Reprod. Nutr. Dev. 45 (2005) 1–28
© INRA, EDP Sciences, 2005
Omega-3 fatty acids and neuropsychiatric disorders
Genevieve YOUNGa, Julie CONQUERa,b*
a Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
b RGB Consulting, London, Ontario, Canada
(Received 24 September 2004; accepted 24 November 2004)
Abstract – Epidemiological evidence suggests that dietary consumption of the long chain omega-3
fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), commonly found in fish
or fish oil, may modify the risk for certain neuropsychiatric disorders. As evidence, decreased blood
levels of omega-3 fatty acids have been associated with several neuropsychiatric conditions,
including Attention Deficit (Hyperactivity) Disorder, Alzheimer’s Disease, Schizophrenia and
Depression. Supplementation studies, using individual or combination omega-3 fatty acids, suggest
the possibility for decreased symptoms associated with some of these conditions. Thus far, however,
the benefits of supplementation, in terms of decreasing disease risk and/or aiding in symptom
management, are not clear and more research is needed. The reasons for blood fatty acid alterations
in these disorders are not known, nor are the potential mechanisms by which omega-3 fatty acids
may function in normal neuronal activity and neuropsychiatric disease prevention and/or treatment.
It is clear, however, that DHA is the predominant n-3 fatty acid found in the brain and that EPA
plays an important role as an anti-inflammatory precursor. Both DHA and EPA can be linked with
many aspects of neural function, including neurotransmission, membrane fluidity, ion channel and
enzyme regulation and gene expression. This review summarizes the knowledge in terms of dietary
omega-3 fatty acid intake and metabolism, as well as evidence pointing to potential mechanisms of
omega-3 fatty acids in normal brain functioning, development of neuropsychiatric disorders and
efficacy of omega-3 fatty acid supplementation in terms of symptom management.
Alzheimer’s disease / attention deficit hyperactivity disorder / autism / depression /
neuropsychiatric disorders / omega-3 fatty acids / post partum depression / schizophrenia
Ach: acetylcholine, AD: Alzheimer’s disease, AA: arachidonic acid, ADD: attention deficit disorder,
ADHD: attention deficit hyperactivity disorder, AI: adequate intake, ALA: alpha-linolenic acid,
BPD: borderline personality disorder, CE: cholesterol ester, DGLA: dihomogammalinolenic acid,
DHA: docosahexaenoic acid, DPA: docosapentaenoic acid, EPA: eicosapentaenoic acid, EFA:
essential fatty acid, GLA: gamma linolenic acid, IFN: interferon, IL-1: interleukin-1, IL-2:
interleukin-2, IL-6: interleukin-6, LTB4: leukotriene B4, LTB5: leukotriene B5, LA: linoleic acid,
LCPUFA: long chain polyunsaturated fatty acids, MMSE: mini mental state examination, NE:
norepinephrine, OCD: obsessive compulsive disorder, PPAR: peroxisome proliferated activated
receptor, PANSS: positive and negative symptom scale, PPD: post partum depression, PG:
prostaglandin, PL: phospholipids, PLA2: phospholipase A2, RBC: red blood cell, SSRI: selective
serotonin reuptake inhibitor, SREBP: sterol regulatory element binding protein, TG: triglycerides,
TNF: tumour necrosis factor.
* Corresponding author: firstname.lastname@example.org
2 G. Young, J. Conquer
In the past decade, interest has surged in
the area of omega-3 fatty acids and their
role in normal brain functioning and neu-
ropsychiatric disease treatment and preven-
tion. Although omega-3 fatty acids are present
in plant-based sources such as alpha-lino-
lenic acid (ALA; 18:3n-3), this review will
focus mainly on the animal derived long
chain n-3 polyunsaturated fatty acids (eicos-
apentaenoic acid; EPA; 20:5n-3 and docosa-
hexaenoic acid; DHA; 22:6n-3). As indicated
herein, epidemiological evidence suggests
that dietary consumption of omega-3 fatty
acids may decrease the risk for certain neu-
ropsychiatric disorders. This review will
summarize the knowledge of omega-3 fatty
acids in terms of dietary intake and metab-
olism, as well as evidence pointing to poten-
tial mechanisms of omega-3 fatty acids in
normal brain functioning and development
of neuropsychiatric disorders. Evidence for
altered omega-3 fatty acid status and sup-
plementation trials will be given for disor-
ders such as Attention Deficit (Hyperactiv-
ity) Disorder, Alzheimer’s disease and other
dementias, Schizophrenia, Depression and
Post-Partum Depression, as well as various
developmental disorders. The information
in this review was obtained after extensive
MedLine searching of each topic area. Ref-
erences from obtained papers that were not
available on MedLine were also used.
2. OMEGA-3 FATTY ACIDS:
BIOCHEMISTRY AND DIETARY
ALA, EPA and DHA are the most com-
mon omega-3 fatty acids in the diet and will
be discussed in more detail below. Until
fairly recently, the commonly accepted path-
way for the metabolic conversion of ALA
to DHA involved the sequential utilization
of delta-6, 5-, and 4-desaturases along with
elongation reactions (2 carbon additions)
(Fig. 1). It has been demonstrated, however,
that the metabolism of docosapentaenoic acid
(DPA; 22:5n-3) is independent of delta-4
desaturase, and instead involves microsomal
elongation of 22:5n-3 to 24:5n-3, followed
by desaturation to 24:6n-3 and peroxisomal
retroconversion to 22:6n-3 . The conver-
sion of ALA to LCPUFA (EPA, DPA, and
DHA) is limited in humans and has been
estimated to be anywhere from less than 1%
to 6% [2, 3], reviewed in ). Interestingly,
DHA can also be “retroconverted” to EPA
at rates in humans of about 10% [5, 6].
Figure 1. Pathway by which unsaturated omega-3
fatty acids are converted to long-chain polyun-
saturated fatty acids in animals.
Omega-3 and neuropsychiatric disorders3
Historical evidence suggests that human
beings evolved consuming a diet that con-
tained approximately 1-2 n-6 fatty acids for
each n-3 fatty acid . However, the current
Western diet contains a ratio of up to 20–
30:1, which means that the present diet is
deficient in n-3 fatty acids compared to that
on which our genetic patterns were estab-
lished . Today’s intake of n-3 fatty acids
is lower because of the decrease in con-
sumption of fish and wild game, and because
modern agriculture emphasizes consump-
tion of cereal grains by animals destined for
meat production. Also, the consumption of
plant-derived oils which contain large amounts
of n-6’s and minimal n-3’s has increased.
Furthermore, cultured fish and eggs, culti-
vated vegetables, and domestic animals con-
tain fewer n-3 fatty acids than do their wild
counterparts . Some common vegetable
oils, including soybean, canola and flax-
seed oil, are concentrated sources of ALA
in the diet, while fatty fish, such as halibut,
mackerel, herring, and salmon are concen-
trated sources of EPA and DHA. Other
sources of dietary n-3 fatty acids are nuts,
seeds, fruits, vegetables, and egg yolks .
It has also recently been demonstrated that
meat, which is a concentrated source of
DPA, is a significant contributor of long-
chain dietary n-3 fatty acids, with beef and
lamb contributing more of these fatty acids
than pork and poultry . Table I shows
the ALA, EPA, and DHA fatty acid content
of fish, shellfish, fish oils, nuts and seeds,
and plant oils that contribute n-3’s to the
An analysis of the consumption of n-3
fatty acids in various populations shows
that modern societies consume low levels
of these dietary lipids, and this has led to the
establishment of guidelines concerning their
recommended daily intake. In the United
States, it has been recommended that EPA
and DHA be consumed at an intake of
0.65 g·d–1, which is a 4-fold increase from
the current level of consumption of 0.1–
0.2 g·d–1 . The adequate intake (AI) for
LNA has been set at 1.6 and 1.1 g per day
(adult men/women), and the target intake
for EPA and DHA has been set at 160 or
110 mg per day (adult men/women) . In
Britain, the British Nutrition Foundation
Task Force on Unsaturated Fatty Acids rec-
ommends a daily intake of 0.5–1.0 g of
long-chain polyunsaturated n-3 fatty acids,
which they suggest can be achieved through
the consumption of an intake equivalent to
1–2 portions of oily fish per week .
Even in Japan, where seafood has tradition-
ally been consumed at very high levels, the
ratio of n-6 to n-3 fatty acids is increasing
as diets become more westernized, leading
some authors to suggest that fish consump-
tion be increased, particularly amongst young
people . In addition to increasing fish con-
sumption, alternative strategies for increasing
levels of n-3 fatty acids in the diet, and/or
decreasing the n-6:n-3 fatty acid ratio, include
use of n-3 fatty acid supplements, consump-
tion of other n-3 containing foods such as
flax, and decreasing the intake of n-6 rich
vegetable oils such as corn and sunflower
oil . There are also several new products
available in North America that have been
supplemented with n-3 fatty acids (both
short and long chain) including eggs, milk,
and bread. Table II shows the fatty acid con-
tent of some commercially available n-3
supplemented food products.
3. N-3 FATTY ACIDS
AND THE BRAIN
In the human body, ALA is found pri-
marily in triglycerides (TG), in cholesterol
esters (CE), and in very small amounts in
phospholipids (PL); EPA is found prima-
rily in CE, TG, and PL; and DHA is found
primarily in PL, and is highly concentrated
in the cerebral cortex, retina, testes and sperm
. In fact, DHA makes up a large propor-
tion of the brain’s lipids, and is the predom-
inant n-3 fatty acid found in this organ .
The structural predominance of DHA in the
brain suggests functional significance, and
as will be demonstrated, both DHA and its
long-chain counterpart EPA can be linked
with several aspects of neural function, includ-
ing, but not limited to, phospholipase A2
4 G. Young, J. Conquer
Table I. The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample
of commonly consumed fish, shellfish, fish oils, nuts and seeds, and plant oils that contain at least
5 g of omega-3 fatty acids per 100 g*.
Food ItemEPA DHAALA
Cod, Atlantic and Pacific
Halibut, Atlantic and Pacific
Mackerel, Pacific and Jack
Ocean Perch, Atlantic
Salmon, Atlantic, Farmed
Salmon, Atlantic, Wild
Seabass, Mixed Species
Trout, Rainbow, Farmed
Trout, Rainbow, Wild
Tuna, Fresh, Bluefin
Tuna, Fresh, Yellowfin
Whitefish, Mixed Species
Clam, Mixed Species
Scallop, Mixed Species
Shrimp, Mixed Species
Cod Liver Oil
Nuts and Seeds
* Adapted from .
† Trace = < 0.1.
Omega-3 and neuropsychiatric disorders5
(PLA2) activity, inflammation, neurotrans-
missio, membrane fluidity, oxidation, ion
channel and enzyme regulation, and gene
expression. Each of these functions will be
considered in terms of their relationship
with the n-3 polyunsaturated fatty acids,
and when available, evidence linking them
with various neuropsychiatric disorders will
3.1. Phospholipase A2
PLA2 is an enzyme that acts on the sn-2
position of phospholipids, thereby generat-
ing a free fatty acid, such as arachidonic acid
(AA; 20:4n-6), EPA or DHA, and a lyso-
phospholipid . Several classes of PLA2
exist in the brain , with the highest
expression of PLA2 seen in the hippocam-
pus , a region of the brain that is related
to learning and memory . While the
function of PLA2 in the human nervous sys-
tem has not been fully elucidated, it has
been implicated in the processes of phos-
pholipid turnover, neurotransmitter release,
detoxification, exocytosis, and membrane
remodelling , and the free fatty acid and
lysophospholipid produced by its action are
known to be highly active cell signalling
A pathological increase in the activity of
PLA2 has been observed in several neu-
ropsychiatric disorders, including schizo-
phrenia. Analysis of the serum levels of
PLA2 in schizophrenics showed increased
levels of activity , and magnetic reso-
nance imaging of the cerebral cortex of
schizophrenics confirmed an increased rate
of phospholipid breakdown . Conse-
quently, Horrobin et al.  proposed the
membrane phospholipid hypothesis of schiz-
ophrenia, which states that the disease is
caused by variations in phospholipid bio-
chemistry associated with increased loss of
highly polyunsaturated fatty acids from mem-
branes owing to enhanced activity of PLA2.
Genetic abnormalities have since been
observed in a gene linked to PLA2 in schiz-
ophrenics thus further substantiating this
hypothesis . Similarly, levels of PLA2
have been shown to be increased in the
blood of dyslexics, leading to the sugges-
tion that dyslexia may be on a continuum
with schizophrenia .
Elevated serum PLA2 has also been found
in patients with depression and bipolar dis-
ease . Further evidence supporting the
association between increased PLA2 activ-
ity and these conditions comes from analy-
sis of the biochemical mechanisms of the
drug lithium, which has been used success-
fully in the treatment of both disorders.
Lithium has been shown to be a strong
inhibitor of PLA2 in the brain via interfer-
ence with transcriptional or post-transla-
tional regulation of the enzyme . This
occurs within the human therapeutic range,
unlike some of the other biochemical effects
of lithium, making inhibition of PLA2 a
likely primary mechanism of action of this
drug . Similarly, carbamazepine, an anti-
convulsant drug with mood regulating prop-
erties also used in the treatment of bipolar
disorder, has similar down-regulating effects
Table II. Omega-3 fatty acid content of commercially available omega-3 enriched foods.
ProductTotal omega-3 content DHA content
Omega-3 enriched eggs
Gray Ridge® egg farms 
Omega-3 enriched milk
Neilson Dairy® Oh! 
0.02 mg·cup–1 (homogenized)
0.01 mg·cup–1 (2%)
0.02 mg·cup–1 (homogenized)
0.01 mg·cup–1 (2%)
Omega-3 enriched bread
Tip Top® UP 
0.27 g·2 slices–1
0.27 g·2 slices–1
6 G. Young, J. Conquer
on PLA2 . While structural variations at
or around the PLA2 gene appear to increase
susceptibility to depression , the same
observation has not been made in bipolar
disease . Moreover, brain activity of
PLA2 was found to be normal in a study of
bipolar patients .
Like lithium, EPA has been shown to
inhibit PLA2 activity , and administra-
tion of EPA has shown some success in the
treatment of schizophrenia  and bipolar
disorder . Dietary lipids began to be
suspected in the aetiology of schizophrenia
more than two decades ago, when it was
found that the ratio of saturated to polyun-
saturated fat was a strong predictor of the
outcome of schizophrenia . Subsequently,
nutritional analysis revealed that a lower
intake of EPA was associated with more
severe psychopathlogy and tardive dyski-
Many mood disorders appear to be linked
to immune system activation, as evidenced
by overactivity of the inflammatory response.
