University of Oxford UK Alexandra Richardson et al omega-3 fatty acids adhd and related

18 Pages·2006·0.12 MB·English

International Review of Psychiatry, April 2006; 18(2): 155–172
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders
ALEXANDRA J. RICHARDSON
Department of Physiology, Human Anatomy and Genetics, University of Oxford, UK
Summary
Omega-3fattyacidsaredietaryessentials,andarecriticaltobraindevelopmentandfunction.Increasingevidencesuggests
thatarelativelackofomega-3maycontributetomanypsychiatricandneurodevelopmentaldisorders.Thisreviewfocuses
on the possible role of omega-3 in attention-deficit/hyperactivity disorder (ADHD) and related childhood developmental
disorders,evaluatingtheexistingevidencefrombothresearchandclinicalperspectives.Theoryandexperimentalevidence
support a role for omega-3 in ADHD, dyslexia, developmental coordination disorder (DCD) and autism. Results from
controlled treatment trials are mixed, but the few studies in this area have involved different populations and treatment
formulations. Dietary supplementation with fish oils (providing EPA and DHA) appears to alleviate ADHD-related
symptomsinatleastsomechildren,andonestudyofDCDchildrenalsofoundbenefitsforacademicachievement.Larger
trialsarenowneededtoconfirmthesefindings,andtoestablishthespecificityanddurabilityofanytreatmenteffectsaswell
asoptimalformulationsanddosages.Omega-3isnotsupportedbycurrentevidenceasaprimarytreatmentforADHDor
related conditions, but further research in this area is clearly warranted. Given their relative safety and general health
benefits, omega-3 fatty acidsoffer a promising complementaryapproach tostandard treatments.
Introduction (Burd, Klug, Coumbe, & Kerbeshian, 2003; Secnik,
Swensen, & Lage, 2005).
Attention-deficit/hyperactivity disorder
No objective biological markers for ADHD have
and related disorders
been identified, and aetiology is obviously both
Attention-deficit/hyperactivity disorder (ADHD) is complex and multi-factorial, involving both genetic
the most common developmental disorder of child- and environmental factors that are likely to differ
hood,withprevalenceestimatesvaryingbetween4% between affected individuals. The heterogeneity of
and 15% for school-age children in the USA and ADHD is further exacerbated by its very high
elsewhere (Costello, Mustillo, Erkanli, Keeler, & comorbiditywithmanyotherdisordersofbehaviour,
Angold, 2003; Wolraich, Hannah, Baumgaertel, & learning or mood. In childhood, these most com-
Feurer, 1998). Lower estimates are obtained monlyincludeconductand/oroppositionaldisorders
when rigorous diagnostic criteria are used, but as well as many forms of specific learning difficulties
some of the variability reflects the actual dimension- such as dyslexia (specific reading disabilities), devel-
ality of ADHD-type symptoms; clear boundaries opmental language disorders, dyspraxia (develop-
between normal and abnormal function are difficult mental coordination disorder or DCD) and the
to establish, because in many respects the core autistic spectrum of disorders (ASD) (Dery,
defining features of inattention and/or hyperactivity- Toupin, Pauze, & Verlaan, 2004; Doyle, Faraone,
impulsivity are simply extremes ofnormal individual DuPre, & Biederman, 2001; Kadesjo & Gillberg,
differences in cognition and behaviour. 2001; Willcutt & Pennington, 2000). In adulthood,
It is now clear that ADHD also persists into ADHD has been linked with anxiety, depression
adulthood, although some of the symptoms change and other mood disorders, antisocial personality,
with age (Kooij et al., 2005). In both children and substance abuse and the schizophrenia spectrum
adults, the associated difficulties in health as well as of disorders (Biederman et al., 1996; Dilsaver,
social, educational and occupational functioning are Henderson Fuller, & Akiskal, 2003; Hellgren,
notonlydamagingtothosedirectlyaffected,butalso Gillberg, Bagenholm, & Gillberg, 1994; Rasmussen
represent a significant burden on society as a whole & Gillberg, 2000; Secnik et al., 2005).
Correspondence: Dr A. J. Richardson, University Laboratory of Physiology, Department of Physiology, Human Anatomy
and Genetics, Parks Road, Oxford OX1 3PTUK. Tel: þ 44 (0)1865 513433. Fax: þ 44 (0) 1865 438304.
E-mail: [email protected]
ISSN0954–0261print/ISSN1369–1627online/06/020155–18(cid:1)InstituteofPsychiatry
DOI:10.1080/09540260600583031
156 A. J. Richardson
As well as their frequent overlap within indivi- Carlson&Neuringer,1999;Haag,2003;Peet,Glen,
duals,thesedisordersalsoshowconsiderablefamilial & Horrobin, 2003). Instead, the following section
aggregation, suggesting some common elements at will briefly outline how omega-3 fatty acid deficien-
the level of biological predisposition. Increasing cies could help to explain both the high comorbidity
evidence, reviewed here, suggests that these may of ADHD with other developmental and psychiatric
include functional deficiencies or imbalances of disorders and many of their associated clinical
omega-3 fatty acids. features, as well as offering no conflict with current
pharmacological approaches to ADHD and related
disorders.
