviour	Other outcomes
Aman 1987	Cross‐over trial of omega‐6 PUFA versus placebo		Parent Omega‐6: 14.97 Placebo: 17.37 P < 0.01 Teacher Omega‐6: 2.69 Placebo: 2.66	Parent ‐ motor excess Omega‐6: 4.48 Placebo: 5.05 P < 0.05 Teacher ‐ motor excess Omega‐6: 2.58 Placebo: 2.58	Parent ‐ conduct Omega‐6: 16.30 Placebo: 17.61 Teacher ‐ conduct Omega‐6: 1.62 Placebo: 1.66	Parent ‐ anxiety Omega‐6: 6.06 Placebo: 5.73 Teacher ‐ anxiety Omega‐6: 1.73 Placebo: 1.70
Belanger 2009	Cross‐over trial of omega‐3 PUFA versus omega‐6 PUFA – first phase	Parent Omega‐3: ‐9.1 Omega‐6: ‐7.1	Parent Omega‐3: ‐7.2 Omega‐6 ‐3.1	Parent Omega‐3: ‐8.8 Omega‐6: ‐5.4
Brue 2001	Parallel trial of omega‐3 PUFA versus dietary supplement		Parent – non‐Ritalin Omega‐3: 12.0 Supplement: 13.7 Teacher – non‐Ritalin Omega‐3: 19.1 Supplement: 15.3 Parent – Ritalin Omega‐3: 15.6 Supplement: 14.6 Teacher – Ritalin Omega‐3: 16.3 Supplement: 12.2 P = 0.04	Parent – non‐Ritalin Omega‐3: 9.4 Supplement: 13.1 P = 0.03 Teacher – non‐Ritalin Omega‐3: 17.9 Supplement: 13.4 P = 0.04 Parent – Ritalin Omega‐3: 13.7 Supplement: 13.5 Teacher – Ritalin Omega‐3: 10.8 Supplement: 12.3

Study	Comparison	PUFA group	Control
Manor 2011	Parallel trial of omega‐3 versus placebo	92%	90%
Raz 2009	Parallel trial of omega‐3/6 versus placebo	92%	86%
Richardson 2002	Parallel trial of omega‐3/6 versus placebo	90%	87%
Sinn 2007	Parallel trial of omega‐3/6 versus placebo	88% across all groups
Voigt 2001	Parallel trial of omega‐3 versus placebo	97%	100%