In patients with major depression, there is
a higher expression of T-cell activation mark-
ers, suggesting a systemic immune activa-
tion . Similarly, plasma levels of inter-
leukin-6 (IL-6) and interleukin-2 (IL-2) in
bipolar patients were found to be signifi-
cantly higher than normal controls, suggest-
ing an increase in cell mediated immune
function . An increase in IL-2 concen-
trations has also been shown in schizo-
phrenics , and all three of the aforemen-
tioned conditions are accompanied by an
acute phase protein response, which is
thought to reflect an increased production
of various cytokines . Psychotropic
drugs have a suppressive effect on IL-6
secretion in schizophrenic patients ,
and acute phase proteins can be suppressed
by treatment with psychotropic drugs in
patients with mania, depression, and schiz-
There is also evidence supporting the
role of inflammation in neurodevelopmen-
tal diseases. Genetic studies have shown
that in children with ADHD, genetic poly-
morphism in the interleukin-1 (IL-1) antag-
onist gene can both increase and decrease
ADHD risk, depending on the allelic vari-
ation . Biochemical studies have shown
that children with autistic spectrum disor-
ders display an increase in the production of
TNF-alpha relative to controls when chal-
lenged with a stimulant for innate immunity
, and that there is an increase in the pro-
duction of IL-1 receptor antagonist and inter-
feron-gamma (INF-gamma) in children with
N-3 fatty acids, when consumed in ade-
quate amounts, can exert anti-inflammatory
actions in vivo. This is primarily accom-
plished through modification of the produc-
tion of cytokines and eicosanoids. IL-1 has
been shown to decrease , while tumor
necrosis factor (TNF) has been shown to
increase, as a consequence of fish oil feed-
ing , thereby reducing inflammation.
The reduction in levels of IL-1 may have
behavioral consequences, since this cytokine
has been shown to induce stress, anxiety-
like behavior, and deficits in spatial mem-
ory in rats, changes which are attenuated by
administration of dietary EPA [46, 47].
Similarly, increasing the consumption of
n-3 fatty acids, particularly the long-chain
polyunsaturated n-3’s, tends to shift the bal-
ance of eicosanoid production from pro- to
anti-inflammatory mediators . For exam-
ple, increasing the amount of EPA in the
diet causes a shift in the production of the
inflammatory eicosanoid leukotriene B4
(LTB4) to the production of the anti-inflam-
matory leukotriene B5 (LTB5), thereby atten-
uating the inflammatory response .
Because of the relationship between inflam-
mation and the pathology of many neuropsy-
chiatric diseases, the influence of n-3 fatty
acids on this physiological process is impor-
tant to consider.
Neurotransmitters are molecules that
mediate intercellular communication .
Omega-3 and neuropsychiatric disorders7
Dopamine is a neurotransmitter that influ-
ences cognitive functions such as learning
and motivation , while serotonin is
involved in modulating emotion and cogni-
tion . Levels of neurotransmitters have
been shown to be affected by diet, which is
not surprising considering that many, includ-
ing serotonin and dopamine, are derived from
nutrient precursors. Serotonin is derived from
the amino acid tryptophan while dopamine
is derived from the amino acid tyrosine .
Modulation of neurotransmitter levels has
long been viewed as a causative factor in
both unipolar and bipolar depression .
In unipolar depression, therapeutic drugs of
the selective serotonin reuptake inhibitor
(SSRI) class act to increase serotonin neu-
rotransmission; for example, fluoxetine (Pro-
zac) increases the concentration of serot-
onin in the synapse by inhibiting reuptake
into the cell . In contrast, pimozide,
which is used in the treatment of bipolar dis-
ease, acts on dopamine receptors . In vivo,
serotonin transporter density is reduced in
depressed patients , and certain variants
of the serotonin transporter gene have been
associated with the disease . Genetic
variation of the serotonin transporter gene
has also been associated with bipolar dis-
ease, as it appears to be a predictor of abnor-
mal response to antidepressant therapy .
Modulation of neurotransmitter levels have
also been suspected in neurodevelopmental
disorders such as ADHD and dyslexia. Sin-
gle emission computed tomography has found
that adults with ADHD exhibit increased
striatal availability of a dopamine transporter
, and medications used to treat ADHD
commonly exert their effect via inhibition
of this transporter . Polymorphisms of
both the dopamine receptor and dopamine
transporter genes have been observed in
ADHD , and ADHD has been linked to
a variant of the serotonin-2A receptor gene
. However, dyslexia, which shows a
high level of comorbidity with ADHD ,
has failed to show similar genetic associa-
tions [64, 65], and there is little evidence to
support an association between neurotrans-
mitter modulation and this disorder.
Neurotransmitters, particularly dopamine,
have similarly been a focus of investigation
in the study of schizophrenia. While it was
previously thought that the symptoms of
schizophrenia were primarily due to an excess
of dopamine in the brain, in a recent re-eval-
uation of this hypothesis, Abi-Dargham 
suggested that the brain of schizophrenic
patients produces more dopamine than nor-
mal brains in the subcortical region and less
dopamine than normal brains in the cortex.
Considerable supportive evidence for the
involvement of dopamine in schizophrenia
comes from analysis of drugs that influence
levels of this neurotransmitter in the brain.
Anti-psychotic drugs, such as haloperidol
and chlorpromazine, act by blocking dopamine
receptors in the brain , whereas drugs
such as methylphenidate that elevate dopamine
in the brain have been shown to exacerbate
symptoms . Genetic polymorphisms of
dopamine genes have been investigated quite
extensively, and studies have yielded both
positive and negative results [69–71], sug-
gesting that in some patients genes may
play a role in the disease.
In addition to dopamine, serotonin has
also been a focus of schizophrenic research.
In 1954, Wooley and Shaw  proposed
that schizophrenia was related to alterations
in serotonergic neurotransmission, since LSD,
which shows structural similarity to serot-
onin, induces psychotic symptoms in nor-
mal individuals. In support of this theory,
clozapine, which is a traditional anti-psy-
chotic drug, is a serotonergic antagonist
, and some new medications function as
both serotonin and dopamine modulators
. As with dopamine, studies investigat-
ing a genetic link between serotonin genes
and schizophrenia have produced both pos-
itive and negative findings [75–77], thus
suggesting that variation of serotonin related
genes may influence the disease.
Although they do not serve directly as
substrates for the formation of serotonin
and dopamine, n-3 polyunsaturated fatty
acids have been shown to influence levels
of these molecules in the brain. When pig-
lets are fed a diet deficient in AA and DHA,
8 G. Young, J. Conquer
there is a decrease in both dopamine and
serotonin concentration in the frontal cor-
tex . Conversely, when their diet was
supplemented with AA and DHA, piglets
showed an increase in the frontal cortex
concentration of serotonin, possibly due to
a decrease in degradation . A similar
situation has been found in rats, who when
fed a diet deficient in n-3 fatty acids, dis-
played inadequate storage of newly synthe-
sized dopamine , as well as an overall
reduction in the dopaminergic vesicle pool
. Alternatively, when rats are fed fish
oil, there is a 40% increase in frontal cortex
dopamine concentrations as well as a greater
binding to dopamine D2 receptors . Ser-
otonergic neurotransmission has also been
shown to be modulated by dietary n-3 poly-
unsaturated fatty acids, with dietary defi-
ciency causing an increase in higher levels
of basal serotonin but a decrease in the
amount released during synaptic transmis-
Acetylcholine (Ach), another neurotrans-
mitter found in the brain, is also modulated
by dietary n-3 fatty acids. Acetylcholine has
been implicated in the etiology of several neu-
ropsychiatric disorders, including Alzhe-
imer’s disease , schizophrenia , and
bipolar disorder . Following a dietary
induced reduction in brain phospholipid
DHA, administration of a DHA enriched
diet increases basal levels of brain Ach .
Moreover, an increase in cerebral Ach lev-
els following administration of dietary DHA
is correlated with an improved performance
in passive avoidance tasks in a model of
stroke-prone spontaneously hypertensive
rats . This could be because an n-3 defi-
cient diet, which leads to a loss of DHA in
both the hippocampus and frontal cortex,
causes changes in cholinergic neurotrans-
mission in the hippocampus only . The
hippocampus is a region of the brain that is
closely associated with learning, attention,
and memory .
The influence of n-3 fatty acids on neu-
rotransmission may be related to the pro-
duction of eicosanoids, since in addition to
their role in inflammation and immune respon-
siveness, eicosanoids also modify neuro-
transmitter release . The eicosanoid pros-
taglandin (PG) E2 appears to play a role in
dopaminergic transmission in the brain
, and is known to act on the receptor of
the inhibitory neurotransmitter glycine to
reduce synaptic transmission . PGD2
increases brain serotonin content and turn-
over [(93], and PGE1 and PGE2 have an
inhibitory effect on serotonin release .
Eicosanoids also affect levels of signal trans-
ducing molecules such as cyclic AMP .
Therefore, eicosanoids may act to affect
neurotransmitter release and modify synap-
tic strength, thereby influencing various
processes that are central to cognitive func-
3.4. Oxidative stress
Free radicals are generated under normal
physiological conditions, and play impor-
tant roles in a variety of biological proc-
esses. However, when these molecules are
generated in excess, they can initiate spon-
taneous chain reactions that may have neg-
ative consequences, such as abnormal neu-
rodevelopment and neuronal function .
Free radicals are considered unstable because
they carry one or more unpaired electrons,
which make them highly reactive. Exam-
ples of free radicals are superoxide radical,
hydroxy radical, and nitric oxide, all of
which are oxygen-containing species and
are therefore referred to as oxyradicals.
These oxyradicals can react with polyun-
saturated fatty acids, and cell membranes of
tissues exposed to high concentrations of
oxygen, such as the brain, are susceptible to
oxidation because of the presence of
unsaturated fatty acids in their phospholip-
ids . Oxyradicals are eliminated by
enzymes such as superoxide dismutase,
glutathione peroxidase, and catalase, endog-
enous antioxidants such as glutathione and
uric acid, and dietary antioxidants such as
vitamins E and C .
While it is generally accepted that oxida-
tive cell damage likely plays a role in many
Omega-3 and neuropsychiatric disorders9
neuropsychiatric conditions including Alzhe-
imer’s disease  neurodevelopmental dis-
orders , and schizophrenia , there
are several different methods of evaluating
oxidative damage, and this must be consid-
ered when assessing the available research.
For example, one study of depressive patients
that looked at different measures of oxida-
tive stress in both plasma and saliva found
that while catalase and total peroxidase
activity were increased in both body fluids,
the activity of superoxide elimination was
decreased in the plasma but increased in the
saliva . However, taken together the
findings cumulatively suggest an increased
level of oxidative stress in depression, and
this is corroborated by the results of other
studies [103–105]. Similarly, in children with
ADHD, exhalant ethane, which is a non-
invasive marker of oxidative damage to n-
3 fatty acids, is increased, suggesting that
some patients with the condition may show
an increased breakdown of n-3 polyunsat-
urated fatty acids . Moreover, schizo-
phrenic patients have shown deficits in both
non-enzymatic antioxidant  and enzy-
matic antioxidant [108, 109] function, and
there is considerable evidence to suggest
increased oxidative stress in patients with
Alzheimer’s disease [110–112]. It is unknown
whether oxidative stress is the primary event
in the pathophysiology of the aforementioned
conditions, or whether it is a secondary con-
tributor to deterioration and poor clinical
N-3 fatty acids may influence oxidative
pathology via replacement of lost mem-
brane phospholipid polyunsaturated fatty
acids following attack by oxyradicals .
In animals, consumption of dietary n-3 fatty
acids has been shown to modulate levels of
these in the brain , and human serum
and erythrocyte phospholipids are very
responsive to dietary n-3 modulation [114–
116]. Because of the vulnerability of lipids
to attack by oxyradicals, it has been sug-
gested that supplementation with n-3 poly-
unsaturated fatty acids should be accompa-
nied by cotreatment with an antioxidant .
However, despite an often cited concern
of an n-3 induced increase in oxidative stress
with fatty acid supplementation, the avail-
able evidence does not appear to support
this contention. In fact, there is evidence to
the contrary demonstrating that EPA and
DHA in fact reduce oxidative stress. Meas-
urement of F2-isoprostanes, which reflect
in vivo lipid production and oxidant stress,
were shown to decrease following dietary
supplementation with either EPA or DHA
, as well as with a daily meal of fish
. N-3 fatty acids may do this by mod-
ifying the activity of antioxidant enzymes,
since there is evidence demonstrating an
increase in the activity of both xanthine oxi-
dase  and superoxide dismutase 
following consumption of an n-3 rich diet.
The antioxidant effect of n-3 fatty acids has
even been shown to extend to neonates fol-
lowing daily maternal fish oil supplemen-
tation . Therefore, the long-chain n-3
fatty acids actually appear to exert protec-
tion against oxidative stress.
3.5. Ion channel and enzyme regulation
Proper physiological function requires
coordinated integration of a number of dif-
ferent cellular components, including ion
channels and enzymes. Sodium channels,
which are glycoproteins that form pores in
the cell membrane, open and close in response
to changes in membrane potential thereby
regulating the generation of action poten-
tials. A similar process occurs with potas-
sium channels, which are also found in the
cell membrane. Enzymes such as the Na+K+
ATPase and Ca-ATPase perform the func-
tions of ion transport, allowing for mainte-
nance of proper intracellular ion concen-
tration and cellular homeostasis, and the
regulation of ion channels and enzymes is
accomplished by molecules such as neuro-
transmitters and G proteins. Therefore, there
are a multitude of levels at which neuronal
functioning might be compromised, poten-
tially resulting in pathology that could give
rise to neuropsychiatric disorders.
10 G. Young, J. Conquer
Ion channel, enzyme, and regulatory mol-
ecule function may be influenced by poly-
unsaturated n-3 fatty acids. EPA has been
found to inhibit voltage-activated Na+ cur-
rents [122, 123], as has DHA [123, 124] and
ALA [123, 125]. It appears that these n-3
polyunsaturated fatty acids modify the func-
tion of the Na+ channel by binding directly
to channel proteins . DHA [126, 127]
and EPA  have also been shown to
inhibit voltage-activated K+ current, and
DHA has been observed to do this via bind-
ing to an external site on the channel struc-
ture . Importantly, the opening of the
K+ channel TREK-1 by ALA and DHA
appears to exert a neuroprotective effect
against ischemia and epileptic damage in
the brain [129, 130]. DHA [124, 131], EPA
, and ALA  have further been
shown to inhibit voltage-activated Ca+ cur-
rents. The ion regulating enzyme Na+K+
ATPase appears to be strongly influenced
by the presence of DHA in the surrounding
cell membrane, in that high concentrations
of DHA have been associated with high
Na+K+ ATPase activity , and both Ca-
ATPase and Na+K+ ATPase activity have
been shown to be inhibited by both EPA and
DHA . While the effect of DHA on
Na+K+ ATPase activity in  and 
appears to be contradictory, the use of dif-
ferent methodologies precludes a direct
comparison between the two, since Turner
et al.  correlated the activity of the
enzyme with pre-existing levels of DHA in
various tissues while Kearns and Haag
 added DHA to the enzymatic assay.