Omega-3 fatty acids
Both omega-3 and omega-6 fatty acids are essential
to human health but must be provided by the diet. Theoretical plausibility of a role for omega-3
The longer-chain, highly unsaturated fatty acids in ADHD and related conditions
(HUFA) of each series are the most important
Omega-3 in other psychiatric disorders
for brain development and function, notably the
omega-6 arachidonic acid (AA) and the omega-3 At the genetic level, associations have been docu-
eicosapentaenoic and docosahexaenoic acids (EPA mented between ADHD and dyslexia, antisocial
and DHA). These and other HUFA can be behaviour, mood disorders and schizophrenia
synthesized within the body from their respective (Faraone et al., 1995; Faraone, Biederman, Jetton,
essential fatty acid (EFA) precursors, the omega-6 & Tsuang, 1997; Willcutt, Pennington, & DeFries,
linoleic acid (LA) and the omega-3 alpha-linolenic 2000), although there are obvious difficulties in
acid (ALA), although this conversion process is not relating genetic factors to any such behaviourally-
very efficient in humans (Pawlosky, Hibbeln, defined phenotypes. Many of the genes involved in
Novotny, & Salem, 2001; Salem, Pawlosky, theseconditionsarelikelytobewidelydistributedin
Wegher, & Hibbeln, 1999) and males appear to be the general population, (Fisher & DeFries, 2002)
at a particular disadvantage in this respect (Burdge, andenvironmentalfactorsremaintheobvioustargets
Jones,&Wootton,2002;Burdge&Wootton,2002). for management or prevention strategies. Dietary
By historical standards, dietary intake of omega-3 influences are firmly among these, as nutrition can
is very low in many modern developed countries. influence gene expression, while genetic differences
Thekeyomega-3HUFA(EPAandDHA)arefound can affect the absorption and utilization of specific
in appreciable quantities only in fish and seafood, nutrients, contributing to individual variation in
andALAisfoundingreenvegetablesandsomenuts dietary requirements. It is more than plausible
and seeds. By contrast, omega-6 fats are usually that some of the numerous genes already known to
abundant in Western-type diets, especially if these influencefattyacidmetabolismmaycontributetothe
rely heavily on processed foods. Most vegetable and risk for a wide range of inter-related developmental
seedoils(aswellaswholenuts,seedsandgrains)are and psychiatric disorders, raising the possibility of
richerinLAthanALA,andthekeyomega-6HUFA, a spectrum of vulnerability (Bennett & Horrobin,
AA, is provided directly by meat, eggs and dairy 2000; Peet et al., 2003).
produce. The dietary ratio of omega-6 to omega-3 There is now abundant experimental evidence of
thus often far exceeds the ratios of between 1:1 and fatty acid abnormalities in a wide range of adult
4:1that prevailed in the ‘hunter-gatherer’ type diets psychiatric disorders, but only properly controlled
on which modern humans evolved (Simopoulos, treatment trials can provide reliable evidence for
2002). Gene transfer studies have provided very HUFA deficiencies as a causal factor. Several such
powerful evidence that the earlier, lower ratios were trials have shown benefits from treatment with
much closer to the optimum for human health omega-3 in schizophrenia, in both medicated and
(Holman, 1998; Kang, 2003). Both epidemiological unmedicated patients, (Peet & Stokes, 2005)
and clinical studies support this picture, and the although the largest trial of this kind was negative
relative disappearance of omega-3 from the diet in (Fenton, Dickerson, Boronow, Hibbeln, & Knable,
developedcountrieshasbeenlinkedwithincreasesin 2001). The evidence for a causal contribution for
a wide range of both physical and mental disorders omega-3 currently appears strongest in relation to
(Haag, 2003; Rudin, 1981; Simopoulos, 2002). disorders of mood and/or impulsivity, most ofwhich
The critical importance of omega-3 fatty acids for show high comorbidity with ADHD. Adjunctive
normal brain development and function—and treatment with omega-3, particularly EPA, has
conversely, their potential relevance to a wide range shown benefits in unipolar depression, (Nemets,
of developmental, psychiatric and neurological Stahl, & Belmaker, 2002; Peet & Horrobin, 2002;
disorders—has been amply reviewed elsewhere and Su, Huang, Chiu, & Shen, 2003) bipolar disorder
cannot be considered in detail here (Bourre, 2004; (Stoll et al., 1999) and borderline personality
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders 157
disorder, (Zanarini & Frankenburg, 2003) although While this male excess may partly reflect referral
one adjunctive study of DHA-rich fish oil for biases and/or sex differences in clinical presentation,
depression was negative, as was a trial of DHA as theevidencepointstoatleastsomebiologicalfactors
monotherapy (Marangell et al., 2003; Silvers, that put males at a greater risk for these and other
Woolley, Hamilton, Watts, & Watson, 2005). neurodevelopmentaldisorders(Arnold,1996;Rutter
Other evidence with relevance to ADHD includes etal.,2004).Sexdifferencesinfattyacidmetabolism
research into possible links between omega-3 defi- may be one such factor, because for hormonal
ciency and various forms of antisocial behaviour. reasons, males are more vulnerable than females to
There is some epidemiological evidence that lower deficiencies in highly unsaturated fatty acids
dietary omega-3 intakes may be associated with (Burdge et al., 2002; Burdge & Wootton, 2002;
increased hostility in adolescents, (Iribarren et al., Giltay, Gooren, Toorians, Katan, & Zock, 2004).
