Omega-3 polyunsaturated fatty acids and anxiety disorders

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Omega-3 polyunsaturated fatty acids and anxiety disorders
Brian M. Ross

Division of Medical Sciences, Northern Ontario School of Medicine and Departments of Biology, Chemistry and Public Health, Lakehead University, Thunder Bay, 955 Oliver Road,
Ontario, Canada P7B5E1
abstract
Anxiety disorders are a common group of psychiatric illnesses which have significant personal, family
and societal costs. Current treatments have limited efficacy in many patients highlighting a need for
new therapeutic approaches to be explored. Anxiety disorders exhibit marked comorbity with mood
disorders suggesting the existence of mechanistic similarities. Such a notion is supported by
observations that some conventional pharmacotherapies are both effective antidepressants and
anxiolytics. As such, given that omega-3 PUFA supplementation may be effective in the treatment of
major depressive disorder it is reasonable to propose that they may also possess anxiolytic properties.
Experimental data in support of such a hypothesis is currently lacking although reduced abundance of
omega-3 PUFA have been reported in patients with anxiety, while supplementation with omega-3 PUFA
appears to inhibit activation of the HPA axis and can ameliorate some of the symptoms of anxiety.
Clinical investigations carried out to date have, however, involved small numbers of participants. Larger
trials using a variety of omega-3 PUFA species in clinically well-defined patients with anxiety will be
required to demonstrate a therapeutic role for omega-3 PUFA in these disorders. Given the excellent side
effect profile of omega-3 PUFA as well as their strong theoretical rationale, such future trials appear
justified.
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1. Introduction
Anxiety disorders are a common class of mental illness
characterized by an inappropriate or exaggerated fear response
leading to distress and impairment. The current edition of the
Diagnostic and Statistical Manual for Mental Disorders (DSM-IV)
includes amongst the anxiety disorders generalized anxiety
disorder, social phobia, other phobias such as agarophobia, panic
disorder and obsessive compulsive disorder [1]. Anxiety disorders
are associated with significant and often severe functional
impairment in social and vocational spheres, and have high
health care and general economic costs, and caregiver burden
[2–7]. Within any one-year period 18% of adults in the United
States will suffer from an anxiety disorder with lifetime
prevalence being approximately double that value [8]. This
compares with 9% of adults having a mood disorder within a
one year period [8]. The most common anxiety disorder are the
phobias (one year incidence approximately 9%), followed by social
phobia (7%), post-traumatic stress disorder (4%), generalized
anxiety disorder (3%), panic disorder (3%), and obsessive compul-
sive disorder (1%), with frequent comorbidity being observed
between anxiety disorders and other type of mental illness[8].
Patients frequently go undiagnosed for many years which may
result in a worsened prognosis [8]. Although pharmacotherapy
and cognitive behavioural therapy can be efficacious, many
patients do not achieve remission or are essentially treatment
refractive [9]. As such, there is much need for new and better
treatments to be developed for the anxiety disorders as well as the
design of strategies aimed at their prevention.
Although anxiety and mood disorders are considered separate
in DSM-IV considerable comorbidity exists between each. For
example, in a primary care setting, if a person is diagnosed with
major depressive disorder they are, within the next 12 months,
approximately 8 times more like to also be diagnosed with
generalized anxiety disorder, 6 times more likely to also have
PTSD, 5 times more likely to have panic disorder and 3 times more
likely to have social phobia [10]. Indeed, study of the overall rates
of comorbidity for mood and anxiety disorders suggest that half or
more of patients with depression also exhibit clinically significant
anxiety [10–12]. Conversely, 20% of patients with an anxiety
disorder will be diagnosed with major depressive disorder within
the next 12 months and are 12 times more likely to suffer from
depression compared to those who do not have an anxiety
disorder [10]. Such a high rate of comorbidity is suggestive of
aetiological and mechanistic similarities between depressed
mood and elevated anxiety. It is notable therefore that in both
animal models and human subjects depressed mood and anxiety
show some overlap in the pattern of changes in brain activity
which both exhibit. Specifically, while depression leads to
decreased activity in brain regions responsible for purposeful
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and sustained positive behaviours, such as the dorsal prefrontal
and cingulate cortices, putamen and motor regions, both anxiety
and depression elevate neuronal activity in the brain stress
centres such as the amygdala, hypothalamus and the subgenal
cingulated gyrus [13,14]. It has been recently proposed that the
activation of the stress centres in both conditions provides the
biological mechanism by which depression may lead to anxiety
and vice versa [14]. Such a model of depression and anxiety is
attractive in that it explains why psychosocial stressors should
have such a large effect on the risk of developing depression [15].