Other cellular functions, such as the rate of
glutamate uptake , the responsiveness
of the NMDA receptor , and the acti-
vation of protein kinase C [136, 137] have
also been shown to be affected by polyun-
saturated n-3 fatty acids.
3.6. Gene expression
The regulation of genetic expression dic-
tates the rate at which genes are transcribed
to effect changes in the production of vari-
ous gene products. Genes can either be up-
or down-regulated, resulting either in an
increase or decrease in transcription. Up-
regulation of a gene may lead to an increase
in the synthesis of a particular protein, while
down-regulation may have the opposite
effect. Modulation of gene expression at the
transcription level can be mediated by n-3
polyunsaturated fatty acids, and Wahle et al.
 recently summarized the generally
accepted mechanisms of this regulation.
The first reported mechanism is activation
of cell signal cascades which results in cov-
alent modification of specific transcription
factors, which can in turn then bind to pro-
moter regions of a gene causing an up- or
down-regulation of transcription. The sec-
ond reported mechanism is by direct bind-
ing of the fatty acid (or its derivative) to spe-
cific transcription factors, which consequently
has a positive or negative effect on its pro-
moter binding capacity. The third reported
mechanism is modification of transcription
factor mRNA, or alteration of the stability
of such mRNA and possibly its DNA-bind-
ing capacity. There are also likely indirect
mechanisms of regulation of gene expres-
sion, such as modulation of the redox state
of the cell. Among the transcription factors
that are known to be activated by n-3 poly-
unsaturated fatty acids are peroxisome pro-
liferated activated receptors (PPARs), liver
X receptors α and β, hepatic nuclear factor-4,
and sterol regulatory element binding pro-
teins (SREBPs) .
The relationship between n-3 polyunsat-
urated fatty acids, gene expression, and neu-
ropsychiatric disorders is suggested by
research that shows that these lipids modu-
late the expression of a number of genes in
the brain, including those involved in syn-
aptic plasticity and signal transduction. For
example, DNA microarray studies performed
on rats following dietary manipulation of
fatty acid content showed that the genes
coding for α- and γ-synuclein and the D-
cadherin gene were up-regulated with feed-
ing of diets rich in ALA and DHA ,
and research suggests that these proteins are
involved in neural plasticity [141, 142]. Sim-
ilarly, the transcript levels of three genes
Omega-3 and neuropsychiatric disorders11
coding for calmodulin were up-regulated,
albeit to a similar extent with diets contain-
ing either ALA, DHA, linoleic acid (LA;
18:2n-6) plus ALA, or LA plus DHA .
Calmodulin has also been shown to play an
important role in synaptic plasticity [143,
144] as well as signal transduction [145,
146]. The expression of numerous other
genes have been found to be affected by die-
tary manipulation of fatty acid content, and
the reader is referred to  for a compre-
hensive review. Due to the association
between n-3 polyunsaturated fatty acids and
regulation of the expression of genes asso-
ciated with neural function, this may be
another mechanism by which these lipids
are involved in the aetiology of neuropsy-
chiatric disorders. Clearly, the effect of n-3
fatty acids on cellular physiology is wide-
spread, and the relationship between impaired
brain function and neuropsychiatric disorders
necessitates that the n-3 fatty acids be con-
sidered as candidates for involvement in the
aetiology of these conditions.
4. OMEGA-3 FATTY ACID STATUS
OF BLOOD AND CELLS
OF INDIVIDUALS WITH
Omega-3 fatty acid deficiencies are asso-
ciated with a wide range of neuropsychiat-
ric disorders, including, but not limited to,
attention deficit hyperactivity disorder
(ADHD), neurodevelopmental disorders
such as dyslexia and autism, depression,
aggression and dementia. This review will
present available information on blood lev-
els of omega-3 fatty acids in individuals
with these and other neuropsychiatric dis-
orders, as compared with healthy controls.
We will also discuss available evidence as
to the efficacy of omega-3 fatty acid sup-
plementation in alleviating the symptoms
of these conditions. The role of omega-3
fatty acids in retinitis pigmentosa and other
retinal degenerative disorders, will not be
discussed in this review. Neither will the
role of omega-3 fatty acids in peroxisomal
disorders, disorders characterized by the
absence of normal peroxisomes and thus
difficulties in beta-oxidation of long chain
fatty acids. The role of omega-3 fatty acids
in these disorders has been discussed pre-
4.1. Attention deficit disorder
Attention Deficit/Hyperactivity Disorder
(ADHD), also known as Attention Deficit
Disorder (ADD), is a condition character-
ized by disabling levels of inattention,
impulsivity, and/or hyperactivity, which
are inappropriate for the individual’s level
of development . The prevalence of
ADHD in North America is approximately
3–5% of the school age population ,
with a male to female ratio of around 4–6:1
. Twenty to twenty five percent of
children with ADHD show one or more spe-
cific learning disabilities in math, reading,
or spelling. Hyperactive children have also
been reported to experience increased thirst,
eczema, asthma, and other allergies, which
are known to be symptoms of essential fatty
acid (EFA) deficiency, more often than nor-
mal children . Although previously
thought to be a condition of childhood, it is
now recognized that in up to 60% of suffer-
ers, ADHD persists into adulthood . In
adults, ADHD is manifest by disorganiza-
tion, impulsivity, and poor work skills, and
sufferers tend to be impatient and easily
Since the 1980’s, both n-3 and n-6 long
chain polyunsaturated fatty acids (LCPU-
FAs) have been suspected of being associ-
ated with ADHD. In one of the first inves-
tigative studies conducted, the serum levels
of DHA, dihomogamma-linolenic acid
(DGLA, 20:3n-6), and arachidonic acid
(AA, 20:4n-6) were found to be significantly
lower in hyperactive children than in con-
trols . Stevens et al.  found that
plasma and red blood cell (RBC) levels of
AA, EPA, and DHA were significantly lower
in ADHD patients as compared to controls,
12 G. Young, J. Conquer
and that a subgroup of ADHD patients exhib-
iting symptoms of LCPUFA deficiency had
even lower plasma concentrations of AA
and DHA than did ADHD subjects with few
LCPUFA-deficiency symptoms. Recently,
Young et al.  demonstrated that adults
with ADHD also have an altered phosphol-
ipid fatty acid status, specifically having
lower levels of omega-6 fatty acids and
DHA in serum and lower levels of omega-3
fatty acids, including DHA in red blood cells.
Low levels of these LCPUFA in blood
could be related to marginal consumption,
inefficient conversion of precursors (lino-
leic acid and ALA) to LCPUFA, or enhanced
metabolism of LCPUFA . Prelimi-
nary work suggests no difference in dietary
intakes of fatty acids between children with
ADHD and healthy children . Recently,
Ross et al.  demonstrated that children
with ADHD exhaled increased levels of
ethane, a non-invasive measure of oxida-
tive damage to omega-3 fatty acids, indicat-
ing increased breakdown.
Based on this body of research, it has
been hypothesized that supplementation
with LCPUFAs, particularly of the n-3 fatty
acid family, may result in an improvement
in the learning and behavioral symptoms of
ADHD. However, very few clinical trials
have been conducted in this field. In 2001,
Voigt et al.  supplemented 63 children
with ADHD with either placebo or 345 mg
DHA·day–1 for 4 months. DHA levels in
blood increased but there were no signifi-
cant improvements in any measure of ADHD
symptoms. However, Richardson and Puri
 showed that supplementation with a
mixture of EPA, DHA, gamma-linolenic acid
(GLA, 18:3n-6), vitamin E, AA, LA and
thyme oil for 12 weeks in children with spe-
cific learning disabilities, improved symp-
toms in 7 out of 14 symptoms of ADHD
(although only 3 were significant) com-
pared to none for placebo. Recently, Ste-
vens et al.  supplemented children
with ADHD with (per day) 480 mg DHA,
80 mg EPA, 40 mg AA, and 96 mg GLA for
4 months. There was an increase in both
EPA and DHA in plasma as well as improve-
ment in parent-rated conduct, teacher-rated
attention and oppositional defiant behav-
iour. Furthermore, there was a significant
correlation between increased RBC EPA
and DHA and a decrease in disruptive
behaviour. Harding et al.  compared
the effect of Ritalin and dietary supple-
ments including, among other ingredients,
omega-3 fatty acids (180 mg EPA, 120 mg
DHA) and 45 mg GLA per day. Although
small and non-randomized, this study sug-
gested that dietary supplementation resulted
in equivalent improvements in attention and
self control as Ritalin. Finally, Hirayama
et al.  examined the effect of DHA
supplementation in food sources for 2 months
on symptoms of ADHD. On average, chil-
dren received 0.5 g DHA·day–1 vs. control
foods. There was no improvement of ADHD
symptoms in this study. These findings
seem to suggest that a combination of LCP-
UFAs is more likely to exert a positive
effect on ADHD symptoms than omega-3
fatty acids alone.
4.2. Alzheimer’s disease and dementia
Alzheimer’s disease (AD) is a progres-
sive neurodegenerative disorder character-
ized by memory loss, intellectual decline
and eventual global cognitive impairment.
The incidence of dementia in western coun-
tries, of which AD is the major cause, is esti-
mated to be approximately 10% of the pop-
ulation over the age of 65 y and 47% of the
population over 80 y of age .
It has long been suggested that AD is
associated with brain lipid defects [165–
170]. More recently, epidemiological stud-
ies [171–177] have suggested that high fish
and/or omega-3 fatty acid consumption is
inversely associated with cognitive impair-
ment, cognitive decline, and/or develop-
ment of dementia or AD.
Blood levels of omega-3 fatty acids of
individuals with existing AD have also
been investigated and compared with con-
trol subjects. One study suggests an inverse
Omega-3 and neuropsychiatric disorders13
association between cognitive decline and
ratio of n-3/n-6 fatty acids in RBC mem-
branes . Furthermore, serum choles-
teryl ester (CE) EPA and DHA levels have
been shown to be lower in AD patients
. This study also suggested that CE-
DHA is an important determinant of mini-
mental state examination (MMSE) score
across the population. Another study by our-
selves  suggests that phospholipid-
(PL) and phosphatidylcholine-(PC) EPA,
DHA and total omega-3 fatty acid levels
are decreased in cognitively impaired and
demented (including AD) individuals. Only
one study  found no significant differ-
ence in plasma PL omega-3 fatty acid levels
between controls and cognitively impaired/
The reason for potential decreased blood
levels of omega-3 fatty acids in individuals
with AD is unclear. Studies have suggested
an increased omega-6 and/or decreased
omega-3 fatty acid consumption in individ-
uals with AD [182, 183] and at least one of
these studies  suggests that this altered
fatty acid intake precedes the development
of AD. Furthermore, Kyle et al.  sug-
gests that decreased blood levels of plasma
DHA is a risk factor for the development of
AD. Although decreased omega-3 fatty
acid consumption prior to the development
of AD is one possibility to explain the
decreased omega-3 fatty acids in the blood
of individuals with AD, increased omega-3
oxidation is also possible. For example, F4-
isoprostane (peroxidized DHA) production
is increased in certain brain cortex regions
of AD brains  as well as in cerebros-
pinal fluid from individuals with AD [185,
There are only three known studies in
which individuals with AD or dementia
have been supplemented with long chain
omega-3 fatty acids. In the first , by
Terano et al., individuals with dementia were
supplemented with 0.72 g DHA per day for
1 year. Blood levels of omega-3 fatty acids
increased and scores on dementia rating
scales improved. In the second study, by
Otsuka , individuals with AD were
supplemented with 900 mg EPA per day for
6 months. MMSE scores increased maxi-
mally by 3 months and remained higher for
6 months. In the third study, by Suzuki et al.
, adults with dementia showed both an
increase in intelligence and an improve-
ment in visual acuity following supplemen-
tation with an oil containing DHA (15%)
and EPA (3%). Non-demented elderly also
showed improvements in both intelligence
and visual acuity in this study.
Schizophrenia is a severe mental illness
characterized by positive (hallucinations and
delusions) and negative (lack of emotional
responsiveness and drive) symptoms. The
global distribution of schizophrenia is even,
despite environmental factors across coun-
tries and cultures. Schizophrenic outcome,
however, has been suggested to be inversely
related to the consumption of saturated fats
and directly related to consumption of
omega-3 fatty acids [189, 190]. Further-
more, blood omega-3 fatty acid levels have
been shown to be correlated with positive
schizotypal trait measures , and this
suggests that these fatty acids may offer
protection against psychotic breakdown.
The reader is referred to Section 3.1. for a
discussion of the membrane hypothesis of
schizophrenia, as proposed by Horrobin 
as evidence of increased catabolism of
phospholipids in this pathology.
Decreased red blood cell omega-3 fatty
acids levels have been shown in first epi-
sode psychotic patients (medication-free)
[192–194], as well as in medicated schizo-
phrenic patients [195–198], as compared
with control subjects. Furthermore, levels
of total omega-3 fatty acids and DHA are
decreased in cultured skin fibroblasts from
schizophrenic patients as compared with
controls . Some studies also suggest
decreased levels of certain omega-6 fatty
acids, mainly AA, accompanies the modi-
fication of omega-3 fatty acid levels in these
individuals . Medication itself may
14 G. Young, J. Conquer
influence the levels of omega-3 fatty acids
in red blood cells of schizophrenic patients
in either a positive [193, 194] or negative
 manner. Interestingly, Hibbeln et al.
, suggests that schizophrenic smokers
have decreased blood levels of DHA and
EPA as compared with schizophrenic non-
smokers. In schizophrenic individuals there
may be an increased breakdown of these
omega-3 and omega-6 fatty acids, as sug-
gested by various authors [192, 196] and/or
there is a decreased activity in one or more
of the enzymes, responsible for the synthe-
sis of the long chain omega-3 and omega-6
fatty acids [199, 202]. Consistent with alter-
ation in fatty acid metabolism in schizo-
phrenic individuals is the finding that there
may also be abnormalities in retinal pho-
toreceptor function .
The findings involving supplementation
of schizophrenic individuals with omega-3
fatty acids have been reviewed by various
authors [204–206]. There is evidence to
suggest positive benefits for omega-3 fatty
acid supplementation in schizophrenic indi-
viduals but more well designed studies are
still needed before definite conclusions can
be made. Most studies have investigated the
ability of ethyl-EPA to modify positive and
negative schizophrenic symptoms in indi-
viduals with residual symptoms despite med-
ication. Most of these studies have shown
improvements in Positive and Negative
Syndrome Scale (PANSS) scores after at
least 12 weeks of supplementation [34, 200,
207]. Levels of ethyl -EPA used range from
1–4 g·day–1 with 2–3 g·day–1 being the
most common, and this level appears to have
the most benefit. Benefits have also been
noted in dyskinesia scores after 12 weeks of
supplementation . Interestingly Peet
et al.  suggests that EPA supplemen-
tation is preferable to DHA supplementa-
tion, which performed no better than placebo
on symptoms in schizophrenic individuals.