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Improvement	2	97	Risk Ratio (M‐H, Fixed, 95% CI)	2.19 [1.04, 4.62]
1.1 Omega‐3/6 PUFAs	2	97	Risk Ratio (M‐H, Fixed, 95% CI)	2.19 [1.04, 4.62]
2 ADHD symptoms: total ‐ parent	5	413	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.38, 0.03]
2.1 Omega‐3 PUFAs	3	293	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.06 [‐0.30, 0.18]
2.2 Omega‐3/6 PUFAs	2	120	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.48 [‐0.88, ‐0.08]
3 ADHD symptoms: inattention ‐ parent	6	469	Std. Mean Difference (IV, Random, 95% CI)	‐0.04 [‐0.29, 0.21]
3.1 Omega‐3 PUFAs	3	286	Std. Mean Difference (IV, Random, 95% CI)	0.10 [‐0.28, 0.47]
3.2 Omega‐3/6 PUFAs	3	183	Std. Mean Difference (IV, Random, 95% CI)	‐0.21 [‐0.52, 0.10]
4 ADHD symptoms: hyperactivity/impulsivity ‐ parent	5	416	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.25, 0.16]
4.1 Omega‐3 PUFAs	2	233	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.32, 0.22]
4.2 Omega‐3/6 PUFAs	3	183	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.34, 0.28]
5 ADHD symptoms: total ‐ teacher	4	324	Std. Mean Difference (IV, Fixed, 95% CI)	0.05 [‐0.18, 0.27]
5.1 Omega‐3 PUFAs	2	228	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.17, 0.37]
5.2 Omega‐3/6 PUFAs	2	96	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.45, 0.35]
6 ADHD symptoms: inattention ‐ teacher	3	260	Std. Mean Difference (IV, Random, 95% CI)	0.26 [‐0.22, 0.74]
6.1 Omega‐3 PUFAs	2	227	Std. Mean Difference (IV, Random, 95% CI)	0.03 [‐0.24, 0.30]
6.2 Omega‐3/6 PUFAs	1	33	Std. Mean Difference (IV, Random, 95% CI)	1.01 [0.28, 1.75]
7 ADHD symptoms: hyperactivity/impulsivity ‐ teacher	3	259	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.16, 0.35]
7.1 Omega‐3 PUFAs	2	226	Std. Mean Difference (IV, Fixed, 95% CI)	0.04 [‐0.24, 0.31]
7.2 Omega‐3/6 PUFAs	1	33	Std. Mean Difference (IV, Fixed, 95% CI)	0.48 [‐0.21, 1.18]
8 ADHD symptoms: total ‐ clinician	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
8.1 Omega‐3/6 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 ADHD symptoms: inattention ‐ clinician	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
9.1 Omega‐3/6 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 ADHD symptoms: hyperactivity/impulsivity ‐ clinician	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
10.1 Omega‐3/6 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11 Behaviour: internalising ‐ parent	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
11.1 Omega‐3 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Behaviour: externalising ‐ parent	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
12.1 Omega‐3 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Behaviour: socialisation ‐ parent	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
13.1 Omega‐3 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Omega‐3/6 PUFAs	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Behaviour: conduct ‐ parent	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
14.1 Omega‐3/6 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
15 Behaviour: oppositional ‐ parent	3	266	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.15, 0.35]
15.1 Omega‐3 PUFAs	2	233	Std. Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.15, 0.39]
15.2 Omega‐3/6 PUFAs	1	33	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.70, 0.67]
16 Behaviour: conduct ‐ teacher	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
16.1 Omega‐3/6 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
17 Behaviour: oppositional ‐ teacher	3	257	Std. Mean Difference (IV, Fixed, 95% CI)	0.11 [‐0.15, 0.36]
17.1 Omega‐3 PUFAs	2	224	Std. Mean Difference (IV, Fixed, 95% CI)	0.10 [‐0.18, 0.37]
17.2 Omega‐3/6 PUFAs	1	33	Std. Mean Difference (IV, Fixed, 95% CI)	0.16 [‐0.53, 0.85]
18 Quality of life	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
18.1 Omega‐3 PUFAs	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
19 Side effects	3		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
19.1 Dermatitis	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 34.36]
19.2 Diarrhoea	1	85	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.17, 3.08]
19.3 Gastrointestinal discomfort	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.21, 2.38]
19.4 Headache	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	0.16 [0.01, 3.82]
19.5 Hyperactivity	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 34.36]
19.6 Nausea	3	306	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.39, 2.70]
19.7 Nose bleed	1	88	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.03, 2.95]
19.8 Tics	1	147	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 34.36]
19.9 General	1	63	Risk Ratio (M‐H, Fixed, 95% CI)	2.91 [0.87, 9.74]
20 Loss to follow‐up	7	589	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.69, 1.31]
20.1 Omega‐3 PUFAs	4	386	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.78, 1.75]
20.2 Omega‐3/6 PUFAs	3	203	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.38, 1.13]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 ADHD symptoms: total ‐ teacher	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
1.1 Omega‐6 PUFAs	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 ADHD symptoms: hyperactivity/impulsivity ‐ teacher	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2.1 Omega‐6 PUFAs	1	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Selection bias: parent‐rated ADHD symptoms	5	413	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.17 [‐0.38, 0.03]
1.1 Low risk	2	228	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.32 [‐0.61, ‐0.03]
1.2 Unclear risk	3	185	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.03 [‐0.32, 0.27]
2 Clinician versus scale: parent‐rated inattention	6	469	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.24, 0.15]
2.1 Clinician	5	382	Std. Mean Difference (IV, Fixed, 95% CI)	0.03 [‐0.18, 0.24]
2.2 Scale	1	87	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.46 [‐0.95, 0.03]
3 Clinician versus scale inclusion criteria: parent‐rated hyperactivity/impulsivity	5	416	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.04 [‐0.25, 0.16]
3.1 Clinician	4	329	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.25, 0.20]
3.2 Scale	1	87	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.61, 0.36]

Date	Event	Description
11 August 2009	Amended	Correction to spelling in the author line
28 June 2008	Amended	Substantive amendment
24 March 2008	Amended	Converted to new review format

