Applied nutritional investigationEicosapentaenoic and docosahexaenoic acids, cognition, and behavior in children with attention-deficit/hyperactivity disorder: A randomized controlled trial
Introduction
Attention-deficit/hyperactivity disorder (ADHD) is commonly diagnosed in childhood and has a high comorbidity with other disorders of behavior and mood such as conduct disorder and developmental coordination disorder [1]. At least one-fourth of children with ADHD also have a learning disorder resulting in difficulties with reading, spelling, and writing [2].
The ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and, to a lesser extent, the ω-6 PUFA arachidonic acid (AA) constitute a large proportion of the lipid in the brain [3]. The ω-3 PUFAs DHA and eicosapentaenoic acid (EPA) are involved in many aspects of brain function including cell growth, neural signaling, and gene expression [4]. The low intake of ω-3 PUFAs in children from Western societies such as Australia is therefore of concern [5], [6], not only for physical health such as blood pressure [7] but also for brain function, with implications for developmental disorders such as ADHD.
Some randomized controlled trials have investigated effects of ω-3 PUFA supplementation on behavior in volunteers with ADHD, with varying success [8]. The inconsistent results seen in these trials could be attributed to methodologic differences including variations in the type of supplement used [9]. Most studies have used supplements containing a combination of EPA and DHA in varying ratios. One study used pure DHA 345 mg [10] in medicated boys with ADHD and reported no effects; another study used a supplement containing only EPA 500 mg and reported improved ADHD symptoms [11], suggesting that pure EPA supplementation will assist in alleviating ADHD symptoms. The effects of the long-chain ω-3 PUFAs, EPA and DHA, on behavior, cognition, and literacy in children with ADHD have not been compared within a single randomized, controlled, intervention trial.
Variations among trials could also be attributed to the choice of volunteers recruited and the outcomes assessed. In the UK, improvements in cognitive and behavioral symptoms were observed after PUFA supplementation in children with dyslexia and ADHD symptoms [12] and in children with dyspraxia (one-third with ADHD symptoms in the clinical range) who were also on average 1 y behind in reading and spelling [13]. An Australian study found improved parent ratings of attention and behavior in children with ADHD symptoms in the clinical range [14], [15]. A more recent Swedish study with children diagnosed with ADHD found that the subgroup with reading and writing difficulties were among the strongest responders [16]. In contrast, a study that included only boys who met strict Diagnostic and Statistical Manual, Fourth Revision criteria for ADHD and excluded comorbid disorders failed to find a treatment effect [10]. Therefore, the effects of ω-3 PUFA supplementation on behavior and literacy in children with ADHD symptoms and comorbidities need further investigation.
Importantly, few of these trials have included blood PUFA analysis [10], [17]. Serum, plasma, or erythrocyte PUFA contents are biomarkers of PUFA intake and bioavailability [18], with the latter being most indicative of long term consumption and tissue incorporation. In the present sample of children, we found that higher ω-6 PUFA and lower ω-3 PUFA levels in erythrocytes were predictive of poorer outcomes at baseline, particularly word reading [19]. The inclusion of PUFA status in supplementation trials could be used to determine if the treatment is efficacious in children with a lower baseline ω-3 PUFA intake or in those who exhibit the greatest increase in PUFA levels over the supplementation period.
The aim of this study was to investigate effects of a selective supplementation with EPA or DHA versus the ω-6 PUFA linoleic acid (LA) on behavior, cognition, and literacy in children 7 to 12 y old with ADHD symptoms in a randomized, placebo-controlled trial. The erythrocyte PUFA status (percentage of total fatty acids) was used to determine if those with lower ω-3 PUFA levels were the greatest responders. In addition, the changes in PUFA levels and their correlation with changes in behavior and literacy/cognition were examined over 4 mo.