One study in the USA  found no dif-
ferences in symptoms, mood or cognition
after supplementation with 3 g ethyl -EPA
for 16 weeks.
At least two studies have been conducted
with EPA and DHA combinations in fish oil,
investigating changes in omega-3 fatty acid
levels of red blood cells and improvement in
symptoms. One of these studies investigated
the combined supplementation of omega-3
fatty acids (EPA plus DHA) and antioxi-
dant vitamins (E and C) , and the other
, investigated the effect of 10 g·day–1
MaxEPA (EPA plus DHA) in an open study.
Both studies had positive results.
Additionally, two authors have presented
results of findings in individual patients. In
one, a 30 year old woman with exacerbation
of symptoms during pregnancy, was sup-
plemented with omega-3 fatty acids .
This resulted in an increase in omega-3 lev-
els of RBC and improvement in positive
and negative symptoms. In a second study,
a drug-naïve patient was supplemented with
2 g EPA·day–1 for 6 months [212–214].
Improvements were noted in PANSS scores,
RBC omega-3 levels, cerebral atrophy and
4.4. Depression and post-partum
Major depression is defined as at least
2 weeks of predominantly low mood or
diminished interests in one’s usual activi-
ties in combination with 4 or more of the
following: increased or decreased sleep pat-
terns, inappropriate guilt or loss of self-
esteem, increased or decreased appetite, low
energy, difficulty concentrating, agitation or
retardation, and suicidal thoughts . Dur-
ing the past century, there has been a dramatic
increase in the rates of depression among
cohorts , and it is thought that there is
a causative environmental factor involved
. Several observational studies have
provided evidence that supports the theory
that decreased fish and/or omega-3 fatty acid
consumption may be involved with increased
incidence of depression and this has been
reviewed by various authors [218, 219].
Societies consuming large amounts of
fish and n-3 fatty acids appear to have lower
Omega-3 and neuropsychiatric disorders15
rates of major depression and bipolar dis-
orders [216, 220, 221] and the likelihood of
having depressive symptoms increases among
infrequent fish consumers versus frequent
fish consumers . Studies have also
suggested that depression associated with
disease diagnosis is also associated with
decreased dietary intake of total omega-3
fatty acids [223, 224]. Seasonal variation of
serum long chain PUFA, including EPA
and DHA, correlates negatively with the
number of violent suicidal deaths in Bel-
gium . However, one study found no
associations between dietary intakes of
omega-3 fatty acids and depressed mood or
major depressive episodes .
Total n-3 PUFA, EPA, and DHA are
depleted in red blood cell membranes of
depressive patients and/or individuals at
risk for the recurrent form of the major
depressive disorder [217, 227, 228], and
there is a negative correlation between lev-
els of blood and adipose tissue n-3 PUFA
and depressive symptoms [227, 229–231].
A study by Mamalakis et al.  suggests
that while there is no relation between adi-
pose tissue n-3 PUFA and depression,
increased ratios of longer chain n-3 and n-6
fatty acids are noted and this suggests
increased fatty acid elongation in general.
N-3 fatty acids are also depleted in the
serum PL and CE of depressed and bipolar
patients [233–235], and an increase in the
AA to EPA ratio has repeatedly been posi-
tively correlated with depression [233, 234,
Post-partum depression (PPD) also appears
to be associated with omega-3 fatty acid
levels. Higher concentrations of DHA in
breast milk and higher seafood consump-
tion predicts lower prevalence of post-par-
tum depression in society . Higher
plasma DHA of the mother is associated
with a reduction in depressive symptom
reporting in the immediate post-partum period
. Plasma DHA was influenced by
maternal education and smoking, however,
so these results should be interpreted with
caution. Another study suggested that the
post-partum normalisation of DHA status
was lower in individuals who were “possi-
bly depressed” versus the non-depressed
group . In mothers who developed
PPD, DHA and total omega-3 fatty acids
(PL and CE) were decreased and the
omega-6:omega-3 ratio was increased as
compared with mothers who did not develop
As with the other neurological disorders
mentioned in this review, there are a few
studies investigating the effect of omega-3
fatty acid supplementation on symptoms of
depression. At least four studies have inves-
tigated the potential efficacy of omega-3
fatty acid supplementation in depressive
individuals. Most of these studies involved
individuals who were on standard medica-
tions. Three of these studies investigated
the effects of ethyl-EPA and found improve-
ments in scores on depressive rating scales
as well as suicidal thoughts and social pho-
bia [241–243], with maximum benefits
observed with the 1 g·day–1 dose . In
another study, individuals were supple-
mented with 6.6 g of omega-3 fatty acids or
placebo for 8 weeks . A decreased
score in the Hamilton rating scale was noted
in the omega-3 supplemented group. One
study investigated the effect of supplemen-
tation with DHA alone (2 g·day–1) versus
placebo for 6 weeks and found no difference
in rating scale scores between the groups
. In bipolar patients on medication,
Stoll et al.  determined that 9.6 g·day–1
omega-3 fatty acids for 4 months, as com-
pared with placebo, resulted in improved
outcome and longer remission.
At least two studies have been conducted
on individuals with PPD. In the first study,
mothers with a history of PPD were supple-
mented with approximately 3 g fish oil from
the 34th–36th week of pregnancy to 12 weeks
post-partum . There were no dropouts
but there was also no evidence of benefit
based on the number of individuals who had
depressive episodes during the study. In the
second study, individuals were supplemented
with 200 mg DHA·day–1 or placebo for
16 G. Young, J. Conquer
4 months following delivery . Increased
plasma DHA was noted in the supplemented
group, whereas there was a decrease in the
placebo group. There was no difference in
self-rating or diagnostic measures of depres-
sion. It is still unclear whether there are
potential benefits of omega-3 fatty acid sup-
plementation from earlier on in pregnancy
and/or prior to conception.
4.5. Other disorders
The role of omega-3 fatty acids has also
been investigated in other neurological dis-
orders, although the information is scarce.
These include dyslexia, autistic spectrum
disorders, dyspraxia, borderline personal-
ity (BPD) disorder and obsessive compul-
sive disorder (OCD), as well as in aggres-
sion and hostility.
In adults and children with dyslexia, signs
of fatty acid deficiencies are correlated with
the severity of dyslexic signs and symptoms
[248, 249]. Cerebral P-31 magnetic reso-
nance in dyslexics indicate increased mem-
brane PL turnover . Increased PLA2
activity has also been suggested . Sup-
plementation with PUFA from the omega-3
and omega-6 series (186 mg EPA, 480 mg
DHA, 96 mg GLA, 864 mg LA and 42 mg
AA per day) improved ADHD symptoms in
children with learning disabilities (mainly
dyslexia)  and supplementation with
DHA for 1 month improved dark adaptation
in dyslexic young adults .
Decreased DHA and total omega-3 fatty
acids have been shown in blood of autistic
children versus mentally retarded children
. Furthermore, there is also decreased
PUFA in RBC membranes of autistic chil-
dren which has been shown to break down
faster than control samples when stored at
–20 °C versus –80 °C . There do not
appear to be any published trials in which
individuals with autistic spectrum disorder
are supplemented with omega-3 fatty acids.
Two supplementation trials have been
conducted in children with dyspraxia. These
trials suggest improvement in movement
skills with high DHA fish oil plus evening
primrose oil for 4 months  and improve-
ment in reading and spelling, with a decrease
in ADHD symptoms after supplementation
with fish oil and evening primrose oil for
12 weeks .
Supplementation with 1 g of E-EPA per
day for 8 weeks was investigated in individ-
uals with BPD. Improvement was noted in
aggression and severity of symptoms .
Omega-3 fatty acid supplementation has
also been investigated in individuals with
OCD on traditional selective serotonin re-
uptake inhibitors (SSRI’s). Individuals were
supplemented with 2 g EPA·day–1 or placebo
for 6 weeks. Scores on the Yale Brown
Obsessive Compulsive Scale decreased in
both groups .
Cross-nationally, it has been observed
that rates of death from homicide are lower
in countries with high n-3 consumption
. In a 5 year prospective interventional
study, an increase in dietary n-3 fatty acids
caused a significant decrease in hostility
Omega-3 supplementation has been inves-
tigated in terms of aggression and hostility.
Supplementation with 1.5 g DHA·day–1 ver-
sus placebo for 2 months resulted in decreased
aggression in educated University workers
but not uneducated villagers after a video-
tape stressor . When aggression was
measured during exam time, after three months
of supplementation with 1.5 g DHA·day–1,
there was an increase in aggression in the
control group, but no change in the DHA
group . This same dose appeared to
decrease the level of norepinephrine (NE),
but not other catecholamines, in medical
students during exams . Interestingly,
when aggression was determined during a
non-stressful time, there was no change in
aggression in the DHA group and a slight
decrease in the control group . It is
possible DHA supplementation is offering
protection during stressful conditions.
In cocaine addicts admitted to hospital,
aggressive patients were shown to have
decreased levels of total omega-3 fatty acids
Omega-3 and neuropsychiatric disorders17
and DHA as well as an increased n-6:n-3
ratio in blood .
It is obvious that there is a limited amount
of work in the field of omega-3 fatty acids
and neuropsychiatric disorders, and thus
there are exciting opportunities for research-
ers. Evidence suggests decreased blood lev-
els of omega-3 fatty acids in individuals with
various psychiatric conditions. The reasons
for this are not clear; they include a decreased
biosynthesis and/or increased breakdown.
Both would increase dietary requirements
in this population. Alterations in the levels
of minerals such as zinc, as observed in
individuals with ADHD, would also play a
role in LCPUFA synthesis. Epidemiologi-
cal evidence suggests that either a decreased
intake of omega-3 PUFA, or decreased lev-
els of omega-3 PUFA in plasma or RBC are
risk factors for the development of at least
some of these conditions. This suggests that
they may play a role in the actual develop-
ment of the disorder as opposed to being a
consequence of the disorder.
Thus far, the benefits of supplementa-
tion, in terms of decreasing disease risk and/
or aiding in symptom management are not
clear and more research is needed. Timing
of dietary changes and/or supplementation
use as well as levels and specific types of
omega-3 fatty acids are still in the process
of being investigated.
 Voss A, Reinhart M, Sankarappa S, Sprecher
H. The metabolism of 7,10,13,16,19-docosa-
pentaenoic acid to 4,7,10,13,16,19-docosa-
hexaenoic acid in rat liver is independent of a
4-desaturase. J Biol Chem 1991, 266: 19995–
 Emken EA, Adolf RO, Gulley RM. Dietary
linoleic acid influences desaturation and
acylation of deuterium-labeled linoleic and
linolenic acids in young adult males. Biochim
Biophys Acta 1994, 1213: 277–288.
 Salem N Jr, Wegher B, Mena P, Uauy R. Ara-
chidonic acid and docosahexaenoic acid are
biosynthesized from their 18-carbon precur-
sors in human infants. Proc Natl Acad Sci
USA 1996, 93: 49–54.
 Burdge G. Alpha-linolenic acid metabolism in
men and women: nutritional and biological
implications. Curr Opin Clin Nutr 2004, 7:
 Conquer JA, Holub BJ. Supplementation with
an algae source of docosahexaenoic acid
increases (n-3) fatty acid status and alters
selected risk factors for heart disease in veg-
etarian subjects. J Nutr 1996, 126: 3032–
 Conquer JA, Holub BJ. Dietary docosahexae-
noic acid as a source of eicosapentaenoic acid
in vegetarians and omnivores. Lipids 1997,
 Simopolous AP. Essential fatty acids in health
and chronic disease. Am J Clin Nutr 1999, 70:
 Simopolous AP. Omega-3 fatty acids in health
and disease and in growth and development.
Am J Clin Nutr 1991, 54: 438–463.
 Kris-Etherton PM, Shaffer D, Yu-Poth S,
Huth P, Moriarty K, Fishell V, Hargrove RL,
Zhao G, Etherton TD. Polyunsaturated fatty
acids in the food chain in the United States.
Am J Clin Nutr 2000, 71: S179–S188.
 Howe PR, Meyer BJ, Record S, Baghurst K.
Contribution of red meat to very long chain
omega-3 fatty acid (VLCOmega3) intake.
Asia Pac J Clin Nutr 2003, 12 (Suppl): S27.
 Institute of Medicine (IOM). Dietary Refer-
ences Intakes for Energy and Macronutrients.
National Academy Press, Washington, 2002.
 British Nutrition Foundation. Task Force on
Unsaturated Fatty Acids. Chapman and Hall,
 Sugano M, Hirahara F. Polyunsaturated fatty
acids in the food chain in Japan. Am J Clin
Nutr 2000, 71: 189S–196S.
 Sastry PS. Lipids of nervous tissue: composi-
tion and metabolism. Prog Lipid Res 1985, 24:
 Dennis EA. Diversity of group types, regula-
tion, and function of phospholipase A2. J Biol
Chem 1994, 269: 13057–13060.
 Balboa MA, Varela-Nieto I, Killermann
Lucas K, Dennis EA. Expression and function
of phospholipase A(2) in brain. FEBS Lett
2002, 531: 12–17.
 Molloy GY, Rattray M, Williams RJ. Genes
encoding multiple forms of phospholipase A2
18 G. Young, J. Conquer
are expressed in rat brain. Neurosci Lett 1998,
 Jarrard LE. On the role of the hippocampus in
learning and memory in the rat. Behav Neural
Biol 1993, 60: 9–26.
 Farooqui AA, Yang HC, Rosenberger TA,
Horrocks LA. Phospholipase A2 and its role
in brain tissue. J Neurochem 1997, 69: 889–
 Farooqui AA, Horrocks LA. Brain phospho-
lipase A2: a perspective on the history. Pros-
taglandins Leukot Essent Fatty Acids 2004,
 Gattaz WF, Hubner CV, Nevalainen TJ, Thuren
T, Kinnunen PK. Increased serum phospholi-
pase A2 activity in schizophrenia: a replica-
tion study. Biol Psychiatry 1990, 28: 495–
 Pettegrew JW, Keshavan MS, Panchalingam
K, Strychor S, Kaplan DB, Tretta MG, Allen
M. Alterations in brain high-energy phosphate
and membrane phospholipid metabolism in
first-episode, drug-naive schizophrenics. A
pilot study of the dorsal prefrontal cortex by
in vivo phosphorus 31 nuclear magnetic res-
onance spectroscopy. Arch Gen Psychiatry
1991, 48: 563–568.
 Horrobin DF, Glen AI, Vaddadi K. The mem-
brane hypothesis of schizophrenia. Schizophr
Res 1994, 13: 195–207.
 Wei J, Hemmings GP. A study of a genetic
association between the PTGS2/PA2G4A
locus and schizophrenia. Prostaglandins Leu-
kot Essent Fatty Acids 2004, 70: 413–415.