2004) and preliminary evidence from small con-
trolled trials suggests that omega-3 might protect
against aggression in both women with borderline Apparent links with allergies and other immune system
personality disorder and otherwise healthy young disorders. Clinically, ADHD, dyslexia and autism
adults under mental stress (Hamazaki et al., 1996; are often associated with physical health conditions
Zanarini & Frankenburg, 2003). Omega-3 HUFA involving overt immune system dysfunction, such as
were also one component of the active supplement increased proneness to infections, atopic conditions
in a rigorous and much larger trial that showed such as asthma, eczema and hayfever, and also with
significant reductions in offending by young prison- somelesscommonautoimmunedisorders(Ashwood
ers, (Gesch, Hammond, Hampson, Eves, & & Van de Water, 2004; Comi, Zimmerman, Frye,
Crowder, 2002) but the dose of omega-3 in this Law,&Peeden,1999;Jyonouchi,Sun,&Le,2001).
study was small, and the treatment also included In early life, the availability and balance of dietary
a broad range of vitamins, minerals and omega-6 omega-3 and omega-6 HUFA can influence the
fatty acids. programming of Th1 and Th2 responses and the
Although the focushere ison omega-3fatty acids, establishment and maintenance of healthy gut
this is an appropriate point to emphasize that no flora, both of which have important consequences
nutrients work in isolation, and deficiencies in many for autoimmune or allergic sensitivity (Das, 2002).
other essential micronutrients have also been docu- The immune system has extensive and highly
mented in ADHD and related disorders. Zinc has complex influences on brain development and
been the most consistently reported, and there is function, and increasing evidence suggests that the
somepreliminarycontrolledtrialevidenceofbenefits neurobiological basis of ADHD and related devel-
fromsupplementation(Arnold&DiSilvestro,2005). opmental disorders may partly reflect inflammatory
Like omega-3 fatty acids, this element plays innu- and/or autoimmune influences operating during
merable roles in human physiology, but in addition early brain development, and possibly throughout
to assisting in blood glucose regulation—which has life (Dalton et al., 2003; Taylor, Richardson, &
obvious implications for mental function—zinc is Stein, 2001; Vargas, Nascimbene, Krishnan,
also an essential co-factor in the synthesis of HUFA Zimmerman, & Pardo, 2005; Vincent et al., 2002).
from EFA, hence these findings may be directly The omega-6 fatty acid AA has pro-inflammatory
relevant to those reviewed here. actions via several different mechanisms, while the
omega-3 HUFA found in fish oils generally have
opposing and complementary actions (Calder,
Clinical features associated with ADHD and
2003). The relatively high ratio of omega-6 to
related conditions
omega-3 in modern diets (and particularly the ratio
Many clinical features associated with ADHD and of AA to EPA) may therefore contribute to risk for
related conditions are consistent with relative any disorders in which inflammation plays a part,
deficiencies in omega-3 fatty acids, as discussed although HUFA from both series play complex
in more detail elsewhere (Richardson, 2004b; and complementary roles in both inflammatory and
Richardson & Puri, 2000; Richardson & Ross, autoimmune responses (Harbige, 2003).
2000). These include:
Abnormalities of mood and arousal. Children
Theexcessofmalesaffected. Reported sexratiosvary with ADHD and related conditions often have
from around 2:1 in favour of males for dyslexia, particular difficulties in the regulation of mood,
dyspraxia and attentional disorders without hyper- arousal and sleep, (Hirshfeld-Becker et al., 2002;
activity to more than 5:1 for more disruptive forms Owens, 2005) not all of which can be explained
of ADHD and autistic spectrum disorders. simply as consequences of their behavioural and
158 A. J. Richardson
learning problems. The evidence for omega-3 as a Fattyacidsandtheirmetabolismcanalsoaffectthe
factorinmooddisordershasalreadybeenmentioned functioning of other major neurotransmitter systems
above,butalongwithomega-6,thesefattyacidsalso implicated in ADHD and related psychiatric
play both direct and indirect roles in the initiation disorders, as reviewed elsewhere (Yehuda, 2003).
and maintenance of normal sleep (Chen & Bazan, Effects of omega-3 on both serotonergic and
2005; Yehuda, 2003). Functional deficiencies or noradrenergic function may help to account for the
imbalances in highly unsaturated fatty acids may be apparent links between omega-3 status and hostility-
one of the common underlying mechanisms in the aggression, depression and other mood-related
association of these traits and features with ADHD disorders as noted above. The effects of fatty acids
and related conditions. on neural signalling can be mediated via a huge
variety of different mechanisms, direct and indirect,
as HUFA and their derivatives not only affect
membrane structure and function, but help to
Sensory processing abnormalities. Subtle abnormal-
regulate blood flow, endocrine and immune func-
ities of rapid visual and auditory processing are
tions and can also modulate ion channels, neuro-
associated with dyslexia, dyspraxia, ADHD and
transmitter uptake, synaptic transmission, apoptosis
other psychiatric disorders, and such sensory impre-
and gene expression among other biological pro-
cisionmayunderliesomeofthecognitivefeaturesof
cesses. Of particular relevance to many psychiatric
these disorders, including impairments in attention
disorders are their effects on cytokine and endocan-
and working memory (Javitt, Shelley, Silipo, &
nabinoid metabolism, which are receiving serious
Lieberman, 2000; Stein & Richardson, 1999). The
attention in relation to schizophrenia, (Yao & van
possible contribution of fatty acid abnormalities to
Kammen, 2004) and may be equally important in
sensory dysfunction in these disorders is discussed
related childhood neurodevelopmental disorders
elsewhere, (Richardson, Cyhlarova, & Puri, 2003;
including ADHD.
