ARTICLE
Auteur(s) : Pierre Astorg
Unité Nutrition et Régulation Lipidique des Fonctions Cérébrales
(Nu.Ré.Li.Ce), INRA, Centre de Jouy, bât. 230, Domaine de Vilvert,
78352 Jouy-en-Josas Cedex
Introduction
Mood disorders include all psychiatric disorders in which one of
the main symptom is an abnormal mood, either low or elevated. They
include unipolar depressive disorders, in which the patients
experience only depressive episodes, and bipolar disorders, where
episodes of depression and of elevated mood (mania or hypomania)
occur. Mood disorders can vary widely according to chronicity and
severity, from a single episode to chronic or highly recurrent
diseases, and from the milder forms (depressive symptoms) to the
well-characterised ones (major depression, bipolar I disorder).
There is no evident limit between the milder forms and normal mood
variations, in contrast the most severe forms are heavy,
life-threatening diseases.
Mood disorders and particularly depression are widespread in
developed countries: lifelong prevalence of major depressive
disorder is estimated between 10 and 20% in Europe and North
America, about twice higher in women than in men, whereas the
prevalence of bipolar I disorder is about 1% in both sexes.
Depression frequency is high in France, where a lifelong prevalence
of about 20% has been found (12-15% in men and 24-27% in women)
[1]. Due to their high prevalence, depressive disorders have major
socio-economic consequences. According to the WHO data, depression
was the fourth cause of disability in the world in 2000, and is
expected to become the second one in 2020 [2]. In addition,
depression increases mortality rate, and not only suicide mortality
[3], and increasing evidence suggests that it is an independent
risk factor for major chronic diseases, especially for dementias
[4]. Thus, in many countries and especially in France, depression
is a major public health problem, and the research of prevention
factors is a major public health issue.
In addition to known risk factors of depression such as familial
history and stressful life events, great international differences
in its prevalence suggest an important impact of sociocultural
and/or environmental factors. Recent research have shown the
possible influence of nutritional factors on depression, especially
of n-3 polyunsaturated fatty acids (n-3 PUFA).
Blood & tissue n-3 PUFA and depression : observations
in clinical settings
A decrease of n-3 PUFA, especially of long-chain n-3 PUFA, has
often been observed in plasma or erythrocyte lipids of unipolar
depressed patients relatively to nondepressed control subjects
[5-9]. This decrease could involve either EPA [5] or DHA [7] or
several n-3 PUFA, including α-linolenic acid [5-10], but were
specific of n-3 PUFA: n-6 PUFA, such as linoleic acid, arachidonic
acid or 22: 5 n-6, were not decreased. In contrast, manic bipolar
patients had strongly decreased levels of both arachidonic and DHA
in erythrocyte lipids. In a few studies, n-3 PUFA contents were
negatively correlated with the intensity of depressive symptoms [5,
6] (figure 1),
which suggests that the decrease of n-3 PUFA was directly linked to
the depressive state. However, the levels of n-3 PUFA were not
found to rise to control levels as the patients under
antidepressant treatment improved with time [9]. Recently, a
selective decrease of DHA has been observed post mortem in the
orbifrontal cortex of patients with major depressive disorder [11]
(figure 2).
Depression is generally accompanied by an inflammatory state, with
an increase of pro-inflammatory cytokines, generating an oxidative
stress [9, 12, 13], which causes an increase of markers of lipid
peroxidation and a decrease of vitamin E in blood, as well as the
induction of antioxidant enzymes [9, 12, 13], and thus could
explain the decrease of n-3 PUFA in depression. However, it does
not explain why the decrease of PUFA is selective of the n-3
family. Since the depressive state often causes a decreased
appetite and a lower food intake, it could result in a decreased
PUFA intake. Again, this hypothesis does not explain the fact that
the PUFA decrease in depression is apparently limited to the n-3
family. An alternative hypothesis is that a pre-existing lower n-3
PUFA status, due in particular to a lower n-3 PUFA intake, could
promote the onset of depression, as suggested by a study where both
the blood levels and the dietary intakes of n-3 PUFA were inversely
correlated to depressive symtoms [6]. Several studies in population
settings have explored this hypothesis.
Fish intake, n-3 PUFA and mood disorders: observational
epidemiological studies
Since fish is, worldwide, the main food source of long-chain n-3
PUFA, epidemiological studies have examined the relation between
fish consumption and mood disorder rate. A cross-national
correlation study has shown an inverse relation between apparent
fish consumption calculated from economical FAO statistics and the
prevalence of major depressive disorder, the Asian countries with a
high fish consumption (Japan, Taiwan, Korea) having a low
depression prevalence [14] (figure 3). The same
cross-national relation has been found for post-partum depression,
the frequency of which is lower in countries with higher intake of
fish or with higher DHA content of maternal milk [15]. Again, Asian
countries (Malaysia, Singapore, Hong Kong, and Japan), but also
Chile, were countries with higher fish consumption and lower
post-partum depression rates. The prevalence of bipolar spectrum
disorders has been found decrease still more steeply with fish and
seafood consumption [16] (figure 4). The inverse
relation appears stronger for bipolar II than for bipolar I
disorder. Interestingly, such a negative correlation is not
observed between the rate of schizophrenia and fish consumption in
the same countries, which suggests that the relation is specific of
mood disorders [16]. This type of ecological study is not
conclusive, since the differences can be due to many confounding
factors, especially to genetic, economical or socio-cultural
differences between countries. However, the fact that Iceland
ranks, with Asian countries, among the countries with low rates of
mood disorders is an argument in favor of the “fish hypothesis”.