 MacDonell LE, Skinner FK, Ward PE, Glen
AI, Glen AC, Macdonald DJ, Boyle RM,
Horrobin DF. Increased levels of cytosolic
phospholipase A2 in dyslexics. Prostagland-
ins Leukot Essent Fatty Acids 2000, 63: 37–39.
 Noponen M, Sanfilipo M, Samanich K, Ryer
H, Ko G, Angrist B, Wolkin A, Duncan E,
Rotrosen J. Elevated PLA2 activity in schiz-
ophrenics and other psychiatric patients. Biol
Psychiatry 1993, 34: 641–649.
 Chang MC, Jones CR. Chronic lithium treat-
ment decreases brain phospholipase A(2)
activity. Neurochem Res 1998, 23: 887–892.
 Horrobin DF, Bennett CN. Depression and
bipolar disorder: relationships to impaired
fatty acid and phospholipid metabolism and to
diabetes, cardiovascular disease, immunolog-
ical abnormalities, cancer, ageing and oste-
oporosis. Prostaglandins Leukot Essent Fatty
Acids 1999, 60: 217–234.
 Ghelardoni S, Tomita YA, Bell JM, Rapoport
SI, Bosetti F. Chronic carbamazepine selec-
tively downregulates cytosolic phospholipase
A2 expression and cyclooxygenase activity in
rat brain. Psychiatry 2004, 56: 248–254.
 Papadimitriou GN, Dikeos DG, Souery D, Del-
Favero J, Massat I, Avramopoulos D, Blairy S,
Cichon S, Ivezic S, Kaneva R, Karadima G,
Lilli R, Milanova V, Nothen M, Oruc L,
Rietschel M, Serretti A, Van Broeckhoven C,
Stefanis CN, Mendlewicz J. Genetic associa-
tion between the phospholipase A2 gene and
unipolar affective disorder: a multicentre
case-control study. Psychiatr Genet 2003, 13:
 Meira-Lima I, Jardim D, Junqueira R, Ikenaga
E, Vallada H. Allelic association study
between phospholipase A2 genes and bipolar
affective disorder. Bipolar Disord 2003, 5:
 Ross BM, Turenne S, Moszczynska A, Warsh
JJ, Kish SJ. Differential alteration of phos-
pholipase A2 activities in brain of patients
with schizophrenia. Brain Res 1999, 821:
 Finnen MJ, Lovell CR. Purification and char-
acterization of phospholipase A2 from human
epidermis. Biochem Soc Trans 1991, 19: 91S.
 Emsley R, Myburgh C, Oosthiuzen P, van
Rensburg SJ. Randomized, placebo-control-
led study of ethyl-eicosapentaenoic acid as
supplemental treatment in schizophrenia. Am
J Psychiatry 2002, 159: 1596–1598.
 Stoll AL, Severus WE, Freeman MP, Rueter
S, Zboyan HA, Diamond E, Cress KK,
Marangell LB. Omega-3 fatty acids in bipolar
disorder: A preliminary double-blind, pla-
cebo-controlled trial. Arch Gen Psychiatry
1999, 56: 407–412.
 Christensen O, Christensen E. Fat consump-
tion and schizophrenia. Acta Psychiatr Scand
1988, 78: 587–592.
 Mellor JE, Laugharne JD, Peet M. Omega-3
fatty acid supplementation in schizophrenia
patients. Hum Psychopharmacol 1996, 11:
 Maes M, Stevens WJ, Declerck LS, Bridts
CH, Peeters D, Schotte C, Cosyns P. Signifi-
cantly increased expression of T-cell activa-
tion markers (interleukin-2 and HLA-DR) in
depression: further evidence for an inflamma-
tory process during that illness. Prog Neu-
ropsychopharmacol Biol Psychiatry 1993, 17:
 Maes M, Bosmans E, Calabrese J, Smith R,
Meltzer HY. Interleukin-2 and interleukin-6
in schizophrenia and mania: effects of neu-
roleptics and mood stabilizers. J Psychiatr Res
1995, 29: 141–152.
 Maes M, Delange J, Ranjan R, Meltzer HY,
Desnyder R, Cooremans W, Scharpe S. Acute
Omega-3 and neuropsychiatric disorders19
phase proteins in schizophrenia, mania and
major depression: modulation by psycho-
tropic drugs. Psychiatry Res 1997, 66: 1–11.
 Segman RH, Meltzer A, Gross-Tsur V, Kosov
A, Frisch A, Inbar E, Darvasi A, Levy S, Goltser
T, Weizman A, Galili-Weisstub E. Preferen-
tial transmission of interleukin-1 receptor
antagonist alleles in attention deficit hyperac-
tivity disorder. Mol Psychiatry 2002, 7: 72–74.
 Jyonouchi H, Sun S, Le H. Proinflammatory
and regulatory cytokine production associated
with innate and adaptive immune responses in
children with autism spectrum disorders and
developmental regression. J Neuroimmunol
2001, 120: 170–179.
 Croonenberghs J, Bosmans E, Deboutte D,
Kenis G, Maes M. Activation of the inflam-
matory response system in autism. Neuropsy-
chobiology 2002, 45: 1–6.
 Bousserouel S, Brouillet A, Bereziat G,
Raymondjean M, Andreani M. Different effects
of n-6 and n-3 polyunsaturated fatty acids on
the activation of rat smooth muscle cells by
interleukin-1 beta. J Lipid Res 2003, 44: 601–
 Hardardottir I, Kinsella JE. Tumor necrosis
factor production by murine resident perito-
neal macrophages is enhanced by dietary n-3
polyunsaturated fatty acids. Biochim Biophys
Acta 1991, 1095: 187–195.
 Song C, Leonard BE, Horrobin DF. Dietary
ethyl-eicosapentaenoic acid but not soybean
oil reverses central interleukin-1-induced changes
in behavior, corticosterone and immune response
in rats. Stress 2004, 7: 43–54.
 Song C, Horrobin D. Omega-3 fatty acid
ethyl-eicosapentaenoate, but not soybean oil,
attenuates memory impairment induced by
central IL-1 beta administration. Lipid Res
2004, 45: 1112–1121.
 Kinsella JE, Broughton KS, Whelan JW. Die-
tary unsaturated fatty acids: interactions and
possible needs in relation to eicosanoid syn-
thesis. J Nutr Biochem 1990, 1: 123–141.
 Youdim KA, Martin A, Joseph JA. Essential
fatty acids and the brain: possible health
implications. Int J Dev Neuroscience 2000,
 Guyton AC, Hall JE. Textbook of Medical
Physiology. 9th ed. WB Saunders CO, PN,
1996, 569 p.
 Wise RA. Dopamine, learning and motiva-
tion. Nat Rev Neurosci 2004, 5: 483–494.
 Baldwin D, Rudge S. The role of serotonin in
depression and anxiety. Int Clin Psychophar-
macol 1995, 9: S41–S45.
 Fernstrom JD. Dietary amino acids and brain
function. Am Diet Assoc 1994, 94: 71–77.
 Paez X, Hernandez L. Simultaneous brain and
blood microdialysis study with a new remov-
able venous probe. Serotonin and 5-hydroxy
indolacetic acid changes after D-norfenflu-
ramine or fluoxetine. Life Sci 1996, 58: 1209–
 Post RM, Jimerson DC, Bunney WE Jr,
Goodwin FK. Dopamine and mania: behavio-
ral and biochemical effects of the dopamine
receptor blocker pimozide. Psychopharma-
cology (Berl) 1980, 67: 297–305.
 Malison RT, Price LH, Berman R, van Dyck
CH, Pelton GH, Carpenter L, Sanacora G, Owens
MJ, Nemeroff CB, Rajeevan N, Baldwin RM,
Seibyl JP, Innis RB, Charney DS. Reduced
brain serotonin transporter availability in major
depression as measured by [123I]-2 beta-car-
bomethoxy-3 beta-(4-iodophenyl)tropane and
single photon emission computed tomogra-
phy. Biol Psychiatry 1998, 44: 1090–1098.
 Ogilvie AD, Battersby S, Bubb VJ, Fink G,
Harmar AJ, Goodwim GM, Smith CA. Poly-
morphism in serotonin transporter gene asso-
ciated with susceptibility to major depression.
Lancet 1996, 347: 731–733.
 Mundo E, Walker M, Cate T, Macciardi F,
Kennedy JL. The role of serotonin transporter
protein gene in antidepressant-induced mania
in bipolar disorder: preliminary findings. Arch
Gen Psychiatry 2001, 58: 539–544.
 Elliot H. Attention deficit hyperactivity disor-
der in adults: a guide for the primary care phy-
sician. South Med J 2002, 95: 736–742.
 Cook EH, Stein MA, Krasowski MD, Cox NJ,
Olkon DM, Kieffer JE, Leventhal BL. Asso-
ciation of attention-deficit disorder and the
dopamine transporter gene. Am J Hum Genet
1995, 56: 993–998.
 Qian Q, Wang Y, Zhou R, Yang L, Faraone
SV. Family-based and case-control associa-
tion studies of DRD4 and DAT1 polymor-
phisms in Chinese attention deficit hyperac-
tivity disorder patients suggest long repeats
contribute to genetic risk for the disorder. Am
J Med Genet 2004, 128B: 84–89.
 Levitan RD, Masellis M, Basile VS, Lam RW,
Jain U, Kaplan AS, Kennedy SH, Siegel G,
Walker ML, Vaccarino FJ, Kennedy JL. Pol-
ymorphism of the serotonin-2A receptor gene
(HTR2A) associated with childhood attention
deficit hyperactivity disorder (ADHD) in
adult women with seasonal affective disorder.
J Affect Disord 2002, 71: 229–233.
 Richardson AJ, Ross MA. Fatty acid metabo-
lism in neurodevelopmental disorder: a new
perspective on associations between atten-
tion-deficit/hyperactivity disorder, dyslexia,
dyspraxia and the autistic spectrum. Prostag-
landins Leukot Essent Fatty Acids 2000, 63:
20 G. Young, J. Conquer
 Marino C, Giorda R, Vanzin L, Molteni M,
Lorusso ML, Nobile M, Baschirotto C, Alda
M, Battaglia M. No evidence for association
and linkage disequilibrium between dyslexia
and markers of four dopamine-related genes.
Eur Child Adolesc Psychiatry 2003, 12: 198–
 Nopola-Hemmi J, Myllyluoma B, Haltia T,
Taipale M, Ollikainen V, Ahonen T, Vouti-
lainen A, Kere J, Widen E. A dominant gene
for developmental dyslexia on chromosome 3.
J Med Genet 2001, 38: 658–664.
 Abi-Dargham A. Do we still believe in the
dopamine hypothesis? New data bring new
evidence. Int J Neuropsychopharmacol 2004,
 Carlsson A, Lindqvist M. Effect of chlorpro-
mazine and haloperidol on formation of
3-methoxytyramine and normetanephrine in
mouse brain. Acta Pharmacol Toxicol 1963,
 Lieberman JA, Kane JM, Gadaleta D, Brenner
R, Lesser MS, Kinon B. Methylphenidate
challenge as a predictor of relapse in schizo-
phrenia. Am J Psychiatry 1984, 141: 633–638.
 Glatt SJ, Faraone SV, Tsuang MT. Meta-anal-
ysis identifies an association between the
dopamine D2 receptor gene and schizophre-
nia. Mol Psychiatry 2003, 8: 911–915.
 Ambrosio AM, Kennedy JL, Macciardi F,
Macedo A, Valente J, Dourado A, Oliveira
CR, Pato C. Family association study between
DRD2 and DRD3 gene polymorphisms and
schizophrenia in a Portuguese population.
Psychiatry Res 2004, 125: 185–191.
 Glatt SJ, Faraone SV, Tsuang MT. DRD2 –
141C insertion/deletion polymorphism is not
associated with schizophrenia: results of a
meta-analysis. Am J Med Genet B 2004, 128:
 Wooley D, Shaw E. A biochemical and phar-
macological suggestion about certain mental
disorders. Proc Natl Acad Sci USA 1954, 40:
 Fink H, Morgenstern R, Oelssner W. Clozap-
ine-A serotonin antagonist? Pharmacol Bio-
chem Behav 1984, 20: 513–517.
 DeLeon A, Patel NC, Lynn Crismon M. Arip-
iprazole: A comprehensive review of its phar-
macology, clinical efficacy, and tolerability.
Clin Ther 2004, 26: 649–666.
 Castensson A, Emilsson L, Sundberg R, Jazin
E. Decrease of serotonin receptor 2C in schiz-
ophrenia brains identified by high-resolution
mRNA expression analysis. Biol Psychiatry
2003, 54: 1212–1221.
 Dubertret C, Hanoun N, Ades J, Hamon M,
Gorwood P. Family-based association study
of the serotonin-6 receptor gene (C267T poly-
morphism) in schizophrenia. Am J Med Genet
B 2004, 126: 10–15.
 Ellingrod VL, Miller D, Ringold JC, Perry PJ.
Distribution of the serotonin 2C (5HT2C)
receptor gene -759C/T polymorphism in
patients with schizophrenia and normal con-
trols. Psychiatr Genet 2004, 14: 93–95.
 De la Presa Owens S, Innis SM. Docosahex-
aenoic acid and arachidonic acid prevent a
decrease in dopaminergic and serotoninergic
neurotransmitters in frontal cortex caused by
a linoleic and alpha-linolenic acid deficient
diet in formula-fed piglets. J Nutr 1999, 129:
 Austead N, Innis SM, de la Presa Owens S.
Auditory evoked response and brain phos-
pholipid fatty acids and monoamines in rats
fed formula with and without arachidonic acid
(AA) and/or docosahexaenoic acid (DHA).
In: Watkins P, Spector A, Hamilton J, Katz R
(Eds), Brain uptake and utilization of fatty
acids: applications to peroxisomal biogenesis
disorders, Maryland: National Institutes of
Health Conference, 2000, p 3.
 Zimmer L, Durand G, Guilloteau D, Chalon
S. n-3 polyunsaturated fatty acid deficiency
and dopamine metabolism in the rat frontal
cortex. Lipids 1999, 34: S251.
 Zimmer L, Delpal S, Guilloteau D, Aioun J,
Durand G, Chalon S. Chronic n-3 polyunsat-
urated fatty acid deficiency alters dopamine
vesicle density in the rat frontal cortex. Neu-
rosci Lett 2000, 284: 25–28.
 Chalon S, Delion-Vancassel S, Belzung C,
Guilloteau D, Leguisquet A, Besnard JC,
Durand G. Dietary fish oil affects monoamin-
ergic neurotransmission and behavior in rats.
J Nutr 1998, 128: 2512–2519.
 Kodas E, Galineau L, Bodard S, Vancassel S,
Guilloteau D, Besnard JC, Chalon S. Serotin-
ergic neurotransmission is affected by n-3 pol-
yunsaturated fatty acids in the rat. Neurochem
2004, 89: 695–702.
