Royal College of Surgeons of Ireland and the Department of Psychiatry, Beaumont Hospital, Dublin, Ireland, UK
Correspondence: Malcolm R.Garland, Royal College of Surgeons of Ireland and the Department of Psychiatry, Beaumont Hospital, Dublin 9, Ireland, UK.Tel: 00 353 1 8093354; 4; fax: 00 353 1 8376982; e-mail: mgarland{at}ireland.com
The biological basis for the major psychiatric disorders is presumed to be a deficit or excess of neurotransmitters or abnormalities in their interactions with their respective receptors or transporters. Accordingly, the vast bulk of biological research, from genetics to psychopharmacology and from the study of signal transduction systems to in vivo molecular imaging, has placed the neurotransmitter and its target proteins centre-stage. This belies the fact that the dry weight of the mammalian brain is approximately 80% lipid (the highest of any organ) and also the steady accumulation of data demonstrating the crucial role of lipids, particularly long-chain polyunsaturated fatty acids (LC-PUFAs), in modulating neural function. The essential fatty acids (EFAs) are LC-PUFAs obtained exclusively through diet and they comprise 1530% of the brains dry weight. Their effect on neuronal membrane dynamics and therefore on receptor, transporter and neurotransmitter function is profound (see below). Moreover, the well-documented shift in the Western diet away from EFAs (and the omega-3 family in particular) parallels the large rise in all psychiatric disorders seen over the past century. Finally, along with the resurgence of interest in lipidneuronal membrane interactions, there are now a considerable number of quality randomised controlled trials demonstrating the efficacy of EFAs in a diverse number of psychiatric conditions. (Additional references to those in the reference list are available from the corresponding author on request.)
FUNCTIONAL BIOCHEMISTRY OF THE ESSENTIAL FATTY ACIDS
The EFAs are divided into two groups, omega-3 (-3) and omega-6
(
-6) fatty acids, depending on where the first double bond in the
carbon chain occurs. The principal sources of EFAs are oily fish and certain
vegetable oils. These are then processed into other long-chain polyunsaturated
fatty acids (LC-PUFAs) by elongation and desaturation. The principal central
nervous system-related EFAs are eicosapentaenoic (EPA) and docosahexaenoic
(DHA) acids (both
-3) and arachidonic acid (
-6). They are
important components of phospholipids and cholesterol esters, which are
themselves integral to the neuronal cell membrane, especially synaptic and
dendritic membranes, but also intracellular membranes such as mitochondria and
vesicles. If unavailable, they will be replaced by non-EFAs, changing the
behaviour of the phospholipid molecules and affecting the tertiary and
quaternary structures of membrane-bound receptors and associated
neurotransmitters. The membrane phospholipid bilayer forms the matrix within
which membrane proteins, such as receptors and ion channels, are embedded and
to which membrane-associated proteins involved in second messenger systems are
attached.
Additionally, cell signalling systems are regulated by lipid products, such
as diacylglycerols, prostaglandins, leukotrienes, free fatty acids and
hydroxy-fatty acids derived from phospholipid membranes. Moreover, EFAs are
the precursors of the eicosanoids, a complex group of highly biologically
active compounds encompassing the prostanoids (including prostaglandins,
thromboxanes and prostacyclins) and leukotrienes. Eicosanoids derived from
-3 EFAs have fewer inflammatory effects than those derived from
-6 EFAs, underpinning the opposing effects that the
-6 EFA
families sometimes have (see below). Eicosanoids perform numerous regulatory
functions in the brain and throughout the rest of the body, in particular for
the regulation of immune and inflammatory responses.
There are now numerous animal studies relating to a wide variety of adverse effects associated with diets low in EFAs. As a converse example, De la Pressa Owens & Innis (1999) demonstrated that in pigs supplemented with EFAs from birth there was a doubling of the major monoamines in the frontal cortex.
MODERN DIET IS ASSOCIATED WITH DRAMATIC REDUCTIONS IN EFA INTAKE
The modern Western diet has evolved into a meat and saturated fat-rich
diet, with falling consumption of fresh vegetables and fish. This has been
coupled with a staggering rise in the consumption of seed oils (such as
sunflower and soybean), whose polyunsaturated fatty acid content is
predominantly -6, at the expense of
-3, EFAs. The
-6:
-3 ratio is estimated to have been 0.42.8:1 in
Palaeolithic and evolutionary diets (Eaton
et al, 1998). These models did not even consider seafood
consumption, which would bring the ratios even lower. The
-6:
-3
ratio is now estimated to have risen to 17:1 in our typical Western diet
(Eaton et al, 1998).
Moreover, wild and free-ranging animals have significantly more
-3
fatty acids in their tissues than do currently produced commercial livestock.
An overproduction of pro-thrombotic eicosanoids such as thromboxane, as well
as pro-inflammatory leukotrienes and cytokines from a diet over-rich in
-6 EFAs, has resulted and may be contributing to the rise in the
incidence of such diseases as atheroma, thrombosis and a variety of
inflammatory conditions (Pischon et
al, 2003). Such a sustained change in diet, as will now be
discussed, may also be affecting mental health.