Methods	Cross‐over trial of omega‐6 PUFA versus placebo
Participants	Inclusion criteria: children with scores on the Attention Problem subscale of the Revised Behavior Problem Checklist (RBPC) and Inattention subscale of the Conners Teacher questionnaire above the 90^th percentile (n = 26). Five additional children from another study diagnosed with DSM III ADD by a child psychiatrist were also included. Exclusion criteria: not stated. Mean age: 8.86 years; gender: 27 boys and 4 girls; loss to follow‐up: 1/31 Baseline IQ 101.07; Conners inattention subscale: 3.08, hyperactivity: 2.80; RBPC attention problem scale: 20.42, motor excess: 6.23 Setting: Auckland, New Zealand
Interventions	Cross‐over trial of 4 weeks of omega‐6 PUFA or placebo, 1 week washout and 4 weeks of alternate. Three capsules of PUFA or placebo were to be taken twice daily. Omega‐6 PUFA: Efamol capsules contained 360 mg linoleic acid and 45 mg gamma‐linoleic acid Placebo: 500 mg of liquid paraffin
Outcomes	ADHD symptoms Parent rated RBPC subscales: attention; motor excess Teacher rated Conners Questionnaire subscales: inattention; hyperactivity and ADD‐H Comprehensive Teacher Rating Scale (ACTeR) subscales: attention, hyperactivity Behaviour Parent‐rated RBPC subscales: conduct; socialised aggression; anxiety‐withdrawal; psychotic behaviour Teacher‐rated Conners Questionnaire subscales: conduct; tension/anxiety and ACTeR subscales: social skills, oppositional behaviour All scales were measured at 4 weeks
Notes	Variances were not reported therefore data could not be included in a meta‐analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The authors stated that the trial was double‐blind and that the intervention and control were given as "indistinguishable capsules"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Capsules "indistinguishable" and parent and teacher‐rated scales used
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	One child lost to follow‐up in the placebo group
Selective reporting (reporting bias)	Low risk	Data were reported for all outcomes
Other bias	Unclear risk	It was not clear whether the additional 5 children included in the trial would have met the original inclusion criteria. Baseline characteristics of each group were not reported. The trial was funded by Efamol Research Inc.

Methods	Cross‐over trial of omega‐6 PUFA, dexamphetamine and placebo
Participants	Inclusion criteria: children of normal intelligence aged between 6 and 12 years with a DSM III diagnosis of ADHD by a child psychiatrist, a score of at least 18 on the Conners hyperactivity index and a score of at least 24 on the first 6 items of David's Hyperkinetic Rating scale Median age: 9 years, gender: all 18 were boys, loss to follow‐up: unclear, 18 participants completed Exclusion criteria: psychoactive drug use in the preceding week or history of seizures Baseline scores: not stated Setting: Ohio, US
Interventions	Cross‐over trial of omega‐6 PUFA, d‐amphetamine and placebo for 1 month each. All were given as 4 capsules twice daily for 1 month. Omega‐6 PUFA Efamol® capsules: contained 500 mg evening primrose oil which provides 350 mg linoleic acid and 40 mg gamma linolenic acid, 13 IU vitamin E as preservative Dextroamphetamine: a 10 or 15 mg time‐released capsule Placebo: paraffin oil
Outcomes	ADHD symptoms Teacher‐rated Conners total score and hyperactivity index at 2 and 4 weeks
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Placebo was described as matched
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Behavioural ratings were blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	High risk	Unclear what other outcomes were used. A parent rating of the Conners scale appears to have been used but was not reported because it was "noncontributory".
Other bias	Unclear risk	Baseline characteristics of each group were not reported. Results for a Psychiatrists' Global Rating were reported but this scale was not described. Study funded by Efamol Research Institute.

Methods	Cross‐over trial of omega‐3 versus omega‐6 PUFA followed by omega‐6 PUFA for all
Participants	Inclusion criteria: children aged 6 years 11 months to 11 years 11 months with DSM IV diagnosis based on parent and teacher questionnaires and clinical evaluation and a IQ above 85 on the Wechsler Intelligence Scale for Children Exclusion criteria: children with mental health disorders (except ADHD comorbidity); taking ADHD medication, sedatives, anxiolytics, or antipsychotics; with a medical condition requiring long‐term treatment, allergy to sunflower or fish oil; or coagulation disorders. Children who consumed natural medicine products, fish, flaxseed oil and omega‐3 enriched food during the trial were also excluded. Mean age: 9.2 years, gender (at completion of both phases): 18 boys and 8 girls, loss to follow‐up (at the end of the first phase): 8/37 Baseline DSM IV symptoms: omega‐3 74.2, omega‐6 71.1; hyperactive‐impulsive: omega‐3 67.7, omega‐6 66.9; inattentive omega‐3 76.4, omega‐6 71.3 Setting: ADHD clinic, Montreal, Canada
Interventions	One group received omega‐3 PUFA and the other omega‐6 PUFA supplements for the first 8 weeks of the trial; both groups received omega‐3 PUFA over the following 8 weeks Omega‐3 PUFA (Nutri‐Santé, Canada): each capsule contained 25 mg phospholipids, 250 mg EPA, 100 mg DHA, 3.75 U vitamin E Based on body weight, children received between 2 and 4 capsules daily Omega‐6 PUFA (described as placebo, Nutri‐Santé, Canada): each capsule contained 500 mg sunflower oil which included 70% linoleic acid, 20% oleic acid and 5% palmitic and stearic acid, 3.75 U vitamin E. It was not clear how many of these capsules were given.
Outcomes	ADHD symptoms Parent and teacher‐rated Strengths and Weaknesses in ADHD and Normal Behaviours (SWAN), parent and teacher‐rated Conners questionnaires. All were measured at 8 weeks. Side effects
Notes	First‐phase data were collected for this review. Variances were not reported therefore data could not be included in a meta‐analysis.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The authors stated that this was a double‐blind trial
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Described as a double‐blind trial but no further detail was given
Incomplete outcome data (attrition bias) All outcomes	High risk	Data was reported for 26 of the 37 enrolled participants at the end of the 8‐week trial
Selective reporting (reporting bias)	High risk	Data from the teacher‐rated Conners and SWAN questionnaires were not reported
Other bias	Unclear risk	The trial was funded by Nutri‐Santé