 Sirvio J. Strategies that support declining
cholinergic neurotransmission in Alzheimer’s
disease patients. Gerontology 1999, 45 (Suppl1):
 Raedler TJ, Knable MB, Jones DW, Urbina
RA, Gorey JG, Lee KS, Egan MF, Coppola R,
Weinberger DR. In vivo determination of
muscarinic acetylcholine receptor availability
in schizophrenia. Am J Psychiatry 2003, 160:
 Leiva DB. The neurochemistry of mania: a
hypothesis of etiology and rationale for treat-
ment. Prog Neuropsychopharmacol Biol Psy-
chiatry 1990, 14: 423–429.
Omega-3 and neuropsychiatric disorders21
 Favreliere S, Perault MC, Huguet F, De Javel
D, Bertrand N, Piriou A, Durand G. DHA-
enriched phospholipid diets modulate age-
related alterations in rat hippocampus. Neu-
robiol Aging 2003, 24: 233–243.
 Minami M, Kimura S, Endo T, Hamaue N,
Hirafuji M, Togashi H, Matsumoto M,
Yoshioka M, Saito H, Watanabe S, Kobayashi
T, Okuyama H. Dietary docosahexaenoic
acid increases cerebral acetylcholine levels
and improves passive avoidance perform-
ance in stroke-prone spontaneously hyperten-
sive rats. Pharmacol Biochem Behav 1997,
 Aid S, Vancassel S, Poumes-Ballihaut C,
Chalon S, Guesnet P, Lavialle M. Effect of
a diet-induced n-3 PUFA depletion on
cholinergic parameters in the rat hippocam-
pus. Lipid Res 2003, 44: 1545–1551.
 Piomelli D. Eicosanoids in synaptic transmis-
sion. Crit Rev Neurobiology 1994, 8: 65–82.
 Di Marzo V, Piomelli D. Participation of
prostaglandin E2 in dopamine D2 receptor-
dependent potentiation of arachidonic acid
release. J Neurochem 1992, 59: 379–382.
 Ahmadi S, Lippross S, Neuhuber WL, Zeil-
hofer HU. PGE(2) selectively blocks inhibi-
tory glycinergic neurotransmission onto rat
superficial dorsal horn neurons. Nat Neuro-
sci 2002, 5: 34–40.
 Wolfe L, Horrocks L. Eicosanoids. In: Seigel
GJ, Agranoff BW, Albers RW, Molinoff PB
(Eds), Basic Neurochemistry: Molecular,
Cellular, and Medical Aspects, 5th ed, Raven
Press, New York, 1994, p 475–490.
 Schlicker E, Fink K, Gothert M. Influence of
eicosanoids on serotonin release in the rat
brain: inhibition by prostaglandins E1 and
E2. Naunyn Schmiedebergs Arch Pharmacol
1987, 335: 646–651.
 Rettori V, Gimeno M, Lyson K, McCann
SM. Nitric oxide mediates norepinephrine-
induced prostaglandin E2 release from the
hypothalamus. Proc Natl Acad Sci USA
1992, 89: 11543–11546.
 Mahadik SP, Mukherjee S. Free radical
pathology and antioxidant defense in schiz-
ophrenia: a review. Schizophr Res 1996, 19:
 Groff JL, Gropper SS, Hunt SM. Advanced
Nutrition and Human Metabolism. 2nd ed.
West Publishing Co, MN, 1995.
 Mahadik SP, Evans D, Lal H. Oxidative
stress and role of antioxidant and ω-3 essen-
tial fatty acid supplementation in schizo-
phrenia. Prog Neuro Psychoparmacol Biol
Psychiatr 2001, 25: 463–493.
 Rosler M, Retz W, Thome J, Riederer P. Free
radicals in Alzheimer’s dementia: currently
available therapeutic strategies. J Neural
Transm Suppl 1998, 54: 211–219.
 Ross MA. Could oxidative stress be a factor
in neurodevelopmental disorders? Prostag-
landins Leukot Essent Fatty Acids 2000, 63:
 Dakhale G, Khanzode S, Khanzode S, Saoji
A, Khobragade L, Turankar A. Oxidative
damage and schizophrenia: the potential
benefit by atypical antipsychotics. Neu-
ropsychobiology 2004, 49: 205–209.
 Lukash AI, Zaika VG, Kucherenko AO,
Miliutina NP. Free radical processes and
antioxidant system in depression and treat-
ment efficiency. Zh Nevrol Psikhiatr Im S S
Korsakova 2002, 102: 41–44.
 Khanzode SD, Dakhale GN, Khanzode SS,
Saoji A, Palasodkar R. Oxidative damage
and major depression: the potential antioxi-
dant action of selective serotonin re-uptake
inhibitors. Redox Rep 2003, 8: 365–370.
 Ozcan ME, Gulec M, Ozerol E, Polat R,
Akyol O. Antioxidant enzyme activities and
oxidative stress in affective disorders. Int
Clin Psychopharmacol 2004, 19: 89–95.
 Tsuboi H, Shimoi K, Kinae N, Oguni I, Hori
R, Kobayashi F. Depressive symptoms are
independently correlated with lipid peroxi-
dation in a female population: comparison
with vitamins and carotenoids. J Psychosom
Res 2004, 56: 53–58.
 Ross BM, McKenzie I, Glen I, Bennett CP.
Increased levels of ethane, a non-invasive
marker of n-3 fatty acid oxidation, in breath
of children with attention deficit hyperactiv-
ity disorder. Nutr Neurosci 2003, 6: 277–
 Yao JK, Reddy R, van Kammen DP. Abnor-
mal age-related changes of plasma antioxi-
dant proteins in schizophrenia. Psychiatry
Res 2000, 97: 137–151.
 Stokiasova A, Zapletalek M, Kudrnova K,
Randova Z. Glutathione peroxidase activity
of blood in chronic schizophrenics. Sb Ved
Pr Lek Fak Karlovi University Hradci
Kralove 1986, 20: 103–108.
 Reddy R, Mahadik SP, Mukherjee S, Murthy
JN. Enzymes of the antioxidant defense sys-
tem in chronic schizophrenic patients. Biol
Psychiatry 1991, 20: 409–412.
 Cecchi C, Fiorillo C, Sorbi S, Latorraca S,
Nacmias B, Bagnoli S, Nassi P, Liguri G.
Oxidative stress and reduced antioxidant
defenses in peripheral cells from familial
Alzheimer’s patients. Free Radic Biol Med
2002, 33: 1372–1379.
22 G. Young, J. Conquer
 Perry G, Castellani RJ, Smith MA, Harris
PL, Kubat Z, Ghanbari K, Jones PK, Cor-
done G, Tabaton M, Wolozin B, Ghanbari H.
Oxidative damage in the olfactory system in
Alzheimer’s disease. Acta Neuropathol (Berl)
2003, 106: 552–556.
 Montine KS, Quinn JF, Zhang J, Fessel JP,
Roberts LJ 2nd, Morrow JD, Montine TJ.
Isoprostanes and related products of lipid
peroxidation in neurodegenerative diseases.
Chem Phys Lipids 2004, 28: 117–124.
 Hargreaves KM, Clandinin MT. Dietary
control of diacylphosphatidylethanolamine
species in brain. Biochim Biophys Acta
1998, 962: 98–104.
 Bjerve KS, Brubakk AM, Fougner KJ,
Johnsen H, Midthjell K, Vik T. Omega-3
fatty acids: essential fatty acids with impor-
tant biological effects, and serum phosphol-
ipid fatty acids as markers of dietary omega
3-fatty acid intake. Am J Clin Nutr 1993, 57:
 Godley PA, Campbell MK, Miller C,
Gallagher P, Martinson FE, Mohler JL,
Sandler RS. Correlation between biomarkers
of omega-3 fatty acid consumption and ques-
tionnaire data in African American and
Caucasian United States males with and
without prostatic carcinoma. Cancer Epide-
miol Biomarkers Prev 1996, 5: 115–119.
 Hjartaker J, Lund E, Bjerve KS. Serum phos-
pholipid fatty acid composition and habitual
intake of marine foods registered by a semi-
quantitative food frequency questionnaire.
Eur J Clin Nutr 1997, 51: 736–742.
 Mori TA, Woodman RJ, Burke V, Puddey
IB, Croft KD, Beilin LJ. Effect of eicosap-
entaenoic acid and docosahexaenoic acid on
oxidative stress and inflammatory markers
in treated-hypertensive type 2 diabetic sub-
jects. Free Radic Biol Med 2003, 35: 772–
 Mori TA, Puddey IB, Burke V, Croft KD,
Dunstan DW, Rivera JH, Beilin LJ. Effect of
omega-3 fatty acids on oxidative stress in
humans: GC-MS measurement of urinary
F2-isoprostane excretion. Redox Rep 2000,
 Songur A, Sarsilmaz M, Sogut S, Ozyurt B,
Zararsiz I, Turkoglu AO. Hypothalamic
superoxide dismutase, xanthine oxidase,
nitric oxide, and malondialdehyde in rats fed
with fish omega-3 fatty acids. Prog Neu-
ropsychopharmacol Biol Psychiatry 2004,
 Barbosa DS, Cecchini R, El Kadri MZ,
Rodriguez MA, Burini RC, Dichi I. Decreased
oxidative stress in patients with ulcerative
colitis supplemented with fish oil omega-3
fatty acids. Nutrition 2003, 19: 837–842.
 Barden AE, Mori TA, Dunstan JA, Taylor
AL, Thornton CA, Croft KD, Beilin LJ,
Prescott SL. Fish oil supplementation in
pregnancy lowers F2-isoprostanes in neonates
at high risk of atopy. Free Radic Res 2004,
 Xiao YF, Kang JX, Morgan JP, Leaf A.
Blocking effects of polyunsaturated fatty
acids on Na+ channels of neonatal rat ven-
tricular myocytes. Proc Natl Acad Sci USA
1995, 92: 11000–11004.
 Kang JX, Leaf A. Evidence that free polyun-
saturated fatty acids modify Na+ channels by
directly binding to the channel proteins. Proc
Natl Acad Sci USA 1996, 93: 3542–3546.
 Vreugdenhil M, Bruehl C, Voskuyl RA,
Kang JX, Leaf A, Wadman WJ. Polyunsat-
urated fatty acids modulate sodium and cal-
cium currents in CA1 neurons. Proc Natl
Acad Sci USA 1996, 93: 12559–12563.
 Renganathan M, Godoy CM, Cukierman S.
Direct modulation of Na+ currents by protein
kinase C activators in mouse neuroblastoma
cells. J Membr Biol 1995, 144: 59–69.
 Bogdanov KY, Spurgeon HA, Vinogradova
TM, Lakatta EG. Modulation of the transient
outward current in adult rat ventricular myo-
cytes by polyunsaturated fatty acids. Am J
Physiol 1998, 274: H571–H579.
 Seebungkert B, Lynch JW. Effects of poly-
unsaturated fatty acids on voltage-gated K+
and Na+ channels in rat olfactory receptor
neurons. Eur J Neurosci 2002, 16: 2085–
 Honore E, Barhanin J, Attali B, Lesage F,
Lazdunski M. External blockade of the
major cardiac delayed-rectifier K+ channel
(Kv1.5) by polyunsaturated fatty acids. Proc
Natl Acad Sci USA 1994, 91: 1937–1944.
 Lauritzen I, Blondeau N, Heurteaux C,
Widmann C, Romey G, Lazdunski M. Poly-
unsaturated fatty acids are potent neuropro-
tectors. EMBO 2000, 19: 1784–1793.
 Heurteaux C, Guy N, Laigle C, Blondeau N,
Duprat F, Mazzuca M, Lang-Lazdunski L,
Widmann C, Zanzouri M, Romey G, Laz-
dunski M. TREK-1, a K+ channel involved
in neuroprotection and general anesthesia.
EMBO 2004, 23: 2684–2695.
 Xiao YF, Gomez AM, Morgan JP, Lederer
WJ, Leaf A. Suppression of voltage-gated
L-type Ca2+ currents by polyunsaturated
fatty acids in adult and neonatal rat ventricu-
lar myocytes. Proc Natl Acad Sci USA 1997,
Omega-3 and neuropsychiatric disorders23
 Turner N, Else PL, Hulbert AJ. Docosahex-
aenoic acid (DHA) content of membranes
determines molecular activity of the sodium
pump: implications for disease states and
metabolism. Naturwissenschaften 2003, 90:
 Kearns SD, Haag M. The effect of omega-3
fatty acids on Ca-ATPase in rat cerebral cor-
tex. Prostaglandins Leukot Essent Fatty
Acids 2002, 67: 303–308.
 Gegelashvili G, Schousboe A. High affinity
glutamate transporters: regulation of expres-
sion and activity. Mol Pharmacol 1997, 52:
 Nishikawa M, Kimura S, Akaike N. Facili-
tatory effect of docosahexaenoic acid on N-
methyl-D-aspartate response in pyramidal
neurons of rat cerebral cortex. J Physiol 1994,
 Graber R, Sumida C, Nunez EA. Fatty acids
and cell signal transduction. J Lipid Mediat
Cell Signal 1994, 9: 91–116.
 Kogteva GS, Bezuglov VV. Unsaturated
fatty acids as endogenous bioregulators. Bio-
chemistry (Moscow) 1998, 63: 6–15.
 Wahle KW, Rotondo D, Heys SD. Polyun-
saturated fatty acids and gene expression in
mammalian systems. Proc Nutr Soc 2003,
 Horrocks LA, Farooqui AA. Docosahexae-
noic acid in the diet: its importance in main-
tenance and restoration of neural membrane
function. Prostaglandins Leukot Essent
Fatty Acids 2004, 70: 361–372.
 Kitajka K, Puskas LG, Zvara A, Hackler L
Jr, Barcelo-Coblijn G, Yeo YK, Farkas T.
The role of n-3 polyunsaturated fatty acids in
brain: modulation of rat brain gene expres-
sion by dietary n-3 fatty acids. Proc Natl
Acad Sci USA 2002, 99: 2619–2624.
 George JM, Jin H, Woods WS, Clayton DF.
Characterization of a novel protein regulated
during the critical period for song learning in
the zebra finch. Neuron 1995, 15: 361–372.
 Huntley GW, Gil O, Bozdagi O. The cad-
herin family of cell adhesion molecules:
multiple roles in synaptic plasticity. Neuro-
scientist 2002, 8: 221–233.
 Junge HJ, Rhee JS, Jahn O, Varoqueaux F,
Spiess J, Waxham MN, Rosenmund C, Brose
N. Calmodulin and Munc13 form a Ca2+ sen-
sor/effector complex that controls short-term
synaptic plasticity. Cell 2004, 118: 389–401.
 Colbran RJ, Brown AM. Calcium/calmodu-
lin-dependent protein kinase II and synaptic
plasticity. Curr Opin Neurobiol 2004, 14:
 Li H, Sanchez-Torres J, Del Carpio A, Salas
V, Villalobo A. The ErbB2/Neu/HER2 recep-
tor is a new calmodulin-binding protein. Bio-
chem J 2004, 381: 257–266.