The association of infrequent fish consumption with a greater risk
of depression or depressive symptoms has been found in several
cross-sectional studies in populations from Finland [17-19], France
[20], or New Zealand [21]. In several of these studies, even a
moderate fish consumption (once a week vs. less than once a week)
was associated to a decreased risk of current depression/depressive
symptoms [18-21]. In one study, both current depressive symptoms
and lifetime diagnoses of depression have been assessed [19].
Interestingly, fish consumption was associated with a decreased
risk of current depression in women (OR = 0.71 [0.55-0.91]), but
more strongly with a decreased risk of both current and past
depression (OR = 0.42 [0.24-0.71]) [19]. In population samples,
subjects with depression or depressive symptoms have been found to
have lower plasma or adipose tissue levels of n-3 PUFA, especially
of DHA, than non-depressed subjects [22, 23]. The study using
adipose tissue fatty acids as biomarkers [22] is suggestive of a
causal effect of a low n-3 PUFA status on depression: since adipose
tissue PUFAs have a very slow turnover (several years), a lower DHA
level in adipose tissue is likely due to a lower habitual intake,
and is not likely to have been caused by the current depressive
state. A case-control study in China has looked for the association
of suicide attempt with the levels of EPA and DHA in plasma
phospholipids, in patients admitted to emergency services of
hospitals either for suicide attempt or for traffic accidents [24].
Subjects in the highest quartile of EPA or DHA had a very strongly
reduced risk of suicide attempt than subjects in the first quartile
(OR = 0.12 [0.04-0.36] for EPA, 0.21 [0.07-0.60] for DHA) [24],
suggesting that a low intake of these n-3 PUFA can be a very
significant risk factor for suicide attempt. Very few studies
having searched the association between fish or n-3 PUFA intake or
status with depression had a prospective design, i.e. in which the
tested causal factor (fish or n-3 PUFA intake or status) was
assessed before the endpoint (depression). Women with post-partum
depression had decreased DHA levels in the lipids of blood taken at
delivery (before the onset of depression) [25], which clearly
suggests that a low DHA status at birth is a risk factor for
postpartum depression. In the French SU.VI.MAX cohort of adult men
and women, we have looked for an association of habitual fish
consumption, measured by repeated 24-hour dietary records at the
beginning of the 8-year follow-up, with the onset of depression
during the follow-up, using antidepressant prescription as a marker
of depressive episodes (Astorg et al., unpublished). Subjects
consuming fatty fish or more than 0.1% of their energy as
long-chain n-3 PUFA have a decreased risk of any depression (OR =
0.70 [0.53-0.82]) and of recurrent depression (OR = 0.64
[0.43-0.95]) during the follow-up. The decrease of risk is more
pronounced in men than in women, and is especially marked for very
recurrent episodes (three or more). In a small prospective study in
USA, blood has been taken up from 31 depressed inpatients, and
their suicide attempts have been recorded during two years after
discharge [26]. A lower plasma DHA level at baseline was predictive
of subsequent suicide attempt: OR = 3.45, p = 0.002 (below vs.
above the median DHA value) (figure 5). A large
national cohort study in Japan had found a protective association
of frequent fish consumption with suicide during the 17-year
follow-up [27]. However, not all studies led to similar
conclusions. In particular, in a large cohort study in Finnish male
smokers, the ATBC study, no association was found between fish or
n-3 PUFA consumption measured at baseline and the risk of
depression during the 5 to 8-year follow-up [28]. In that cohort,
however, a higher intake of omega-3 fatty acids from fish had been
previously associated with a higher risk of cardiac mortality, a
result opposite to most other studies [29], which suggests an
abnormal response of this population to n-3 PUFA intake, perhaps
due to interaction with smoking. In summary, many, but not all,
observational studies in populations have shown an association
between a low fish intake or a low intake or status of long-chain
n-3 PUFA and an increased depression risk. The association appeared
stronger with recurrent depression and with suicide attempt and
suicide. This association has been found in a few studies having a
prospective design, which suggests the existence of a causal link
between a low intake or status of n-3 PUFA and an increased risk of
subsequent depression [25-27] (Astorg, unpublished).
n-3 PUFA and mood disorders: clinical trials
As soon as 1981, uncontrolled clinical trials on isolated cases of
unipolar depression or bipolar disorder have reported
antidepressant effects of large doses of linseed oil (containing
about 50% of α-linolenic acid) [30]. In the last ten years,
randomised, placebo-controlled trials, most of them of small size,
have tested the effects of long-chain n-3 PUFA supplementation in
patients with mood disorders, either unipolar or bipolar, with
ongoing treatment in most cases, but sometimes untreated. Ethyl-EPA
or EPA-rich fish oil led to short-term improvement of unipolar
depressive patients, resistant to ongoing treatment [31-33].