Methods	Parallel trial of omega‐3 PUFA versus a dietary supplement
Participants	Inclusion criteria: children diagnosed with DSM IV ADHD‐combined type by a physician or psychologist Exclusion criteria: serious pre‐existing medical or psychological condition or stimulant medication other than Ritalin Mean age: 8.4 years, gender (at follow‐up): 44 boys and 7 girls, loss to follow‐up: 9/60 Baseline scores: not stated Setting: US
Interventions	This was the second of 2 12‐week trials. In this second trial an omega‐3 PUFA in combination with a dietary supplement (given to the group who received a single dietary supplement in trial 1) was compared to a double dose of the dietary supplement (placebo group in trial 1). Both were given twice a day for 12 weeks. Omega‐3 PUFA Flax seed (rich in omega‐3 PUFA) 100 mg plus single dietary supplement: Ginkgo biloba 10 mg, Melissa officialis 200 mg, grapine 30 mg, dimethylaminoethanol 35 mg, l‐glutamine 100 mg Double dietary supplement: Ginkgo biloba 20 mg, Melissa officialis 400 mg, grapine 60 mg, dimethylaminoethanol 70 mg, l‐glutamine 200mg
Outcomes	ADHD symptoms Parent and teacher‐rated Conners Rating Scales (revised: long form): inattentive and hyperactive‐impulsive subscales measured at 12 weeks
Notes	Participant numbers were not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not stated
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Parents and teachers did not know what the participant was allocated until the trial was completed. Only the trial physician had access to this information.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Data collectors did not know what the participants were allocated until the trial was completed
Incomplete outcome data (attrition bias) All outcomes	High risk	9 children were lost to follow‐up but it is not clear what sample numbers were used in the analysis
Selective reporting (reporting bias)	Low risk	All outcomes appear to have been reported
Other bias	Unclear risk	Baseline characteristics of each group were not reported. The PUFA group had received an additional 12 weeks of dietary supplement before this second trial was started.

Methods	Parallel trial of omega‐3 PUFA versus placebo
Participants	Inclusion criteria: children aged between 7 and 12 years with a diagnosis of ADHD combined type meeting DSM IV criteria, inclusive of any neuropsychiatric comorbidity, and had been evaluated for pharmacological treatment Exclusion criteria: mental retardation (IQ < 70), autism, major depression, epileptic seizure during the preceding 2 years, other neurological or endocrine disorders, fish allergy, severely impaired hearing or vision, severe sleeping disorder, psychotic symptoms or ongoing psychoactive, anticonvulsant or stimulant medication. If the child had taken a PUFA, a washout period of 10 weeks was required. Age: 7 to 12 years, gender: not stated, loss to follow‐up: 17/109 Baseline parent‐rated Conners score: placebo 46.0; PUFA 51.0; teacher‐rated: placebo 43.5, PUFA 49.7 Setting: 8 Child and Adolescent Psychiatric and Paediatric clinics, Sweden
Interventions	Omega‐3 PUFA (PlusEPA® Minami Nutrition, Belgium): 1 capsule daily containing 500 mg eicosapentaenoic acid (EPA), 2.7 mg docosahexaenoic acid (DHA), 10 mg vitamin E for 15 weeks. All took the supplement for at least 70 days. Placebo: 1 placebo capsule (rape seed oil and medium chain triglycerides) daily for 15 weeks
Outcomes	ADHD symptoms Parent and Teacher Conners Rating Scale total, inattentive and hyperactive‐impulsive subscales Behaviour Parent and Teacher Conners Rating Scale oppositionality subscales Side effects: nausea, diarrhoea, nose bleed All scales measured at 15 weeks
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were assigned a study number and randomised in blocks of 4 according to a computer‐generated code
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo and PUFA were in "identical" capsules
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Capsules "identical" and parent and teacher‐rated scales used
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	The authors reported that ITT analysis was done on 92 participants but this did not include "17 drop‐outs"
Selective reporting (reporting bias)	Low risk	All outcomes appear to have been reported
Other bias	Unclear risk	Minami Nutrition sponsored the study

