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Editorial
Éditorial
Dietary fat intake and the brain:
a developing frontier in biological psychiatry
Carol E. Greenwood, PhD; Simon N. Young, PhD
Greenwood — Department of Nutritional Sciences, Faculty of Medicine, University of Toronto and Kunin Lunenfeld Applied
Research Unit, Baycrest Centre for Geriatric Care, Toronto, Ont.; Young — Department of Psychiatry, McGill University,
Montreal, Que. and co-editor-in-chief, Journal of Psychiatry & Neuroscience
Some ideas are many years ahead of their time. In the
last quarter of the nineteenth century, Thudichum, one
of the founding fathers of neurochemistry, studied the
composition of the brain. (For reviews of Thudichum’s
work and his contributions to the development of neurochemistry, see Sourkes1,2). His aim was to determine
the composition of the brain, as far as was possible, in
order to discover what changes occur in brain disorders, including mental illness. The major part of his
work concerned lipids, the main constituent of the
brain after water. The idea that brain lipid content may
be important in the etiology or treatment of psychiatric
disorders lay dormant until relatively recently, but it is
growing in importance.
Lipid is an important constituent of the brain, not
only because of myelin, but also because of the large
surface-to-volume ratio of neurons — neurons contain
a higher proportion of lipid than other cells because
lipid is the main constituent of the neuronal cell membrane. The precise characteristics of this lipid bilayer
may affect not only the electrical properties of the
membrane, but also the properties of proteins embedded in it, such as receptors. However, the extent to
which the lipid content of the brain can be altered and
the implications this has, both for variations in normal
behaviour and for psychopathology, remain uncertain.
Reports of altered plasma, red cell or brain lipid profiles in certain psychiatric disorders, including depression3 and schizophrenia,4 have led some investigators
to postulate that impaired fatty acid and phospholipid
metabolism may play a major role in the etiology of
psychiatric disorders. Specifically reported are lower
levels and altered ratios of the omega-6 and omega-3
essential fatty acids.3,4 Whether these changes are secondary to other behavioural attributes of patients (e.g.,
altered food intake, smoking or alcohol use) or a primary metabolic event associated with the disease has
not been unequivocally answered. However, increasing evidence is pointing to altered membrane turnover
and release of fatty acids from phospholipids via phospholipase A2 in individuals with depression or schizophrenia. These released fatty acids, which are ultimately converted to omega-6 or omega-3 series
eicosanoids, contribute to a wide variety of cellular
responses, thus implicating genetic disturbances in
lipid metabolizing enzymes in the psychopathology of
these disorders.
Although genetic disturbances in brain lipid metabolism may be associated with psychopathologic disorders, an important question is whether dietary fat can
play a contributory role, a therapeutic role or both. At
one time, the lipid content of the brain was considered
Correspondence to: Dr. Simon N. Young, Department of Psychiatry, McGill University, 1033 Pine Ave. W, Montreal QC H3A 1A1;
fax: 514 398-4370; [email protected]
Medical subject headings: biological psychiatry; brain; cholesterol; dietary fats; lipids; neurochemistry; psychopathology
J Psychiatry Neurosci 2001;26(3):182-4.
© 2001 Canadian Medical Association
182
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Vol. 26, no 3, 2001
Éditorial
relatively resistant to change induced by dietary intake.
However, in the late 1980s, it became apparent that diet
could alter the content and function of the rat brain in a
short period of time. For example, rats have different
brain lipid contents and demonstrate differences in
cognition and behaviour after only a few weeks on diets containing soybean oil or lard.5,6 The composition of
the developing human brain is also dependent on dietary lipid intake. For example, the brains of breast-fed
infants have higher levels of total omega-3 fatty acids
and lower levels of omega-6 fatty acids than formulafed infants.7 The extent to which changes in dietary fat
intake alter brain lipid composition in adult human
brain is unknown, however.