 Schmitt JM, Wayman GA, Nozaki N,
Soderling TR. Calcium activation of ERK
mediated by calmodulin kinase I. J Biol Chem
2004, 279: 24064–24072.
 Kitajka K, Sinclair AJ, Weisinger RS,
Weisinger HS, Mathai M, Jayasooriya AP,
Halver JE, Puskas LG. Effects of dietary
omega-3 polyunsaturated fatty acids on
brain gene expression. Proc Natl Acad Sci
USA 2004, 101: 10931–10936.
 Martinez M. Polyunsaturated fatty acids in
the developing human brain, erythrocytes
and plasma in peroxisomal disease: thera-
peutic implications. J Inherit Metab Dis
1995, 18 (Suppl 1): 61–75.
 Uauy R, Peirano P, Hoffman D, Mena P,
Birch D, Birch E. Role of essential fatty acids
in the function of the developing nervous
system. Lipids 1996, 31 (Suppl): S167–
 Hoffman DR, Birch DG. Omega-3 fatty acid
status in patients with retinitis pigmentosa
1998, 83: 52–60.
 Martinez M. Restoring the DHA levels in the
brains of Zellweger patients. J Mol Neurosci
2001, 16: 309–316.
 Pary R, Lewis S, Matuschka PR, Lippmann
S. Attention-deficit/hyperactivity disorder:
an update. South Med 2002, 95: 743–749.
 Richardson AJ, Puri BK. The potential role
of fatty acids in attention-deficit/hyperactiv-
ity disorder. Prostaglandins Leukot Essent
Fatty Acids 2000, 63: 79–87.
 Burgess JR, Stevens L, Zhang W, Peck L.
Long-chain polyunsaturated fatty acids in
children with attention-deficit hyperactivity
disorder. Am J Clin Nutr 2000, 71: 327–330.
 Spencer T, Biederman J, Wilens TE, Faraone
SV. Is attention deficit hyperactivity disor-
der in adults a valid disorder? Harv Rev Psy-
chiatry 1994, 1: 326–335.
 Mitchell EA, Aman MG, Turbott SH, Manku
M. Clinical characteristics and serum essen-
tial fatty acid levels in hyperactive children.
Clin Pediatr 1987, 26: 406–411.
 Stevens LJ, Zentall SS, Deck JL, Abate ML,
Watkins BA, Lipp SR, Burgess JR. Essential
fatty acid metabolism in boys with attention-
deficit hyperactivity disorder. Am J Clin
Nutr 1995, 62: 761–768.
24 G. Young, J. Conquer
 Young GS, Maharaj NJ, Conquer JA. Blood
phospholipid fatty acid analysis of adults
with and without attention deficit/hyperac-
tivity disorder. Lipids 2004, 39: 117–123.
 Voigt RG, Llorente AM, Jensen CL, Fraley
JK, Berretta MC, Heird WC. A randomized,
double-blind, placebo-controlled trial of
docosahexaenoic acid supplementation in
children with attention-deficit/hyperactivity
disorder. J Pediatr 2001, 139: 189–196.
 Richardson AJ, Puri BK. A randomized dou-
ble-blind, placebo-controlled study of the
effects of supplementation with highly unsatu-
rated fatty acids on ADHD-related symp-
toms in children with specific learning diffi-
culties. Prog Neuro-Psychopharmacol Biol
Psychiatry 2002, 26: 233–239.
 Stevens L, Zhang W, Peck L, Kuczek T,
Grevsted N, Mahon A, Zentall SS, Arnold E,
Burgess JR. EFA supplementation in chil-
dren with inattention, hyperactivity, and
other disruptive behaviours. Lipids 2003, 38:
 Harding KL, Judah RD, Gant CE. Outcome-
based comparison of ritalin versus food-sup-
plement treated children with AD/HD. Altern
Med Rev 2003, 8: 319–330.
 Hirayama S, Hamazaki T, Terasawa K. Effect
of docosahexaenoic acid-containing food
administration on symptoms of attention-
deficit/hyperactivity disorder-a placebo-con-
trolled double-blind study. Eur J Clin Nutr
2004, 58: 467–473.
 Evans DA, Funkenstein HH, Alber M,
Scherr PA, Cook NR, Chown M, Herbert L,
Hennekens C, Taylor J. Prevalence of Alzhe-
imer’s disease in a community population of
older persons: higher that previously reported.
J Am Med Assoc 1989, 262: 2551–2556.
 Nitsch R, Pittas A, Blustztajn JK, Slock BE,
Growdon J. Alterations of phospholipid
metabolites in post-mortem brains from
patients with Alzheimer’s disease. Ann NY
Acad Sci 1991, 640: 110–113.
 Soderberg M, Edlund C, Kristensson K,
Dallner G. Fatty acid composition of brain
phospholipids in aging and Alzheimer’s dis-
ease. Lipids 1991, 26: 421–428.
 Soderberg M, Edlund C, Kristensson K,
Alafuzoff I, Dallner G. Lipid composition in
different regions of the brain in Alzheimer’s
disease/senile dementia of Alzheimer’s type.
J Neurochem 1992, 59: 1646–1653.
 Coorigan FM, Horrobin DF, Skinner ER,
Besson JA, Cooper MB. Abnormal content
of n-6 and n-3 long-chain unsaturated fatty
acids in the phosphoglycerides and choles-
terol esters of parahippocampus cortex from
Alzeimer’s disease patients and its relation-
ship to acetyl CoA content. Int J Biochem
Cell Biol 1998, 30: 197–207.
 Mulder M, Ravid R, Swaab DF, deLoet ER,
Haasdijk ED, Julk J, van der Bloom J,
Havekes LM. Reduced levels of cholesterol,
phospholipids, and fatty acids in CSF of
Alzheimer’s disease patients are not related
to Apo E4. Alzheimer Dis Assoc Disord
1998, 12: 198–203.
 Prasad MR, Lovell MA, Yatin M, Dhillon H,
Markesbery WR. Regional membrane phos-
pholipid alterations in Alzheimer’s disease.
Neurochem Res 1998, 23: 81–88.
 Barberger-Gateau P, Letenneur L, Deschamps
V, Peres K, Dartigues JF. Fish, meat, and
risk of dementia: cohort study. Br Med J
2002, 325: 932–933.
 Larrieu S, Letenneur L, Helmer, C, Dartigues
JF, Barberger-Gateau P. Nutritional factors
and risk of incident dementia in the PAQUID
longitudinal cohort. J. Nutr Health Aging
2004, 8: 150–154.
 Grant WB. Dietary Links to Alzheimer’s
Disease. Alzheimer Dis Rev 1997, 2: 42–55.
 Kalmijn S, Feskens EJ, Launer LJ, Kromhout
D. Polyunsaturated fatty acids, antioxidants,
and cognitive function in very old men. Am
J Epidemiol 1997, 145: 33–41.
 Grant WB. Diet and risk of dementia: Does
fat matter? The Rotterdam study. Neurology
2003, 60: 2020–2021.
 Morris MC, Evans DA, Bienias JL, Tangney
CC, Bennett DA, Wilson RS, Aggarwal N,
Schneider J. Consumption of fish and n-3
fatty acids and risk of incident Alzheimer
disease. Arch Neurol. 2003, 60: 940–946.
 Kalmijn S, van Boxtel MPJ, Ocke M,
Verschuren WMM, Kromhout D, Launer
LJ. Dietary intake of fatty acids and fish in
relation to cognitive performance at middle
age. Neurology 2004, 62: 275–280.
 Heude B, Ducimetiere P, Berr C. Cognitive
decline and fatty acid composition of eryth-
rocyte membranes. The EVA study 2003, 77:
 Tully AM, Roche HM, Doyle R, Fallon C,
Bruce I, Lawlor B, Coakley D, Gibney MJ.
Low serum cholesteryl ester-docosahexae-
noic acid levels in Alzheimer’s disease: a
case-control study. Br J Nutr 2003, 89: 483–
 Conquer JA, Tierney MC, Zecevic J, Bettger
WJ, Fisher RH. Fatty acid analysis of blood
plasma of patients with Alzheimer’s Dis-
ease, other types of dementia and cognitive
impairment. Lipids 2000, 35: 1305–1312.
Omega-3 and neuropsychiatric disorders25
 Laurin D, Verreault R, Lindsay J, Dewailly
E, Holub BJ. Omega-3 fatty acids and risk of
cognitive impairment and dementia. J Alzhe-
imer Dis 2003, 5: 315–322.
 Otsuka M, Yamaguchi K, Ueki A. Similari-
ties and differences between Alzheimer’s
disease and vascular dementia from the
viewpoint of nutrition. Ann NY Acad Sci
2002, 977: 155–161.
 Otsuka M. Analysis of dietary factors in
Alzheimer’s disease: clinical use of nutri-
tional intervention for prevention and treat-
ment of dementia. Nippon Ronen Igakkai
Zasshi 2000, 37: 970–973.
 Kyle DJ, Schaefer E, Patton G, Beiser A.
Low serum docosahexaenoic acid is a signif-
icant risk factor for Alzheimer’s dementia.
Lipids 1999, 34 (Suppl): S245.
 Nourooz-Zadeh J, Liu EH, Yhlen B, Anggard
EE, Halliwell B. F4-isoprostanes as specific
marker of docosahexaenoic acid peroxida-
tion in Alzheimer’s disease. J Neurochem
1999, 72: 734–740.
 Montine TJ, Beal MF, Cudkowicz ME,
O’Donnell H, Margolin RA, McFarland L,
Bachrach AF, Zackert WE, Roberts LJ,
Morrow JD. Increased CSF F2-isoprostane
concentration in probable AD. Neurology
1999, 52: 562–565.
 Terano T, Fujishiro S, Ban T, Yamamoto K,
Tanaka T, Noguchi Y, Tamura Y, Yazawa K,
Hirayama T. Docosahexaenoic acid supple-
mentation improves the moderately severe
dementai from thrombotic cerebrovascular
diseases. Lipids 1999, 34: S345–S346.
 Suzuki H, Morikawa Y, Takahashi H. Effect
of DHA oil supplementation on intelligence
and visual acuity in the elderly. World Rev
Nutr 2001, 88: 68–71.
 Christensen O, Christenesen E. Fat con-
sumption and schizophrenia. Acta Psychiatr
Scand 1988, 78: 587–591.
 Mellor JE, Laugharne JDE, Peet M. Omega-3
fatty acid supplementation in schizophrenia
patients. Hum Psychopharmacol 1996, 11:
 Richardson AJ, Cyhlarova E, Ross MA.
Omega-3 and omega-6 fatty acid concentra-
tions in red blood cell membranes relate to
schizotypal traits in healthy adults. Prostag-
landins Leukot Essent Fatty Acids 2003, 69:
 Evans DR, Parikh VV, Khan MM, Coussons
C, Buckley PF, Mahadik SP. Red blood cell
membrane essential fatty acid metabolism in
early psychotic patients following antipsy-
chotic drug treatment. Prostaglandins Leu-
kot Essent Fatty Acids 2003, 69: 393–399.
 Arvindakshan M, Sitasawad S, Debsikdar V,
Ghate M, Evans D, Horrobin DF, Bennett C,
Ranjekar PK, Mahadik SP. Essential poly-
unsaturated fatty acid and lipid peroxide lev-
els in never-medicated and medicated schiz-
ophrenia patients. Biol Psychiatry 2003, 53:
 Khan MM, Evands DR, Gunna V, Scheffer
RE, Parikh VV, Mahadik SP. Reduced eryth-
rocyte membrane essential fatty acids and
increased lipid peroxides in schizophrenia at
the never-medicated first-episode of psycho-
sis and after years of treatment with antipsy-
chotics. Schizophr Res 2002, 58: 1–10.
 Assies J, Lieverse R, Vreken P, Wanders RJ,
Dingemans PM, Linszen DH. Significantly
reduced docosahexaenoic and docosapen-
taenoic acid concentrations in erythrocyte
membranes from schizophrenic patients com-
pared with a carefully matched control group.
Biol Psychiatry 2001, 49: 510–522.
 Peet M, Laugharne J, Rangarajan N, Horrobin
D, Reynolds G. Depleted red cell membrane
essential fatty acids in drug-treated schizo-
phrenic patients. J Psychiatr Res 1995, 29:
 Ranjekar PK, Hinge A, Hegde MV, Ghate M,
Kale A, Sitasawad S, Wagh UV, Debsikdar
VB, Mahadik SP. Decreased antioxidant
enzymes and membrane essential polyunsat-
urated fatty acids in schizophrenic and bipo-
lar mood disorder patients. Psychiatry Res
2003, 121: 109–122.
 Laugharne JD, Mellor JE, Peet M. Fatty
acids and schizophrenia. Lipids 1996, 31
 Mahadik SP, Mukherjee S, Horrobin DF,
Jenkins K, Correnti EE, Scheffer RE. Plasma
membrane phospholipid fatty acid composi-
tion of cultured skin fibroblasts from schiz-
ophrenic patients: comparison with bipolar
patients and normal subjects. Psychiatry Res
1996, 63: 133–142.
 Fischer S, Kissling W, Kuss HJ. Schizo-
phrenic patients treated with high dose phe-
nothiazine or thioxanthene become deficient
in polyunsaturated fatty acids in their throm-
bocytes. Biochem Pharmacol 1992, 44: 317–
 Hibbeln JR, Makino KK, Martin CE,
Dickerson F, Boronow J, Fenton WS. Smok-
ing, gender, and dietary influences on eryth-
rocyte essential fatty acid composition among
patients with schizophrenia or schizoaffec-
tive disorder. Biol Psychiatry 2003, 53: 431–
 Mahadik SP, Shendarkar NS, Scheffer RE,
Mukherjee S, Correnti EE. Utilization of pre-
cursor essential fatty acids in culture by skin
26 G. Young, J. Conquer
fibroblasts from schizophrenic patients and
normal controls. Prostaglandins Leukot Essent
Fatty Acids 1996, 55: 65–70.
 Warner R, Laugharne J, Peet M, Brown L,
Rogers N. Retinal function as a marker for
cell membrane omega-3 fatty acid depletion
in schizophrenia: a pilot study. Biol Psychi-
atry 1999, 45: 1138–1142.
 Joy CB, Mumby-Croft R, Joy LA. Polyun-
saturated fatty acid supplementation for
schizophrenia. Cochrane Database Syst Rev
 Peet M. Eicosapentaenoic acid in the treat-
ment of schizophrenia and depression: ration-
ale and preliminary double-blind clinical
trial results. Prostaglandins Leukot Essent
Fatty Acids Acids 2003, 69: 477–485.
 Peet M. Nutrition and schizophrenia: beyond
omega-3 fatty acids. Prostaylandins Leukot
Essent Fatty Acids 2004, 70: 417–422.
 Peet M, Horrobin DF, E-E Muticentre group.