Methods	Cross‐over trial of omega‐3/6 PUFA versus placebo
Participants	Inclusion criteria: children and adolescents aged 8 to 18 years; diagnosed with ADHD of any type (according to DSM‐IV criteria); scoring at least 1.5 standard deviations above the age norm for their diagnostic subtype using the parent ADHD Rating Scale IV. Exclusion criteria: autism, psychosis, bipolar disorder, mental retardation, uncontrolled seizure disorder, hyper‐ or hypo‐thyroidism, significant other medical conditions, weight below 20 kg, alcohol or drug abuse, use of psychoactive drugs or omega‐3 preparations in the last 3 months Mean age: 12 years, gender: 54 boys and 11 girls, loss to follow‐up: 11/75 Baseline ADHD Rating Scale IV‐total: PUFA 33.5 placebo 32.4, inattention: PUFA 19.8 placebo 19.5, hyperactivity/impulsivity: PUFA 14.2, placebo 12.5 Setting: 3 child neurology/psychiatry clinics in Southwest Sweden
Interventions	Cross‐over trial of omega‐3/6 versus placebo followed by supplement for all Omega‐3/6 PUFA (Equazen eye q); 3 capsules twice daily corresponding to 558 mg EPA, 174 mg DHA, 60 mg GLA, 10.8 mg vitamin E for 3 months Placebo: olive oil, 3 capsules twice daily
Outcomes	Improvement Defined as more than 25% improvement in ADHD symptoms ADHD symptoms Clinician rated ADHD‐RS score ‐ total, inattention and hyperactive/impulsive score All measured at 12 weeks
Notes	Authors described as cross‐over because supplement was given to all in 2^nd phase. First‐phase data was used in the meta‐analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were assigned to treatment in random order using a code list but it is not clear how the code list sequence was generated
Allocation concealment (selection bias)	Low risk	Treatment assignment was determined using a code list, which not accessible to investigators and was not broken until all patients had completed the study
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The authors described this trial as double‐blind. Also "identical capsules" were used.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Described as double‐blinded but no further details given
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not stated
Selective reporting (reporting bias)	Unclear risk	The authors state that several outcomes will be reported in future publications
Other bias	Unclear risk	Study funded by Equazen UK

Methods	Parallel trial of omega‐3/6 PUFA versus placebo
Participants	Inclusion criteria: participants were recruited through advertisement on a radio health programme, in health newspapers and ADHD clinics. Children aged 7 to 13 years with a written diagnosis of ADHD from a child psychiatrist, neurologist, paediatrician or clinical psychologist were included Exclusion criteria: use of ADHD medication in the past month, use of EFA supplements in the past 3 months, presence of pervasive developmental disorder, seizure disorder, schizophrenia, major depression or bipolar disorder Mean age: 10.5 years, gender (at follow‐up): 38 boys and 25 girls, loss to follow‐up: 15/78 Baseline parent‐rated DSM‐IV attention: PUFA 4.05, placebo 4.43, hyperactivity‐impulsivity: PUFA 3.29, placebo 3.14; teacher‐rated Conners’ ADHD: PUFA 3.85, placebo 3.71 Setting: Bar‐Ilan University,Tel‐Hashomer Israel and Hillel‐Yaffe Medical Center, Hadera, Israel
Interventions	Omega‐3/6 PUFA: an oral softgel capsule containing 240 mg linoleic acid, 60 mg alpha‐linolenic acid, 95 mg mineral oil and 5 mg alpha‐tocopherol twice daily for 7 weeks Placebo: 500 mg ascorbic acid as an oral tablet twice daily for 7 weeks
Outcomes	ADHD symptoms Parent‐rated DSM‐IV attention and hyperactivity‐impulsivity, teacher‐rated Conners’ ADHD measured at 7 weeks Side effects, nausea
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of randomisation was not described except that participants were matched for gender and age and then randomised within each pair
Allocation concealment (selection bias)	Unclear risk	Assignment of treatments was based on study number
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	The authors described the trial as double‐blind. However, active and control interventions were different i.e. softgel capsules and tablets respectively.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The researchers, teachers, parents and children were all directly involved in data collection, and all were blinded to treatment allocation until the end of the study
Incomplete outcome data (attrition bias) All outcomes	High risk	Data were reported for the 63 of 75 enrolled participants who remained in the trial at 7 weeks
Selective reporting (reporting bias)	High risk	The authors stated that the Conners subscales were "found to be unreliable" but not how this was demonstrated. These data were not reported.
Other bias	Low risk	There were no statistically significant differences between groups in stimulant use, co‐morbidities, inattention, hyperactivity/impulsivity, EFA deficiency score or blood biochemistry