One of the more common types of diets recommended by physicians is designed to lower cholesterol
levels, and, as shown in the nineteenth century, cholesterol is an important constituent of the brain. Muldoon
et al8 reviewed several studies on men (n = 24 847) with
lowered cholesterol levels and found that, although
mortality from cardiovascular disease tended to be
lower, more patients were dying from accidents and
suicide. Giving cholesterol to monkeys increases indices of serotonin function;9 perhaps lowering cholesterol levels in humans lowers serotonin function and
increases impulsivity, thereby increasing deaths due to
accidents and suicide. A number of studies found no
relationship between low cholesterol and suicide or accidents.10,11 However, a recent study showed that low
cholesterol was related more to a measure of impulsivity than to parasuicide.12
When patients lower their cholesterol intake, they
are probably not only lowering their total fat intake,
but also substituting other fats for saturated fats and
cholesterol. At its extreme, some have argued that the
overall trend for decreased consumption of omega-3
fatty acids is associated with the increasing lifetime
prevalence of depression seen in the last century. In a
cross-country comparison, Hibbeln and Salem13 found
a strong inverse association between omega-3 fatty
acid intake and prevalence of depressive illnesses. This
could indicate that dietary intake of omega-3 fatty
acids has a large enough impact on brain function to
significantly affect mental health. Results from therapeutic trials using omega-3 fatty acids in the treatment
of depression are inconsistent.14 However, a preliminary study showed that pharmacological doses of
omega-3 fatty acids (9.6 g/day) helped to stabilize patients with bipolar affective disorder.15 A lower dose
Vol. 26, No. 3, 2001
(1.5–1.8 g/d) also decreased aggression in students
who were stressed by taking final exams.16 Conflicting
results have been obtained in several studies on patients with schizophrenia,4,14 but these studies may not
have used the best treatment. Preliminary evidence
suggests that only the 20-carbon (eicosapentaenoic
acid; EPA), but not the 22-carbon (docosahexaenoic
acid; DHA) omega-3 fatty acid results in improvement.17
The fact that EPA, but not DHA, can inhibit phospholipase A2, which may be elevated in schizophrenia, may
help to explain the specificity of this fatty acid.3
One of the problems in studying the effects of fat intake on the brain is the large number of fats present in
the diet and the many possible mechanisms by which
they may alter brain function. It has long been argued
that dietary fat, via its ability to alter brain membrane
fatty acid composition, can alter membrane fluidity. A
recent human study supported this notion by demonstrating that patients taking omega-3 fatty acids show
changes in proton magnetic resonance transverse relaxation time, indicating an increase in membrane
fluidity.18 Changes in membrane fluidity, in turn, can
influence the availability and activity of membraneassociated proteins (e.g., neurotransmitter receptors
and enzymes), as well as the flexibility or movement of
ion channels (reviewed in Fenton et al4). In addition to
alterations in membrane properties, fats are the precursor of a variety of messenger substances, including
prostaglandins, thromboxanes and leukotrienes, collectively called eicosanoids. Once released from membrane phospholipids under the action of various phospholipases, the omega-6 and omega-3 fatty acids
produce different series of eicosanoids. It has long been
known that the essential fatty acids and eicosanoids
participate in cellular signal transduction and their
deficiency or excess can alter cellular communication.
Furthermore, the omega-3 fatty acids can inhibit phospholipase A2 and interfere with the conversion of the
omega-6 fatty acids into their respective eicosanoids.19
However, recent identification of the eicosanoid ligand,
anandamide, the endogenous ligand for the cannabinoid receptor, and its ability to increase the production
of interleukins and other cytokines, opens the possibility that lipids alter the functioning of the cytokine network.20 Cytokines have been implicated in the pathophysiology of several psychiatric disorders, including
depression and schizophrenia.21 Finally, evidence is
emerging that fatty acids may also have direct nuclear
effects. For example, in mouse brain, DHA was re-
Journal of Psychiatry & Neuroscience
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Editorial
cently identified as a ligand for the retinoid X receptor,22 a nuclear receptor that functions as a ligandactivated transcription factor and that has been implicated in the differentiation of a variety of neuronal
subtypes, including cholinergic neurons.23
The degree to which any of these changes occur in
human brain and their contribution of psychiatric disorders are unknown. Unfortunately, the vast number
of potential mechanisms makes it unlikely that a single factor will be identified to explain the complex associations between fat intake, metabolism and brain
function.