Taylor & Richardson, 2000) but omega-3 fatty
acids—particularly DHA—are critical for the devel-
opment and functioning of the visual system
Experimentalevidenceforfattyacidabnormalities
(Litman, Niu, Polozova, & Mitchell, 2001; Uauy,
in ADHD and related disorders
Hoffman, Peirano, Birch, & Birch, 2001), and
emerging evidence shows that the dietary intake of Physical signs consistent with fatty acid deficiency
HUFA can also affect the development and matura-
In animals, essential fatty acid deficiencies cause
tion of low-level auditory processing systems
physical signs and symptoms including excessive
(Haubner et al., 2002; Unay et al., 2004). Visual
thirst, frequent urination, rough, dry hair and skin,
andauditorysymptomsindyslexiahavebeenrelated
and follicular keratosis. An increased prevalence of
tophysicalsignsconsistentwithfattyaciddeficiency,
these signs in hyperactive children was first reported
(Taylor et al., 2000) and experimental studies to
25years agobyaUK support group, (Colquhoun &
follow up these observations are in progress.
Bunday, 1981) who also pointed out that fatty acid
deficiencies could help to explain other character-
istics often associated with ADHD, such as zinc
Neurotransmitter models of ADHD
deficiency (zinc is a co-factor in HUFA synthesis);
and related disorders
the apparent intolerance of some children to foods
Standard pharmacological treatment for ADHD containing salicylates (these inhibit cyclo-oxygenase
involves stimulant medications that increase the enzymes that convert AA and EPA into prostaglan-
availability of dopamine, as reflected in all current dins, and could thus exacerbate any problems
etiological theories of this condition. It is therefore stemming from low levels of these key HUFA
notable that in animal studies, chronic omega-3 derivatives); and the frequency of atopic conditions
deficiencies can reduce dopamine and its binding to in these children. Noting that non-affected siblings
D2 receptors both in frontal cortex and other brain consumed similar diets, these authors further
regions, and are associated with attentional and suggested that the primary problem might lie in
behavioural dysfunctions comparable to those poor EFA-HUFA conversion.
involved in ADHD (Takeuchi, Fukumoto, & Subsequent investigations confirmed that these
Harada, 2002; Zimmer et al., 2002). Emerging physical signs of fatty acid deficiency were more
evidence indicates that subsequent dietary supple- common in ADHD children than controls, (Stevens
mentation may be able to remedy some of the et al., 1995; Stevens, Zentall, Abate, Kuczek, &
dopaminergic abnormalities induced by omega-3 Burgess,1996)andalsoshowedthathighscoresona
deficiencies during early development, but not simple checklist rating scale devised to assess such
others (Levant, Radel, & Carlson, 2004). signswereassociatedwithlowplasmaconcentrations
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders 159
of AA, DHA and total omega-3 fatty acids. Both found (Bell et al., 2004b). Poor working memory
clinical signs and biochemical measures of fatty acid performance—a central feature of both ADHD and
status were also correlated with measures ofphysical dyslexia—wasalsorelatedtolowomega-3status,but
health and behaviour in these studies, as discussed only in dyslexic adults, not in controls (Ross et al.,
further below. 2004). In addition to making case-control compar-
In children and adults, the same physical signs isons, other researchers have also explored correla-
suggestive of fatty acid deficiency have also been tionsbetweenbloodbiochemicalindicesoffattyacid
linked with both dyslexia (Richardson et al., 2000; status and various behavioural and/or health mea-
Taylor et al., 2000) and autistic spectrum disorders sures. In a combined sample of 96 boys with and
(Bell,Sargent,Tocher,&Dick,2000;2004a).While without ADHD-type difficulties, HUFA deficiencies
these signs can obviously have other causes, their were associated with a range of behavioural and
significance and their apparent association with learning and health problems, irrespective of clinical
ADHD and related neurodevelopmental disorders diagnosis, (Stevens et al., 1996) supporting the idea
clearly merits further investigation. that fatty acid abnormalities may relate in a dimen-
sional rather than a categorical way to ADHD-type
symptoms. It was also found that low omega-6
Biochemical measures of fatty acid
concentrations related only to some physical health
status or metabolism
measures (such as dry skin and hair, frequency of
Blood fatty acid deficiencies or imbalances. Reduced colds, and antibiotic use), not to parental ratings
blood concentrations of HUFA in ADHD children of either behaviour or learning. By contrast, low
relative to controls have been reported in several omega-3 fatty acid status was associated not only
studies (Bekaroglu et al., 1996; Burgess, Stevens, with clinical ratings of physical signs consistent with
Zhang, & Peck, 2000; Burgess & Stevens, 2003; fatty acid deficiency, but also with both behavioural
Chen, Hsu, Hsu, Hwang, & Yang, 2004; Mitchell, problems(includingconductdisorder,hyperactivity-
Aman, Turbott, & Manku, 1987; Stevens et al., impulsivity, anxiety, temper tantrums and sleep
1995). Although the specific pattern of results has problems) and learning difficulties in these children.
varied, reductions of AA, DHA and total omega-3 This pattern of findings is consistent with other
have usually been found in ADHD subjects, and the evidence that omega-3 rather than omega-6 status
most consistent findings appear to be from plasma is likely to be more relevant to ADHD and related
rather than red blood cell (RBC) membranes. Thus behavioural disorders.
in one study, membrane concentrations of key
HUFA were actually elevated in ADHD children
relative to controls, while the same fatty acids were Enzyme abnormalities. A few biochemical investiga-
unusually low in plasma (Burgess & Stevens, 2003). tions have focused on particular enzymes involved
Reductions of omega-3 (in both RBC and plasma) in fatty acid metabolism. Abnormalities of phospho-
were also reported in the only study to date lipase A2 (PLA2) enzymes that selectively remove
investigating blood fatty acids in adults with HUFA from membrane phospholipids have already
ADHD (Young, Maharaj, & Conquer, 2004). In been extensively documented in schizophrenia,
childrenandadults withautistic spectrum disorders, and an initial study also found elevations of a
fatty acid abnormalities have been reported in both Type IV PLA2 enzyme in RBC membranes of
plasma(Vancasseletal.,2001)andRBCmembranes dyslexic adults (MacDonell et al., 2000). Increases
(Belletal.,2000;2004a).Findingsincludeparticular in the same PLA2 enzyme have also been reported
reductions in omega-3 HUFA, an elevated ratio of in some subgroups of children and adults with
AA:EPA (consistent with tendencies towards autistic spectrum disorders, although preliminary
inflammation) and an apparent increased suscep- observations suggested that this did not apply
tibility to breakdown of membrane fatty acids, to those already taking omega-3 supplementation
possibly reflecting increased oxidative stress. Few (Bell et al., 2004a).