Methods	Cross‐over trial of omega‐3/6 PUFA +/‐ multivitamins versus placebo followed by PUFA and multivitamin supplement for all
Participants	Inclusion criteria: children aged 7 to 12 years were recruited via media releases and school newsletters. Children with scores 2 SD or more above the population average on the parent‐rated Conners Abbreviated ADHD index were included. Exclusion criteria: if they taken stimulant medication and any form of omega‐3 supplementation in the previous 3 months Mean age: 9.4 years, gender (at follow‐up): 77 boys and 27 girls, loss to follow‐up: 63/167 Mean baseline parent‐rated Conners ADHD Index: PUFA 26.68, placebo 26.67 Setting: South Australia
Interventions	One group received omega‐3/6 PUFA, one group received omega‐3/6 PUFA plus multivitamin and one received placebo for the first 15 weeks of the trial. All groups received omega‐3 PUFA plus multivitamin over the following 15 weeks. PUFA: (eye q ^TM Equazen, UK and Novasel, Australia): each capsule contained 400 mg fish oil, 100 mg primrose oil containing EPA 93 mg, DHA 29 mg and GLA 10 mg, and vitamin E 1.8 mg. Six capsules daily. Multivitamin (Blackmores, Australia): vitamin A, thiamine, vitamin B2, B6, C, D, B12, E, Biotin, B5, E, biotin, B5, CaH P04, Fe fumarate, MgO, MnSO4, ZnO, Cu gluconate, KI. One tablet per day. There was no placebo for the multivitamin but contents of intervention packaging was blinded. Placebo: 6 capsules of palm oil daily
Outcomes	Symptoms Parent and teacher‐rated Revised Conners Rating Scales
Notes	First‐phase data were collected for this review. Although adjusted mean data were available for 104 participants at the end of this phase the unadjusted data which were available for 87 participants were used.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were randomised within age and gender
Allocation concealment (selection bias)	Low risk	Independently held code numbers were used to conceal allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The authors described phase 1 as double‐blind. Packaging was designed to maintain blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Packaging was designed to maintain blinding and parent‐rated scales used
Incomplete outcome data (attrition bias) All outcomes	High risk	Missing data were replaced with the variable mean value for 1 or 2 missing responses. Cases with 3 or more missing responses were deleted from the data set.
Selective reporting (reporting bias)	High risk	Teacher‐rated outcomes which were not significantly different were not reported
Other bias	Unclear risk	Children who withdrew had significantly higher baseline scores on the Conners Index (withdrew before starting: 28.92, withdrew during phase 1: 28.74, completed phase 1: 26.27)

Methods	Parallel trial of omega‐3/6 PUFA vs placebo
Participants	Inclusion criteria: children aged 6 to 13 years diagnosed with ADHD by a clinical psychologist, psychiatrist or paediatrician with thirst and/or skin symptoms Exclusion criteria: chronic health problems, distance from the test site, inability to swallow capsules, lack of interest Mean age: 9.8 years, gender (at baseline): 41 boys and 6 girls, loss to follow‐up: 17/50 Baseline parent‐rated Conners Abbreviated Questionnaire: PUFA 16.5, placebo 19.9; teacher‐rated: PUFA 10.5, placebo 13.1 Setting: central Indiana, US
Interventions	Omega‐3/6 PUFA (Efalex, Efamol Ltd. UK): capsules contained 60 mg DHA, 10 mg EPA, 5 mg AA, 12 mg GLA, 3 mg vitamin E. 8 capsules were given daily for 4 months. Placebo: 0.8 g olive oil given as 8 capsules daily for 4 months
Outcomes	Improvement Defined as no longer meeting the parent criteria for hyperactivity ADHD symptoms Parent and teacher‐rated Conners questionnaire Parent and teacher‐rated Disrupted Behavior Disorders Rating Scale: hyperactivity, attention Behaviour Parent and teacher‐rated Disrupted Behavior Disorders Rating Scale: conduct, oppositional defiant behaviour
Notes	SDs calculated from range
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation was balanced for age and gender
Allocation concealment (selection bias)	Unclear risk	Not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The authors described the trial as double‐blind. The odour and appearance of the placebo capsules were described as comparable to the PUFA capsules.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Capsules were "comparable" and parent and teacher‐rated scales used
Incomplete outcome data (attrition bias) All outcomes	High risk	The authors reported that ITT analysis was done but reported data from the 33 participants who completed the trial
Selective reporting (reporting bias)	Low risk	All outcomes appear to have been reported
Other bias	Unclear risk	Both groups were comparable over a large range of variables except the Conners parent's score and reaction time which were significantly lower in the PUFA group Not clear how the screening sample was identified. Diagnoses of ADHD were not verified by a clinician and the reliability and validity of the thirst/skin symptom scales were not reported.