Curiously, one of these trials having tested several doses of
ethyl-EPA found an effect for the lower dose (1 g/day), but not for
higher doses (2 and 4 g/day) [32]. A recent trial on depressed
children without antidepressant treatment has shown a remarkable
improvement of depressive symptoms in children receiving a moderate
dose of n-3 PUFA: 0.4 g EPA + 0.2 g DHA/day [34]. Children
receiving EPA/DHA had a 50% decrease of their depressive symptoms
score after 12 weeks, whereas those in the placebo group did not
improve, which clearly shows the antidepressant potency of
long-chain n-3 PUFA (figure 6). At variance,
DHA or DHA-enriched fish oil at doses of 2-2.4 g/day had no effect
on treated or untreated depressive patients [35, 36], and a low
dose of DHA (0.2 g/day) did not prevent post-partum depression in
parturient women [37]. N-3 long-chain PUFA also showed some
efficiency to improve depression or to prevent depressive relapses
in bipolar patients: either ethyl-EPA at moderate doses (1 or 2
g/day) [38] or a high dose of fish oil (6.2 g EPA + 3.4 g DHA/day)
[39]. In the latter study, fish oil was active to prevent
depressive relapses in both untreated and treated bipolar patients
(figure 7).
Ethyl-EPA (1 g/day) also improved both depressive and aggressive
symptoms in untreated women with borderline personality disorder
[40]. However ethyl-EPA at a high dose (6 g/day) was not active in
depressed bipolar patients [41], and fish oil (4.4 g EPA + 2.4 g
DHA/day) had no effect on bipolar patients in acute manic phase
[42]. The results of these studies are heterogenous, mainly because
of the diversity of the patients’ diagnoses and of the supplements
used (nature and doses). However, some provisional remarks can be
made: 1) long-chain n-3 PUFA can be active against depression, in
both unipolar and bipolar patients, but not against mania in
bipolar patients in manic phase; 2) the supplements found to be
active were EPA or EPA-containing mixtures (EPA/DHA 2/1); DHA alone
or as a main component of a mixture has shown no effect until now;
3) pure EPA (ethyl-EPA) has shown effects at moderate doses (1-2
g/day), but not at higher doses (4-6 g/day), however the mixture
EPA/DHA 2/1 showed antidepressant effects both at moderate doses
(0.6 g/day in children) and at high doses (6-10 g/day in adults).
Other placebo-controlled trials are necessary to confirm and extent
these results, in the aim of knowing the cases where omega-3
long-chain PUFA could be useful in the treatment or in the
prevention of mood disorders. Because of their harmlessness and
quasi-absence of side-effects, omega-3 PUFA appear to be of first
interest in cases where a standard antidepressant treatment is not
indicated or not desired by the patient: minor depression,
depression in pregnancy or post-partum, depression in children. As
depression is a very recurrent disorder, and since fish or omega-3
PUFA consumption have been found to be associated with a lower risk
of recurrent depression in observational studies [19] (Astorg,
unpublished), it would be would be worth to test the effect of
long-chain omega-3 PUFA, especially of EPA, as a maintenance
treatment in at-risk subjects, i.e. those having experienced a
first depressive episode. Such a prophylaxy, if proven to be
efficient, could be followed lifetime without any side-effects.
Conclusions
On the whole, the involvement of n-3 PUFA, and especially of
long-chain n-3 PUFA, in depression and mood disorders is now
abundantly documented, in both clinical and population settings,
and there is evidence in favor of both a preventive and a
therapeutic potency of n-3 PUFA against mood disorders, especially
depression. However, many research works are still necessary before
one can rely on firm conclusions, as many points remain obscure or
controversial. In particular, most of the population studies have
ecological, case-control or cross-sectional designs, which are not
free from confounding biases and do not prove the existence of a
causal link between a higher intake of fish or of n-3 PUFA and a
lower depression rate. There is on this point a lack of
population-based observational prospective studies of sufficient
power, using either food questionnaires or biomarkers, and in which
depression or mood events or symptoms are recorded along the
follow-up, since recurrence appears to be an important feature in
the relation of n-3 PUFA and depression. Concerning the therapeutic
properties of n-3 PUFA, most of the trials published until now are
of small size, and with somewhat heterogeneous, although
encouraging, results. Clinical trials of sufficient size are
awaited, to determine which n-3 PUFA are efficient (EPA, DHA,
mixtures?), at which doses, on which type of patients, as a
monotherapy or as adjunct treatment, in the treatment of the acute
phase or as maintenance treatment. On the basis of to-day’s
knowledge, it seems that n-3 PUFA could be of interest in the
management of mood disorders: 1) in their prophylaxy, either in the
general population or in at-risk subjects; 2) in the treatment of
patients where a standard antidepressant treatment is not indicated
or not desired: mild depression, depression in pregnancy or in
children; 3) as adjunct treatment. Last, although some mechanistic
studies have been performed in animals [43-45], further research is
awaited to explore the mechanisms by which n-3 PUFA can act on mood
disorders or prevent them.
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