blood biochemical studies have yet focused on
dyslexia, and none on dyspraxia/DCD, but one
early case report noted fatty acid deficiencies in Intepretation of the experimental evidence. Preliminary
a dyslexic child whose learning difficulties were findings fromexperimentalstudiesgenerallysupport
reduced following dietary intervention (Baker, the proposal that fatty acid abnormalities are
1985). Preliminary results from ongoing studies of associated withADHD andrelatedchildhood devel-
dyslexic and non-dyslexic adults showed that higher opmental disorders, although the evidence remains
RBC omega-3 concentrations were associated with limited. Some of the blood biochemical evidence
better reading ability in both groups, although no suggestsspecificdifficultiesinthesynthesisofHUFA
significant group differences in fatty acid status were fromtheirEFAprecursors,excessivesusceptibilityto
160 A. J. Richardson
oxidative stress and/or an unusual distribution of of the existing evidence for clinicians dealing with
fatty acids between RBC and plasma. While these ADHD and related disorders.
findings may reflect metabolic abnormalities that
have some constitutional basis, they could equally
ADHD
arise from dietary and other environmental factors
that it is not always possible to monitor, let alone The first RCT of omega-3 fatty acids for childhood
control (Hibbeln et al., 2003). Interpretation is also behaviour and learning difficulties involved 63 USA
difficult because even with biochemical measures children aged between 6 and 12 years with formal
that have good reproducibility, too little is currently diagnoses of DSM-IV ADHD (Voigt et al., 2001).
known about the functional significance of, for All were judged to be receiving effective and stable
example, RBC versus plasma fatty acid concentra- treatment with stimulant medication, and children
tions, let alone the more detailed distribution and with other psychiatric disorders (except conduct
metabolism of these fatty acids in different tissues disorder or oppositional defiance) were excluded.
and intracellular compartments. Furthermore, Subjects were randomised to adjunctive treatment
becausedietaryintakeofomega-3inmanycountries with 345mg/day of pure DHA (from an algal
is so low by historical standards, it cannot safely be source) or placebo for four months, and stimulant
assumed that reference values from control groups medicationwaswithdrawnbeforestudyassessments.
arenecessarilyoptimalwithrespecttoeitherphysical Analyses were presented on 54 subjects who
or mental health. Investigations of the functional completed the study.
significance of these kinds of measures in general No benefits of DHA treatment over placebo were
population samples are therefore needed, as well as found on a wide range of behavioural ratings or
further research into their potential relevance for computerised measures of inattention and impul-
ADHD and related disorders. sivity, despite the fact that active treatment was
associatedwithsignificantlyincreasedbloodconcen-
trations of DHA. In fact, close inspection showed
that active treatment was associated with a slightly
Clinical trials of omega-3 supplementation
worseoutcomeonalmostallmeasuresthanplacebo,
in ADHD and related developmental
although these group differences did not reach
disorders of childhood
statistical significance.
Anecdotal evidence, case reports and open Similarly negative findings came from a Japanese
studies have long suggested potential benefits study of 40 ADHD-type children aged between 6
from treatment with highly unsaturated fatty and 12 years attending a special summer camp
acids in ADHD and related childhood develop- (Hirayama, Hamazaki, & Terasawa, 2004). No
mental disorders (Baker, 1985; Stordy, 1995; 2000) formaldiagnoseswereavailableandonlysixchildren
Unfortunately, the randomised controlled trials were receiving medication, apparently owing to
(RCT) needed to investigate this possibility properly parental preferences for non-pharmacological
still remain few, although additional studies are approaches. For two months, the children received
in progress. foods fortified with DHA (providing approximately
Two early RCTs assessed the effects of evening 500mg/day) or indistinguishable control foods
primroseoil(providingtheomega-6fattyacidGLA) containing olive oil. Outcome measures included
in hyperactive or ADHD children, (Aman, Mitchell, parent and teacher ratings of ADHD symptoms
& Turbott, 1987; Arnold et al., 1989) but few if any and aggression, measures of visual and auditory
benefits were apparent. With the recognition that perception, working memory and visual-motor
omega-3 were far more likely than omega-6 to be integration, and a continuous performance test.
lacking from modern diets, and increasing evidence The only group difference initially reported was a
for omega 3 deficiency in other psychiatric disorders significant improvement between pre- and post-
inadults,theemphasisthenshiftedtowardsomega-3 treatment measures of visual and auditory memory
fattyacids.TableIprovidesasummaryoftheRCTs in the placebo group, which was not evident in
published to date that have involved omega-3 thechildrenreceivingDHA.Insubsequentanalyses,
treatment for ADHD and related childhood devel- however, slight modifications to scoring methods
opmental disorders. (combining parent and teacher ratings) indicated
Basic reviews encompassing most of these studies greater reductions in aggression for DHA supple-
canbefoundelsewhere,(Richardson,2004a;2004b) mentation over placebo (Hamazaki & Hirayama,
soaftersummarisingthekeyfindingsfromcontrolled 2004).