Study	Reason for exclusion
Anon 2009	Review of Johnson 2009
Doebel 2005	Overview of articles and trials of nutrients in children with ADHD
Harding 2003	Not randomised
Joshi 2006	Pre‐post study
Richardson 2002	The Conners cut‐off score used as an inclusion criteria was not clear

Trial name or title	Effects of N‐3 fatty acids (DHA and EPA) on cognitive control and associated brain activity in ADHD
Methods	A double‐blind, placebo‐controlled study
Participants	Boys with ADHD (n = 40) and typically developing boys (n = 40) aged 8 to 12 years
Interventions	Dietary supplementation with omega‐3 fatty acids (EPA and DHA)
Outcomes	Cognitive control and associated brain activity in prefrontal and striatal areas
Starting date
Contact information	Dienke Bos Department Child and Adolescent Psychiatry Rudolf Magnus Institute University Medical Center Utrecht d.j.bos‐2@umcutrecht.nl
Notes	Email sent 7 September 2011 but no response received

Trial name or title	Omega‐3 supplementation and attention‐deficit‐hyperactivity disorder (ADHD)
Methods	Randomised, placebo‐controlled trial
Participants	40 children, 6 years to 13 years, diagnosed with ADHD will be randomised to consume either ALA (3 grams of ALA‐containing plant oil) or placebo for 2 months Inclusion criteria: ADHD diagnosis Exclusion criteria: any comorbidities, any medication or supplement use
Interventions	Dietary supplement: omega‐3 fatty acid alpha‐linolenic acid (ALA) Dietary supplement: placebo
Outcomes	Baseline and end assessments will include both ADHD‐related questionnaires and tests, and blood fatty acid composition
Starting date	April 2009
Contact information	Gal Dubnov‐Raz The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel Email: gal.dubnov‐raz@sheba.health.gov.il
Notes	Email sent 23 April 2012 to check on progress of study

Trial name or title	PAD‐Study ‐ Efficacy of polyunsaturated fatty acids in children and adolescents with attention deficit/hyperactivity disorder (ADHD)
Methods	A randomised, double‐blind, parallel, placebo‐controlled study
Participants	Children and adolescents aged 6 to 17 years diagnosed with ADHD (n = 438)
Interventions	Polyunsaturated fatty acids (PUFA) in combination with zinc and magnesium
Outcomes	Attention Deficit Hyperactivity Disorder Rating Scale, Parent Version IV (ADHDRS‐IV)
Starting date	Recruiting 1 August 2011
Contact information	Professor Michael Huss University Medicine Mainz, Germany michael.huss@ukmainz.de
Notes	Email sent 7 September 2011. Professor Huss responded that the trial completion could not be expected before end of 2012

Trial name or title	Clinical trial to evaluate the efficacy and the tolerance of an omega 3 fatty acids supplementation in ADHD children
Methods	A randomised, double‐blind, parallel, placebo‐controlled study
Participants	Children aged 6 to 15 years with ADHD (n = 160)
Interventions	Omega‐3 fatty acid supplementation
Outcomes	ADHD rating scale
Starting date	October 2008
Contact information	Dr Olivier Revol Pierre Wertheimer Hospital olivier.revol@chu‐lyon.fr
Notes	Email sent 7 September 2011 but no response received