Section snippets
Materials and methods
A 4-mo parallel comparison of effects of a DHA-rich or an EPA-rich fish oil with an LA-rich safflower oil was undertaken as stage 1 of a 12-mo randomized, controlled, three-way crossover trial in children 7 to 12 y old with ADHD symptoms. The study was conducted in Adelaide and Brisbane, Australia and was approved by the human research ethics committees of the University of South Australia and the Queensland University of Technology. It was registered with the Australian New Zealand Clinical
Description
Of the 90 children 6 to 13 y old who commenced the study (52 at the University of South Australia and 38 at the Queensland University of Technology), three were excluded owing to a lack of an ADHD diagnosis or ADHD symptom severity scores below the 90th percentile on the Conners Global Scale. Seventy children completed the 4-mo assessments. Blood samples were obtained from 75 volunteers at baseline and 52 volunteers at 4 mo and from 48 children at the two time points. There were no differences
Discussion
This study investigated the effects of supplementation with EPA- or DHA-rich oil on literacy, cognition, and behavior of children with ADHD symptoms. No treatment effects were observed with the EPA or DHA-rich supplements compared with the LA control. However, an increased erythrocyte DHA over 4 mo was associated with improved word reading and oppositional behavior in the entire sample, and this effect was much stronger in the subgroup with learning difficulties, who also showed associations
Conclusion
An increase over 4 mo in erythrocyte ω-3 PUFAs, particularly DHA, was associated with improvements in literacy and the behavior of some children with ADHD. The greatest benefit was observed in children who had comorbid learning difficulties.
Acknowledgments
The authors acknowledge the assistance of Jacqueline Boon, Shelley Appleton, Suzanne Hegarty, and Liz Anderson with the recruitment and data collection in Brisbane and all the children and their parents for their participation.
References (33)
- et al.
Developmental coordination disorder: associated problems in attention, learning, and psychosocial adjustment
Hum Mov Sci
(2002) - et al.
Australian children are not consuming enough long-chain omega-3 polyunsaturated fatty acids for optimal health
Nutrition
(2011) - et al.
Dietary intake and food sources of fatty acids in Australian adolescents
Nutrition
(2011) - et al.
Moderate consumption of fatty fish reduces diastolic blood pressure in overweight and obese European young adults during energy restriction
Nutrition
(2010) - et al.
A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder
J Pediatr
(2001) - et al.
A randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties
Prog Neuropsychopharmacol Biol Psychiatry
(2002) - et al.
Cognitive effects of polyunsaturated fatty acids in children with attention deficit hyperactivity disorder symptoms: a randomised controlled trial
Prostaglandins Leukot Essent Fatty Acids
(2008) - et al.
Correlation between changes in blood fatty acid composition and visual sustained attention performance in children with inattention: effect of dietary n-3 fatty acids containing phospholipids
Am J Clin Nutr
(2008) - et al.
Fatty acid composition of plasma, blood cells and whole blood: Relevance for the assessment of the fatty acid status in humans
Prostaglandins Leukot Essent Fatty Acids
(2007) - et al.
Erythrocyte polyunsaturated fatty acid status, memory, cognition and mood in older adults with mild cognitive impairment and healthy controls
Prostaglandins Leukot Essent Fatty Acids
(2011)
Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study
Am J Clin Nutr
Learning disabilities and ADHD: overlapping spectrum disorders
J Learn Disabil
The accumulation of arachidonate and docosahexaenoate in the developing rat brain
J Neurochem
Omega 3 fatty acids and the brain: review of studies in depression
Asia Pac J Clin Nutr
The impact of polyunsaturated fatty acids in reducing child attention deficit and hyperactivity disorders
J Atten Disord
Oiling the brain: a review of randomised controlled trials of omega-3 fatty acids in psychopathology across the lifespan
Nutrients
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Ms. Milte is supported by a Ph.D. scholarship from the South Australian Health Department. Drs. Sinn, Young, and Howe are recipients of an Australian Research Council Linkage Project grant (LP0776922) in partnership with Novasel Australia (“Cognitive and Behavioral Benefits of Omega-3 Fatty Acids Across the Lifespan”).