trials, the aim here is to focus primarily on their TheonlyotherRCTofchildrenselectedprimarily
broader interpretation, highlighting key issues for forADHD-typedifficultieswascarriedoutatPurdue
further research while also discussing the relevance University, USA, (Stevens et al., 2003) and showed
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders 161
Outcome NoeffectoftreatmentonawiderangeofbehaviouralandcomputerizedmeasuresofADHD-relatedsymptoms Active>placeboforchangesinparentratingsofADHD-relatedsymptoms Active>placeboforchangesinteacher-ratedattention,parent-ratedconduct,and%meetingclinicalcriteriaforoppositionaldefiantdisorder Noeffectoftreatmentonawiderangeofbehaviouralandpsychometricmeasures ¼ActivePlaceboforchangesinmotorfunctionActive>Placeboforchangesinteacher-ratedADHD-relatedsymptomsandage-standardisedmeasuresofreadingandspellingachievement
s
Durationoftreatmentinparallelgroup 4months 12weeksþ(12weeks) 16weeks 2months? 12weeksþ(12weeks)
s. e
ateddevelopmentaldisorder Trialdesign RCT,double-blind,parallelgroups;adjunctivetopharmacotherapy RCT,double-blind,parallelgroupsþ(one-wayplacebo-activcrossover);monotherapy RCT,double-blind,parallelgroups;adjunctivetopharmacotherapy RCT,double-blind,parallelgroups;adjunctivetopharmacotherapy RCT,double-blind,parallelgroupsþ(one-wayplacebo-activecrossover);monotherapy
el
r
d
nchildrenwithADHDan Activetreatment:þDailydosesofOmega-3Otherconstituents HA345mg(fromalgae) PA186mgDHA480mg(fromfishoil)Omega-6(GLA96mg,AA42mg)VitaminE60IU PA80mg,DHA480mg(fromfishoil)Omega-6(GLA96mg,AA40mg)VitaminE56IU PA100mgapproxDHA510mgapprox(fromfishoil&fermentedsoybeanoil) PA558mgDHA174mg(fromfishoil)Omega-6(GLA60mg)VitaminE15IU
i D E E E E
s
d
ci
a
fatty male)
omega-3 N(male,fe 54(42,12) 29(25,4) 47(41,6) 40(32,8) 117(78,39)
h
wit
nt cal
olledtrialsoftreatme Diagnosisþ(Ascertainment) SM-IVADHDwithminimalornocomorbidity(Psychiatricclinic,USA) þyslexiaADHDfeatures(Specialschool,UK) DHD-typeþdifficultiesphysicalsignsconsistentwithEFAdeficiency(Community-basedsample,USA) DHD(Specialsummercamp,Japan) SM-IVDCD(mainstreamschoolsinoneUKgeographiregion)
ntr D D A A D
o
c
TableI.Randomised Investigators Voigtetal.,2001 Richardson&Puri,2002 Stevensetal.,2003 Hamazakietal.,2004 Richardson&Montgomery,2005
162 A. J. Richardson
some modest benefits from fatty acid treatment. Following an additional 12 weeks in which there
Participants were recruited from the community by wasaone-waytreatmentcrossover(placebotoactive
advertisement, and although full psychiatric evalua- treatment) similar improvements were seen in the
tions were not available, participants had all been crossover group, while children continuing with
diagnosed with ADHD by a psychiatrist, clinical active treatment maintained or improved on their
psychologist or paediatrician according to parental earlier symptom reductions (Richardson, 2003).
report, and around 80% were receiving pharmaco-
logical treatment, mainly stimulant medications.
In an attempt to reduce heterogeneity and provide
Developmental coordination disorder
a valid test of the fatty acid hypothesis, volunteers
were further selected for elevated scores on clinical The largest trial to date of fatty acids for child
ratings of physical signs consistent with fatty acid behavioural and learning difficulties involved 117
deficiency (such as excessive thirst and dry skin). children aged 5–12 years with DSM-IV DCD,
Fifty children with a mean age of around 10 years identified from mainstream schools in one UK
were randomised to treatment for four months with geographical region (Richardson & Montgomery,
either fish oil and evening primrose oil—supplying 2005).BecauseofthehighcomorbidityofDCDwith
mainly omega-3 fatty acids (80mg EPA and 480mg dyslexia and ADHD, primary outcomes were
DHA daily) with some omega-6 (96mg GLA and
selected to reflect each of these domains, consisting
40mg AA)—or an olive oil placebo. Three recruits
ofage-standardised measuresofmotorperformance,
dropped out at a very early stage, so intention-
reading and spelling, and teacher-rated ADHD-type
to-treat analyses were conducted on 47 children.
symptoms (CTRS-L [Conners, 1997]). Active treat-
Significant benefits of active treatment over
ment was a high-EPA fish oil with some evening
placebo were found for teacher-rated attention and
primrose oil (providing 558mg EPA, 174mg DHA
parent rated conduct, as well as clinical ratings of
and 60mg GLA daily) and placebo was olive oil,
oppositional defiant disorder, but no group differ-
administered for 12 weeks in parallel groups. None
ences were seen on a range of other measures.
ofthechildrenwerereceivinganyothertreatmentfor
Interpretation was also complicated by the fact that
their behavioural and learning difficulties, and all
biochemical measures showed significant increases
analyseswereconductedonastrictintention-to-treat
for some omega-3 fatty acids in both treatment
basis.
groups, as discussed further below.