After more than a century, research relating brain
lipid composition and brain function remains in its infancy. On the basic science side, we need to know
much more about which specific lipids can influence
the brain and the mechanisms mediating these effects.
Clinically, more studies are needed to establish the
therapeutic effects of pharmacological doses of different fats. Further in the future is an understanding of
how dietary fat intake may influence normal and abnormal mood and behaviour. In all probability, the
brains of an Argentinean gaucho, a Canadian Inuk and
an Indian Hindu have distinctive lipid profiles. Similarly, changes in diet, whether promoted by health professionals or the latest fad, may alter brain composition
and function. We are far from understanding the implications of these changes for mental health.
9.
Kaplan JR, Shively CA, Fontenot MB, Morgan TM, Howell SM,
Manuck SB, et al. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys. Psychosom Med 1994;56:479-84.
10.
Muldoon MF, Manuck SB, Mendelsohn AB, Kaplan JR, Belle SH.
Cholesterol reduction and non-illness mortality: meta-analysis of
randomised clinical trials. BMJ 2001;322(7277):11-5.
11.
Stewart RA, Sharples KJ, North FM, Menkes DB, Baker J,
Simes J. Long-term assessment of psychological well-being in
a randomized placebo-controlled trial of cholesterol reduction
with pravastatin. The LIPID Study Investigators. Arch Intern
Med 2000;160:3144-52.
12.
Garland M, Hickey D, Corvin A, Golden J, Fitzpatrick P, Cunningham S, et al. Total serum cholesterol in relation to psychological correlates in parasuicide. Br J Psychiatry 2000;177:77-83.
13.
Hibbeln JR, Salem N. Dietary polyunsaturated fatty acids and
depression: when cholesterol does not satisfy. Am J Clin Nutr
1995;62:1-9.
14.
Maidment ID. Are fish oils an effective therapy in mental illness: an analysis of the data. Acta Psychiatr Scand 2000;102:3-11.
15.
Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA,
Diamond E, et al. Omega 3 fatty acids in bipolar disorder: a
preliminary double-blind, placebo-controlled trial. Arch Gen
Psychiatry 1999;56:407-12.
16.
Hamazaki T, Sawazaki S, Itomura M, Asaoka E, Nagao Y,
Nishimura N, et al. The effect of docosahexaenoic acid on aggression in young adults: a placebo-controlled double-blind
study. J Clin Invest 1996;97:1129-33.
18.
Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism
and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate
genes. Prostaglandins Leukot Essent Fatty Acids 1999;60:217-34.
Stoll AL, Hirashima F, Parow A, Rohan M, Cohen BM, Eskesen J, et al. Omega-3 fatty acids and cerebral membrane fluidity: a T2 mapping MR study [abstract]. Meeting of the American College of Neuropsychopharmacology; 2000 Dec 10–14;
San Juan, Puerto Rico. Nashville (TN): American College of
Neuropsychopharmacology; 2000.
19.
Fenton WS, Hibbeln J, Knable M. Essential fatty acids, lipid
membrane abnormalities, and the diagnosis and treatment of
schizophrenia. Biol Psychiatry 2000;47:8-21.
Wainwright PE. Essential fatty acids and behavior: is there a role
for the eicosanoids? In: Yehuda S, Mostofsky D, editors. Handbook of essential fatty acid biology: biochemistry, physiology, and behavioral neurobiology. Clifton (NJ): Humana Press; 1997. p. 299-341.
20.
Klein TW, Lane B, Newton CA, Friedman H. The cannabinoid
system and cytokine network. Exp Biol Med 2000;225:1-8.
21.
Kronfol Z, Remick DG. Cytokines and the brain: implications
for clinical psychiatry. Am J Psychiatry 2000;157:683-94.
22.
de Urquiza AM, Liu S, Sjöberg M, Zetterström RH, Griffiths W,
Sjövall J, et al. Docosahexaenoic acid, a ligand for the retinoid
X receptor in mouse brain. Science 2000;290:2140-4.
23.
Malik S, Blusztajn JK, Greenwood CE. Nutrients as trophic factors in neurons and the central nervous system: role of retinoic
acid. J Nutr Biochem 2000;11:2-13.
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7.
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