Moreover, if anxiety and mood are mechanistically related then it
may be more useful to think of them as lying on a spectrum
between pure depression and pure anxiety with most patients
lying somewhere between the two extremes.
Such a model would also predict that therapeutic approaches
to depression and anxiety should show a degree of overlap.
Clinical data is supportive of such a possibility given that while
some anxiolytics such as the benzodiazepines have no antide-
pressant activity, many antidepressants such as selective seroto-
nin reuptake inhibitors and tricyclic antidepressants are effective
in ameliorating at least some of the symptoms of anxiety [16].
Furthermore, they reverse the brain activity changes observed in
the positive motivational and stress regions of the brain in mood
disorders [17] As such it is reasonable to hypothesise that other
antidepressants may also have anxiolytic activity. In this regard,
recent clinical investigations have provided strong evidence that
long chain omega-3 polyunsaturated fatty acids (PUFA), in
particular eicosapentaenoic acid (EPA), possess significant anti-
depressant activity [18–23]. Indeed recent meta-analyses have
reported a moderate effect size for omega-3 PUFA in depression
comparable to that of conventional antidepressants [24–26].
Complementing such supplementation data are reports of
reduced omega-3 PUFA abundance in the blood of patients with
depression [27–34] and epidemiological observations which
report a correlation between omega-3 PUFA intake and the
development of the disorder [35–37]. Further, hostility and anger
have also been associated with insufficient fatty acid intake, while
anger was reduced in substance misusers following supplementa-
tion [38,39]. While such findings may well be mechanistically
divisible from the reduction in anxiety symptoms observed in the
same patients, hostility and anxiety, and often depression, have
been found to be correlated in many different contexts [40–42].
Such observations are suggestive of the existence of a spectrum of
symptoms possessing similar aetiology in at least a subset of
patients with mood and/or anxiety disorders. It would therefore
be of interest to know whether a deficit in omega-3 PUFA intake
and levels also occurs in anxiety disorders. In patients with social
phobia, the abundance of EPA and docosahexaenoic acid (DHA) in
erythrocyte membranes is decreased in those with the illness and
the extent of the reduction is correlated with the severity of the
illness [43]. Although no inference can be drawn regarding
causation such data does suggest that, in a similar way to those
with depression, social phobia is associated with either decreased
intake of omega-3 PUFA or decreased uptake of omega-3 PUFA
into cell membranes [34]. Whether similar reductions occur in
other anxiety disorders is unclear as is how any changes in omega-
3 PUFA levels might be correlated with other potentially
important factors such as socioeconomic class [44].
Fatty acid signaling abnormalities have also been reported in
social phobia. Methylnicotinate, applied topically, can induce
vasodilatation by means of stimulating the release of arachidonic
acid (an omega-3 PUFA) from membrane phospholipids [45]. The
free arachidonic acid is then metabolized to form prostaglandin D
2
which acts upon capillary endothelial cells to causes vasodilatation
[45]. Patients with social phobia were found to display a reduced
maximal vasodilatatory response to methylnicotinate the extent of
which was correlated with the severity of the patients’ symptoms
[46]. Although such observations are suggestive of lipid abnorm-
alities in the disorder, the explanation and significance of this
finding is unclear given that omega-3 PUFA supplementation is
generally thought to be antagonistic to arachidonic acid-depen-
dent effects. Moreover, patients with major depressive disorder do
not exhibit reduced maximal vasodilatatory response to methylni-
cotinate but rather a delayed response, differing from the anxiety
disorder [47].