No effect of treatment was found for motor
functioning, although a clear placebo effect was
Dyslexia seen for these measures, in that both groups showed
significant improvements after 12 weeks compared
Only one peer-reviewed RCT to date has involved
with their baseline scores. By contrast, highly
children with a primary diagnosis of dyslexia
significant group differences in favour of active
(Richardson&Puri,2002).Fromchildrenattending
treatment were found for the changes in reading
a special school in the UK, volunteers were further
and spelling, and also for a wide range of ADHD-
selected for scoring >1SD above population norma-
related symptoms. With respect to literacy skills,
tive values on age-standardized parent ratings
average gains for children on active treatment were
of inattention, hyperactivity and combined-type
three times the normal expected rate of progress for
ADHD symptoms (a criterion met by 41 of 74
reading and twice the normal rate for spelling, while
children screened). No child had a formal ADHD
children on placebo made only the age-expected
diagnosis, however, or was receiving any treatment
progress in reading and fell further behind in
for this condition. Parent-rated ADHD-type symp-
toms were the primary outcome measure, and spelling. On teacher ratings of ADHD, significant
children were treated for 12 weeks with either an improvementsforactivetreatmentoverplacebowere
omega-3/omega-6 combination very similar to that seen on almost all the symptom scales, with
used in the Purdue study, or an olive oil placebo. reductions of 0.3 and just over 0.5 SD on the core
In this pilot study, analyses were conducted only ADHD dimensions of hyperactivity and inattention
on the 29 children who completed the 12 week respectively.
study period. In the follow-up period involving a one-way
Groupcomparisonsshowedanadvantageofactive treatmentcrossover,childrenswitchingfromplacebo
treatment over placebo for changes in all compo- to active treatment made gains similar to those
nents of the rating scales used (CPRS-L [Conners, shown by children on active treatment during the
1997]) but these differences reached significance main parallel group phase, while those continuing
only for inattention, anxiety/withdrawal and with active treatment maintained or improved on
one global measure of disruptive behaviour. their earlier progress.
Omega-3 fatty acids in ADHD and related neurodevelopmental disorders 163
Interpretation of findings from controlled good rationale for including more females in future
treatment trials studies of ADHD and related conditions.
At this stage, controlled trials of omega-3 fatty acids
as a treatment for ADHD and related conditions
Clinical diagnosis. Treatment trials to date have
remain too few, and their findings too diverse, for
typically focused on one particular diagnostic cate-
any firm conclusions to be drawn. Most studies in
gory, be this ADHD, dyslexia or DCD/dyspraxia.
this area have been small and researcher-led, using
Given the substantial heterogeneity and comorbidity
different populations, outcome measures, and treat-
associated with these conditions, however, and the
ment formulations. Although direct comparisons
fact that all these diagnoses are based on purely
between these studies, or a clear synthesis of their
behavioural criteria, it seems a priori unlikely that
collective findings, is therefore difficult, the balance
omega-3 deficiency would play a major role in more
of evidence to date does suggest that supplemen-
than a subset of children within any particular
tation with highly unsaturated omega-3 fatty acids
diagnostic category. In the studies of ADHD-type
may improve behaviour and learning in at least
children, differences in selection criteria might help
some children with dyslexia, dyspraxia or ADHD.
to account for at least some of the inconsistency in
The findings from these studies have also illumi-
findings. The negative USA study (Voigt et al.,
nated several key issues that now need further 2001)usedastrictDSM-IVdiagnosisofADHDand
investigation, and provided useful pointers for the deliberatelyruledoutmostpsychiatriccomorbidities,
design of future research studies. An evaluation of while the only positive study focusing on ADHD
the existing evidence is therefore offered here with (also from the USA) involved a community-based
particular reference to these issues, followed by sampleofchildreninwhomhighcomorbiditywould
discussion of their potential clinical implications. normally be expected, and who were also pre-
selected for showing physical signs consistent
with fatty acid deficiency (Stevens et al., 2003).
Thetwootherpositivestudiesinvolvedchildrenwith
Key issues for future research
a primary diagnosis of either dyslexia (Richardson &
Populations studied Puri, 2002) or dyspraxia/DCD, (Richardson &
Montgomery, 2005), and although ADHD symp-
Ageandsex. Treatmenttrialsofomega-3fattyacids
tomswereaprimaryoutcomemeasureinbothtrials,
for ADHD and related disorders have primarily
none of the children studied had a formal ADHD
involvedchildrenagedfrom5–13yearsofage.These
diagnosis. On average, their pre-treatment scores on
disorders are usually evident in infancy, however,
age-standardizedparentorteacherratingscaleswere
and also persist into adulthood, so there is a clear
only around one standard deviation above the mean
need for studies of younger children as well as
for the general population, although up to one third
adolescents and adults. Possible sex differences in
scored more than 2 SD above this level, placing
both behavioural correlates of omega-3 status and
them well inside the usual clinical range for ADHD.
responsetotreatment alsodeserve specificinvestiga-
Improvements following fatty acid treatment
tion. Existing studies have included far more males
appeared to apply to both lower and higher-scoring
thanfemales,asisthecasewithresearchintoADHD
children, suggesting that a trait-based or symptom-
in general, (Arnold, 1996) but this probably reflects
based approach using dimensional measures may be
ascertainmentbiasratherthantherelativeprevalence
more appropriate than a reliance on categorical
of these disorders by sex in the general population.
diagnoses.