DIETARY REDUCTIONS IN EFA PARALLEL THE RISE IN PSYCHIATRIC DISORDER
Bearing in mind that fish are the principal source of -3 EFAs,
Hibbeln (1998) reports that the
documented 60-fold variation across countries in the annual prevalence of
major depression is strongly inversely correlated with national fish
consumption. A similar inverse relationship exists for the prevalence of
post-partum depression and fish consumption. In a survey of 3204 adults in
Finland, infrequent fish consumption was associated with depressive symptoms
in women (P<0.01) and a similar trend, although not statistically
significant, was noted in men (Tanskanen
et al, 2001).
For bipolar affective disorder, Hibbelns group have demonstrated that prevalence rates rise precipitously below an apparent annual fish intake threshold of approximately 75 lb per person, with prevalence rates of, for example, 0.04% in Taiwan (81.6 lb per person) and 6.5% in Germany (27.6 lb per person), which is a nearly 60-fold difference. The same group did not find a relationship between fish consumption and prevalence rates for schizophrenia.
For suicide, daily fish eating had a positive effect (odds ratio=0.81) in
reducing the risk of death from suicide compared with subjects having a
non-daily consumption in 17-year follow-up of 256 118 Japanese subjects
(Hirayama, 1990). With regard
to dementia, in a study of elderly men, estimates of high -6 fatty acid
intake were associated with cognitive impairment and, conversely, fish
consumption was inversely associated with cognitive impairment, the
significance in both cases persisting after controlling for confounders
(Kalmijn et al,
1997).
LOWER EFA LEVELS IN PSYCHIATRIC ILLNESS
In one of several consistent studies on depression, Peet et al
(1998) demonstrated that total
-3 fatty acid levels were decreased (5.39 mg/100 mg phospholipid
compared with 9.04 mg/100 mg phospholipid for controls; P=0.02), DHA
especially (1.61 mg/100 mg phospholipid compared with 2.50 mg/100 mg
phospholipid; P=0.04), on red blood cell membranes in patients with
major depressive disorder (n=15) compared with normal controls. The
same group reported similar data in schizophrenia
(Peet et al, 1995).
We have demonstrated lowered plasma levels of cholesterol
(Garland et al, 2000)
and EFA (details available from the author upon request) in populations of
patients with self-harm. There are now also considerable data supporting
plasma EFA deficiency in attention-deficit hyperactivity disorder (e.g.
Richardson & Puri, 2000)
and dementia (Tully et al,
2003).
SUPPLEMENTATION IN CLINICAL POPULATIONS: THE EVIDENCE
All but one of the four EFA supplementation randomised controlled trials
(RCTs) in depression report significant improvement with supplementation. The
largest of these studies (Peet &
Horrobin, 2001) involved 70 patients, who remained on adequate
standard therapy throughout the trial; at optimum dosage, there was a
three-fold treatment-to-placebo effect, using a 50% reduction in Hamilton
Rating Scale for Depression (HRSD) scores as evidence of clinical response.
For bipolar affective disorder, in a 4-month RCT
(Stoll et al, 1999)
of high-dose -3 fatty acids, patients (n=30) had longer
periods of remission in the
-3-treated group (P<0.02) and
significant improvements in depressive, but not manic, symptomatology were
observed, suggesting that depressive symptoms may be more responsive than
manic symptoms to supplementation. For schizophrenia, the evidence is less
equivocal. As reviewed recently (Joy et
al, 2003), only one of five small studies demonstrated
substantial clinical improvement, and larger studies are clearly needed. There
are only limited and inconsistent data on supplementation in attention-deficit
hyperactivity disorder and dementia, although there are striking data on
Huntingtons chorea (n=17 patients) where treatment was
associated not just with stabilisation but with reversal of clinical signs
(Vaddadi et al,
2002).
There are various, generally positive data in
psychopathic/aggressive/impulsive populations. In a carefully conducted RCT in
young adult prisoners, a combination of -6 and
-3 EFAs reduced
offences by 26.3%, increasing to 35.1% if on supplementation for a minimum of
2 weeks (P<0.01; Gesch et
al, 2002). The greatest reduction occurred for the most
serious incidents including violence. As reviewed elsewhere
(Hallahan & Garland, 2004),
EFAs have proved beneficial also in stabilising aggression in a normal
population of young university students at exam time (n=41) compared
with randomised controls and in a population (n=30) of patients with
borderline personality disorder treated for 8 weeks. Finally, we are shortly
to conclude recruitment into an RCT of EFAs in a population of patients with
self-harm.
CONCLUSIONS
There is no doubt that cerebral lipids, and EFA-derived LC-PUFAs in particular, have significant direct and indirect actions on cerebral function. Not only does the lipid composition of neural membranes affect the function of their embedded proteins, but also many LC-PUFAs are converted to neurally active substances. There is good evidence that psychiatric illness is associated with depletion of EFAs and, crucially, that supplementation can result in clinical amelioration. As well as challenging traditional views of aetiology and therapeutics in psychiatry, the clinical trial data may herald a simple, safe and effective adjunct to our standard treatments for many disabling conditions.
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Received for publication March 29, 2004. Revision received September 14, 2004. Accepted for publication September 30, 2004.
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