Trial name or title	Randomised controlled trial investigating effect of supplementation with omega‐3 fatty acids EPA and DHA versus omega‐6 fatty acid LA on ADHD symptoms and learning difficulties in 7‐12 year old children
Methods	Cross‐over, randomised, double‐blind controlled trial of omega‐3 versus omega‐6 PUFA
Participants	Inclusion criteria: 120 children aged 7 to 12 years, ADHD diagnosis, parent‐reported learning difficulties Exclusion criteria: on stimulant medication, taken omega‐3 supplements for up to 3 months, haemophilia
Interventions	1 g eicosapentaenoic acid (EPA), 1 g of docosahexaenoic acid (DHA) or linolenic acid (LA; sunflower oil placebo) in 4 capsules per day) in a 3 x 3 cross‐over trial over 12 months
Outcomes	Conners’ parent rating scales, cognitive assessments of attention, impulsivity and literacy at 0, 4, 8 and 12 months
Starting date	16 July 2007
Contact information	Dr Natalie Sinn Nutritional Physiology Research Centre, University of South Australia, GPO Box 2471, Adelaide, SA 5001, Australia +61 8 83021757 natalie.sinn@unisa.edu.au
Notes	Email sent 23 April 2012 to check on progress of study

PERMALINK

Polyunsaturated fatty acids (PUFA) for attention deficit hyperactivity disorder (ADHD) in children and adolescents

Donna Gillies

John KH Sinn

Sagar S Lad

Matthew J Leach

Melissa J Ross

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Polyunsaturated fatty acids (PUFA) supplements for attention deficit hyperactivity disorder (ADHD) in children and adolescents

Background

Description of the condition

Aetiology

Diagnosis of ADHD

Treatment for ADHD

Description of the intervention

Use of polyunsaturated fatty acids (PUFA) in ADHD

How the intervention might work

Physiology of polyunsaturated fatty acids (PUFA)

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Binary data

Continuous data

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Publication bias

Data synthesis

Data collection intervals

Skewed data

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Figure 1.

Included studies

Excluded studies

Risk of bias in included studies

Figure 2.

Allocation

Random sequence generation

Allocation concealment

Blinding

Participants and personnel

Outcome assessors

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

PUFA versus placebo ‐ parallel trials

ADHD symptoms

Analysis 1.1.

Analysis 1.2.

Analysis 1.3.

Analysis 1.4.

Analysis 1.5.

Trial name or title	Omega‐3 fatty acids supplementation for adolescent boys with attention deficit hyperactivity disorder: a double‐blind, randomized controlled trial
Methods	Double‐blind, parallel, randomised, placebo‐controlled trial
Participants	Male adolescents aged 12 to 17 years of age from special schools in the UK who meet ADHD diagnosis criteria and have Conners’ Parents ADHD Rating Global Scale and Conners’ Teachers ADHD Rating Global Scale above 65
Interventions	Omega‐3 fatty acids supplementation for 3 months
Outcomes	Conners’ teacher rating scale ADHD index
Starting date	20 March 2006
Contact information	Dr Eric Taylor Child and Adolescent Psychiatry Institute of Psychiatry London United Kingdom e.taylor@iop.kcl.ac.uk
Notes	Email sent 7 September 2011. Dr Taylor responded that a paper was in preparation.

Trial name or title	Omega‐3 fatty acids as an adjunctive therapy for treatment in attention‐deficit hyperactivity disorder (ADHD)
Methods	Double‐blind, cross‐over, randomised, placebo‐controlled trial
Participants	Children and adolescents aged between 6 and 15 years with a diagnosis of ADHD according to the DSM‐IV‐TR and on current treatment with stimulants (30 to 150)
Interventions	Prescription omega‐3 fatty acids as an adjunctive therapy to stimulants
Outcomes	Improvement in ADHD symptoms
Starting date	June 2009
Contact information	Dr Jose M Torrijos Maimonides Medical Center Brooklyn jtorrijos@maimonidesmed.org
Notes	Email sent 7 September 2011 but no response received

Trial name or title	Effect of long chain polyunsaturated fatty acids on behavior and cognition in children with attention deficit hyperactivity disorder
Methods	Double‐blind, parallel, randomised, placebo‐controlled trial
Participants	Children aged 6 to 12 years with attention deficit hyperactivity disorder (n = 100)
Interventions	Omega‐3 supplement for 16 weeks
Outcomes	Behaviour and cognition
Starting date	April 2009
Contact information	Dr Katharina A Widenhorn‐Mueller Sozialpädiatrisches Zentrum und Kinderneurologie Ulm, Germany katharina.mueller@znl‐ulm.de
Notes	Email sent 7 September 2011. Dr Widenhorn‐Mueller responded that trial completion was expected at the end of 2012.