As already noted, males have a higher risk of HUFA
deficiencies than females owing to sex differences in
fatty acid metabolism, but the potential significance Other selection criteria. Biological markers (genetic
ofthesedifferencesforbehaviour,learningandmood or biochemical) that could reliably index fatty acid
iscurrentlyunknown.Preliminaryevidencefromthe status and/or individual metabolic differences would
studies reviewed here suggests that attentional seem a more promising way to identify individuals
difficulties (and perhaps impulsivity) may respond who may be particularly likely to benefit from fatty
better to omega-3 treatment than hyperactivity acid treatment. Unfortunately, however, the devel-
per se, and the predominantly inattentive subtype opment of such markers still requires further
of ADHD is relatively more common in girls. In research. Blood fatty acid profiles were monitored
addition, some successful trials of omega-3 in adults intwoofthethreetreatmenttrialsinvolvingADHD-
with mood-related disorders have involved predomi- type children, but only in the Purdue study were
nantly or exclusively female samples, (Stoll et al., subjects pre-selected in any way according to
1999; Zanarini & Frankenburg, 2003) so there is a presumed fatty acid status, (Stevens et al., 2003)
164 A. J. Richardson
and this was done using checklist ratings of physical containing both EPA and DHA in varying ratios.
signs and symptoms previously found to correlate By contrast, the negative studies both involved
with blood biochemical measures of fatty acid treatment primarily or exclusively with DHA
deficiency. In fact, 75% of the initial respondents (Hirayama et al., 2004; Voigt et al., 2001). This
met this criterion, but blood biochemical measures pattern of findings is consistent with other evidence
takenatthepre-treatmentbaselinelaterrevealedthat from studies of adult psychiatric patients, suggesting
these children in fact had unusually high membrane that EPA may be more effective than DHA in the
concentrations of key omega-3 (and omega-6 treatment of functional disturbances of attention,
HUFA) relative to non-ADHD controls, although cognitionormood.ThusDHAwasineffectiveinthe
they did show relative deficiencies of the same fatty few studies using primarily or exclusively this fatty
acidsinplasma(Burgess&Stevens,2003).Verylittle acid in either major depression or schizophrenia,
isyetknownaboutthenormalrangeofbloodHUFA (Marangell et al., 2003; Peet, Brind, Ramchand,
concentrations in the general population or their Shah, & Vankar, 2001; Silvers et al., 2005) while
functional significance, but it is notable that the trialsusingprimarilyorexclusivelyEPAhaveusually
ADHDchildreninthisstudystillappearedtobenefit shown some benefits in these conditions, (Nemets
from supplementation despite their apparently high et al., 2002; Peet & Horrobin, 2002; Peet et al.,
blood fatty acid status pre-treatment. 2002; Su et al., 2003) although not in all cases
In summary, although existing studies have shown (Fentonetal.,2001).PureethylEPAhasalsoshown
that at least some children with ADHD and related some benefits in other disorders such as Borderline
disorders can benefit from omega-3 treatment, Personality Disorder and Huntington’s disease (Puri
several important issues still remain to be explored. et al., 2005; Zanarini & Frankenburg, 2003). While
it is DHA that matters most in the structure of
. Within ADHD, might omega-3 fatty acids be
neuronal membranes, EPA nonetheless plays many
particularly (or only) beneficial for children with
critical roles in brain function. Its eicosanoid
particularpatternsofcomorbidity—suchasmood
derivatives are key regulators of immune, endocrine
disorders, oppositional defiance and/or specific
and cardiovascular functions, and direct actions of
learning difficulties?
EPA on cyclo-oxygenases, lipoxygenases, phospholi-
. Is omega-3 more helpful for children with milder
pases, acylating systems, ion channels, mitochondria
ADHD-type difficulties than for those with more
and peroxisome proliferator-activated receptors
extreme symptoms?
(PPARs) are the focus of current investigations
. What proportion of children in the general
across many different fields of study. Existing
population might benefit from an increased
evidence indicates that EPA is likely to be more
dietary intake of omega-3 fatty acids?
effective than DHA for the conditions considered
Mostofthesequestionswouldbebestaddressedvia here, but further studies involving direct compar-
large-scale studies, ideally drawing from samples isons, anddifferent ratiosofEPAandDHA, arestill
representative of the general population. needed to investigate this issue.
Omega-3 treatment formulations and dosages
Omega-6 and antioxidant components. In all three of
The optimal composition and dosage of fatty acid thepositivetrials,butnotinthetwonegativestudies,
treatment for ADHD and related conditions also the active treatments also contained both some
requiressystematicinvestigation. Studiesinthisarea omega-6 fatty acids in the form of evening primrose
so far have used supplements containing varying oil, and also some vitamin E. (The latter is often
amounts of the highly unsaturated omega-3 EPA added to specialist fish oil supplements for its
and/or DHA, mainly from fish oils. None have used antioxidant properties in protecting membrane
flax oil or other sources of ALA, although a recent HUFA from peroxidation, although recent research
study explored the effects of high doses of flax oil indicates reciprocal effects, in that HUFA supple-
versus fish oils on blood fatty acids in adults with mentationmayalsohelptoenhanceVitaminEstatus
ADHD, and again confirmed the poor in vivo [Kaempf Rotzoll, Hellstern, & Linderkamp, 2003]).
conversion of ALA from the former into EPA and Despite the fact that two early trials of evening
DHA (Young, Conquer, & Thomas, 2005). primrose oil alone for ADHD gave essentially
negative results, (Aman et al., 1987; Arnold et al.,
1989) the possibility that this may have made some
Omega-3: EPA versus DHA. In the three positive contribution to the benefits observed cannot yet be
studies (Richardson & Montgomery, 2005; ruled out. Studies using EPA-rich fish oils without
Richardson & Puri, 2002; Stevens et al., 2003), any omega-6 component are now in progress, which
treatment consisted predominantly of fish oils, may help to address this. The possible contribution