A dose-ranging exploratory study of the
effects of ethyl-eicosapentaenoate in patients
with persistent schizophrenic symptoms. J
Psychiatr Res 2002, 36: 7–18.
 Peet M, Brind-J, Ramchand CN, Shah S,
Vankar GK. Two double-blind placebo-con-
trolled pilot studies of eicosapentaenoic acid
in the treatment of schizophrenia. Schizophr
Res 2001, 49: 243–251.
 Fenton WS, Dickerson F, Boronow J,
Hibbeln JR, Knable M. A placebo-controlled
trial of omega-3 fatty acid (ethyl eicosapen-
taenoic acid) supplementation for residual
symptoms and cognitive impairment in
schizophrenia. Am J Psychiatry 2001, 158:
 Arvindakshan M, Ghate M, Ranjekar PK,
Evans DR, Mahadik SP. Supplementation
with a combination of omega-3 fatty acids
and antioxidants (vitamins E and C) improves
the outcome of schizophrenia. Schizophr
Res 2003, 62: 195–204.
 Su KP, Shen WW, Huang SY. Omega-3 fatty
acids as a psychotherapeutic agent for a preg-
nant schizophrenic patient. Eur Neuropsy-
chopharmacol 2001, 11: 295–299.
 Richardson AJ, Easton T, Puri BK. Red cell
and plasma fatty acid changes accompany-
ing symptom remission in a patient with
schizophrenia treated with eicosapentaenoic
acid. Eur Neuropsychopharmacol 2000, 10:
 Puri BK, Richardson AJ, Horrobin DF,
Easton T, Saeed N, Oatridge A, Hajnal JV,
Bydder GM. Eicosapentaenoic acid treat-
ment in schizophrenia associated with symp-
tom remission, normalisation of blood fatty
acids, reduced neuronal membrane phos-
pholipid turnover and structural brain changes.
Int J Clin Pract 2000, 54: 57–63.
 Richardson AJ, Easton T, Gruzelier JH, Puri
BK. Laterality changes accompanying symp-
tom remission in schizophrenia following
treatment with eicosapentaenoic acid. Int J
Psychophysiol 1999, 34: 333–339.
 American Psychiatric Association. Diagnos-
tic and statistical manual for mental disorders
(DSM-IV). Washington DC, APA, 1994.
 Hibbeln JR, Salem N. Dietary polyunsatu-
rated fatty acids and depression: when cho-
lesterol does not satisfy. Am J Clin Nutr
1995, 62: 1–9.
 Peet M, Murphy B, Shay J, Horrobin D.
Depletion of omega-3 fatty acid levels in red
blood cell membranes of depressive patients.
Biol Psychiatry 1998, 43: 315–319.
 Logan AC. Neurobehavioural aspects of
omega-3 fatty acids: possible mechanisms
and therapeutic value in major depression.
Altern Med Rev 2003, 8: 410–425.
 Mischoulon D, Fava M. Docosahexaenoic
acid and omega-3 fatty acids in depression.
Psychiatr Clin North Am 2000, 23: 785–794.
 Noaghiul S, Hibbeln JR. Cross national rela-
tionship of seafood consumption and rates of
bipolar disorders. Am J Psychiatry 2003,
 Hibbeln JR. Fish consumption and major
depression. Lancet 1998, 351: 1213.
 Tanskanen A, Hibbeln JR, Tuomilehto J,
Uutela A, Haukkala A, Viinamaki H, Lehtonen
J, Vartiainen E. Fish consumption and depres-
sive symptoms in the general population in
Finland. Psychiatr Serv 2001, 52: 529–531.
 Suzuki S, Akechi T, Kobayashi M, Taniguchi
K, Goto K, Sasaki S, Tsugane S, Nishiwaki
Y, Miyaoka H, Uchitomi Y. Daily omega-3
fatty acid intake and depression in Japanese
patients with newly diagnosed lung cancer.
Br J Cancer 2004, 90: 787–793.
 Frasure-Smith N, Lesperance F, Julien P.
Major depression is associated with lower
omega-3 fatty acid levels in patients with
recent acute coronary syndromes. Biol Psy-
chiatry 2004, 55: 891–896.
 De Vriese SR, Christophe AB, Maes M. In
humans, the seasonal variation in poly-
unsaturated fatty acids is related to the sea-
sonal variation in violent suicide and sero-
tonergic markers of violent suicide. Prostag-
landins Leukot Essent Fatty Acids 2004, 71:
Omega-3 and neuropsychiatric disorders27
 Hakkarainen R, Partonen T, Haukka J,
Virtamo J, Albanes D, Lonnqvist J. Is low
dietary intake of omega-3 fatty acids associ-
ated with depression? Am J Psychiatry 2004,
 Edwards R, Peet M, Shay J, Horrobin D.
Omega-3 polyunsaturated fatty acid levels in
the diet and in red blood cell membranes of
depressed patients. J Affect Disord 1998, 48:
 Assies J, Lok A, Bockting CL, Weverling
GJ, Lieverse R, Visser I, Abeling NGGM,
Duran M, Schene AH. Fatty acids and homo-
cysteine levels in patients with recurrent
depression: an explorative pilot study. Pros-
taglandins Leukot Essent Fatty Acids 2004,
 Mamalakis G, Kiriakakis M, Tsibinos G,
Kafatos A. Depression and adipose polyun-
saturated fatty acids in the survivors of the
Seven Countries Study population of Crete.
Prostaglandins Leukot Essent Fatty Acids
2004, 70: 495–501.
 Tiemeier H, van Tuijl HR, Hofman A, Kiliaan
AJ, Breteler MM. Plasma fatty acid compo-
sition and depression are associated in the
elderly: the Rotterdam study. Am J Clin Nutr
2003, 78: 40–46.
 Mamalakis G, Tornaritis M, Kafatos A.
Depression and adipose essential polyunsat-
urated fatty acids. Prostaglandins Leukot
Essent Fatty Acids 2002, 67: 311–318.
 Mamalakis G, Kiriakakis M, Tsibinos G,
Kafatos A. Depressin and adipose polyunsat-
urated fatty acids in an adolescent group.
Prostaglandins Leukot Essent Fatty Acids
2004, 71: 289–294.
 Maes M, Smith R, Christophe A, Cosyns P,
Desnyder R, Meltzer H. Fatty acid composi-
tion in major depression: decreased ω3 frac-
tions in cholesteryl esters and increased
C20:4 ω6/C20:5 ω3 ration in cholesteryl
esters and phospholipids. J Affect Disord
1996, 38: 35–46.
 Maes M, Christophe A, Delanghe J, Altamura
C, Neels H, Meltzer HY. Lowered omega3
polyunsaturated fatty acids in serum phos-
pholipids and cholesteryl esters of depressed
patients. Psychiatry Res 1999, 85: 275–291.
 Ranjekar PK, Hinge A, Hegde MV, Ghate M,
Kale A, Sitasawad S, Wagh UV, Debsikdar
VB, Mahadik SP. Decreased antioxidant
enzymes and membrane essential polyunsat-
urated fatty acids in schizophrenic and bipo-
lar mood disorder patients. Psychiatry Res
2003, 121: 109–122.
 Adams PB, Lawson S, Sanigorski A, Sinclair
AJ. Arachidonic acid to eicosapentaenoic
acid ratio in blood correlates positively with
clinical symptoms of depression. Lipids
1996, 31 (Suppl): S157–S161.
 Hibbeln JR. Seafood consumption, the DHA
content of mothers’ milk and prevalance
rates of postpartum depression: a cross-
national, ecological analysis. J Affect. Dis-
ord. 2002, 69: 15–29.
 Makrides M, Crowther CA, Gibson RA,
Gibson RS, Skeaff CM. Docosahexaenoic
acid and post-partum depression-is there a
link? Asia Pac J Clin Nutr 2003, 12 (Suppl):
 Otto SJ, de Groot RH, Hornstra G. Increased
risk of postpartum depressive symptoms is
associated with slower normalization after
pregnancy of the functional docosahexae-
noic status. Prostaglandins Leukot Essent
Fatty Acids 2003, 69: 237–243.
 De Vriese SR, Christophe AB, Maes M.
Lowered serum n-3 polyunsaturated fatty
acid (PUFA) levels predict the occurrence of
postpartum depression: further evidence that
lowered n-3 PUFAs are related to major
depression. Life Sci 2003, 73: 3181–3187.
 Peet M, Horrobin DF. A dose-ranging study
of the effects ethyl-eicosapentaenoate in
patients with ongoing depression despite
apparently adequate treatment with standard
drugs. Arch Gen Psychiatry 2002, 59: 913–
 Puri BK, Counsell SJ, Hamilton G, Richardson
AJ, Horrobin DF. Eicosapentaenoic acid in
treatment resistant depression associated
with symptom remission, structural brain
changes and reduced neuronal phospholipid
turnover. Int J Clin Pract 2001, 55: 560–563.
 Nemets B, Stahl Z, Belmaker RH. Addition
of omega-3 fatty acid to maintenance medi-
cation treatment for recurrent unipolar depres-
sive disorder. Am J Psychiatry 2002, 159:
 Su KP, Huang SY, Chiu CC, Shen WW.
Omega-3 fatty acids in major depressive dis-
order. A preliminary double-blind, placebo-
controlled trial. Eur Neuropsychopharmacol
2003, 13: 267–271.
 Marangell LB, Martinez JM, Zboyan HA,
Kertz B, Kim HF, Puryear LJ. A double-blind,
placebo-controlled study of the omega-3
fatty acid docosahexaenoic acid in the treat-
ment of major depression. Am J Psychiatry
2003, 160: 996–998.
 Marangell LB, Martinez JM, Zboyan HA,
Chong H, Puryear LJ. Omega-3 fatty acids
28 G. Young, J. Conquer Download full-text
for prevention of postpartum depression:
negative data from a preliminary, open-label
pilot study. Depress Anxiety 2004, 19: 20–23.
 Llorente AM, Jensen CL, Voigt RG, Fraley
JK, Berretta MC, Heird WC. Effect of mater-
nal docosahexaenoic acid supplementation
on postpartum depression and information
processing. Am J Obstet Gynecol 2003, 188:
 Taylor KE, Higgins CJ, Calvin CM, Hall JA,
Easton T, McDaid AM, Richardson AJ. Dys-
lexia in adults is associated with clinical
signs of fatty acid deficiency. Prostaglandins
Leukot Essent Fatty Acids 2000, 63: 75–78.
 Richardson AJ, Calvin CM, Clisby C,
Schoenheimer DR, Montgomery P, Hall JA,
Hebb G, Westwood E, Talcott JB, Stein JF.
Fatty acid deficiency signs predict the sever-
ity of reading and related difficulties in dys-
lexic children. Prostaglandins Leukot Essent
Fatty Acids 2000, 63: 69–74.
 Richardson AJ, Cox IJ, Sargentoni J, Puri
BK. Abnormal cerebral phospholipid metab-
olism in dyslexia indicated by phosphorus-
31 magnetic resonance spectroscopy. NMR
Biomed 1997, 10: 309–314.
 MacDonnell LEF, Skinner FK, Ward PE,
Glen AI, Glen AC, Macdonald DJ, Boyle RM,
Horrobin DF. Increased levels of cytosolic
phospholipase A2 in dyslexics. Prostagland-
ins Leukot Essent Fatty Acids 2000, 63: 95–
 Stordy BY. Dark adaptation, motor skills,
docosahexaenoic acid, and dyslexia. Am J
Clin Nutr 2000, 71 (Suppl 1): 323S–326S.
 Vancassel S, Durand G, Barthelemy C,
Lejeune B, Martineau J, Guilloteau D,
Andres C, Chalon S. Plasma fatty acid levels
in autistic children. Prostaglandins Leukot
Essent Fatty Acids 2001, 65: 1–7.
 Bell JG, Sargent JR, Tocher DR, Dick JR.
Red blood cell fatty acid compositions in a
patient with autistic spectrum disorder: a
characteristic abnormality in neurodevelop-
mental disorders? Prostaglandins Leukot
Essent Fatty Acids 2000, 63: 21–25.
 Richardson AJ. Clinical trials of fatty acid
treatment in ADHD, dyslexia, dyxpraxia and
the autistic spectrum. Prostaglandins Leukot
Essent Fatty Acids 2004, 70: 383–390.
 Zanarini MC, Frankenburg FR. Omega-3
fatty acid treatment of women with border-
line personality disorder: a double-blind,
placebo-controlled pilot study. Am J Psychi-
atry 2003, 160: 167–169.
 Fux M, Benjamin J, Nemets B. A placebo-
controlled cross-over trial of adjunctive EPA
in OCD. J Psychiatr Res 2004, 38: 323–325.
 Hibbeln JR. Seafood consumption and hom-
icide mortality. World Rev Nutr Diet 2001,
 Iribarren C, Markovitz JH, Jacobs DR Jr,
Schreiner PJ, Daviglus M, Hibbeln JR. Die-
tary intake of n-3, n-6 fatty acids and fish:
relationship with hostility in young adults –
the CARDIA study. Eur J Clin Nutr 2004, 58:
 Hamazak T, Thienprasert A, Kheovichai K,
Samuhaseneetoo S, Nagasawa T, Watanabe
S. The effect of docosahexaenoic acid on
aggression in elderly Thai subjects – a pla-
cebo controlled double blind study. Nutr
Neurosci 2002, 5: 37–41.
 Hamazaki T, Sawazaki S, Itomura M,
Asaoka E, Nagao Y, Nishimura N, Yazawa
K, Kuwamori T, Kobayashi M. The effect of
docosahexaenoic acid on aggression in
young adults. A placebo-controlled double-
blind study. J Clin Invest 1996, 97: 1129–
 Sawazaki S, Hamazaki T, Yazawa K,
Kobayashi M. The effect of docosahexae-
noic acid on plasma catecholamine concen-
trations and glucose tolerance during long-
lasting psychological stress: a double-blind
placebo-controlled study. J Nutr Sci Vitami-
nol 1999, 45: 655–665.
 Hamazaki T, Sawazaki S, Nagao Y,
Kuwamori T, Yazawa K, Mizushima Y,
Kobayashi M. Docosahexaenoic acid does
not affect aggression of normal volunteers
under nonstressful conditions. A randomized,
placebo-controlled, double-blind study. Lip-
ids 1998, 33: 663–667.
 Buydens-Branchey L, Branchey M, McMakin
DL, Hibbeln JR. Polyunsaturated fatty acid
status and aggression in cocaine addicts.
Drug Alcohol Depend 2003, 71: 319–323.
 Available from URL: http://www.ahrq.gov/
pdf [consulted: 13 Sept 2004].
 Nutrition Facts “Omega 3” eggs, Gray Ridge
Egg Farms, RR#7, Strathroy, ONN7G 3H8.
 Available from URL: http://www.dairy-oh.
com/nutrition.htm [consulted: 13 Sept 2004].
 Available from URL: http://www.tiptop.com.
up+omega+3+dha [consulted: 13 Sept 2004].