There therefore exists significant theoretical and circumstan-
tial evidence supporting the use of omega-3 PUFA as anxiolytics.
Some preclinical data is supportive of such a hypothesis. Song and
colleagues found that an EPA-rich diet could reduce the develop-
ment of anxiety like behaviours in rats as well as normalizing
dopamine levels in the ventral striatum [48,49]. In terms of
human trials, however, most trials involving patients with mood
disorders have not investigated anxiety symptoms or have
specifically excluded patients with anxiety disorders at intake,
despite the high comorbidity between depressed mood and
anxiety. Indeed, it may be useful to monitor anxiety symptoms
in future trials using established rating scales such as the
Hamilton Anxiety Disorder Scale [50]. Nevertheless, a few clinical
investigations testing the efficacy of fatty acids in anxiety
disorders have been conducted. In a provocative study 126
university students who had experienced significant anxiety
associated with examinations were administered a mixture of
omega-3 and omega-6 PUFA containing 90 mg alpha-linolenic
acid (an omega-3 PUFA) and 360 mg of linoleic acid (an omega-3
PUFA) or a mineral oil placebo for 3 weeks [51]. The investigators
reported improvements relative to placebo on measures of
appetite, mood, concentration, fatigue and organization while
levels of salivary cortisol were reduced [51]. This apparent
axiolytic effect is of great interest although it should be noted
that the study subjects had not been diagnosed with a recognized
anxiety disorder nor was a routinely used anxiety rating scale
administered making extension of these results to other contexts
difficult [51]. Furthermore the amount, type, and duration of PUFA
administration differed from that used in mood disorders trials
which typically were longer, administered 1 g or more of PUFA
and utilized 20 carbon EPA or 22 carbon DHA rather than 18
carbon alpha-linolenic acid. Although alpha-linolenic acid can be
metabolized to produce EPA and DHA the rate of conversion is
slow [52], and it is very likely that the mixture used by these
authors produced different changes to membrane composition
compared to supplementation with either EPA, DHA, or a mixture
of the two. As such this anxiety treatment trial and the mood
disorders trials are rather dissimilar in methodology and are
potentially explained by different mechanisms. More directly
comparable, however, is the reduced plasma adrenaline and
noradrenaline levels which occur following supplementation with
approximately 400 mg EPA and 300 mg DHA per day for 2 months
compared to placebo treated subjects [53]. Such results suggest
that omega-3 PUFA supplementation decreases activation of the
hypothalamic-pituitary-adrenal axis, a physiological finding com-
patible with an anxiolytic effect.
The effect of 2 g/day EPA upon the symptoms of post-traumatic
stress disorder (PTSD) was the subject of an open label trial
conducted by Zeev and collaborators [54]. In 5 out of the initial 6
subjects included, depression, hostility and anger were found to
worsen post-treatment leading to the investigators to terminate the
trial. While such finding cannot be considered more than suggestive
of a deleterious effect of omega-3 PUFA in the disorder such results
are certainly not supportive of supplementation being a potential
therapy for PTSD. A further two placebo controlled double-blinded
trials have been published. Studying 11 patients with obsessive
compulsive disorder Fux and colleagues administered either 2 g/day
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EPA or placebo to subjects for 6 weeks followed by a cross-over
phase lasting a further six weeks [55]. These authors reported that,
relative to placebo, no relative differences were observed post-
treatment using depression, anxiety, or obsessive compulsive
behaviour rating scales. The small size and, compared to most
mood disorders trials, relatively short treatment duration, rather
weakens strength of the conclusions which can be drawn from this
trial. Another small trial has also been conducted, this time utilizing
24 males who were undergoing treatment for substance misuse.
Patients administered 2.2 g/day EPA and 0.5 g/day DHA reported
reduced levels of anxiety as well as anger (in contrast to the
apparent worsening of anger in PTSD [54])comparedtoplacebo
treated patients [39,56]. The use of a patient-reported outcome
measure as well as the small number of study subjects make the
findings of the trial preliminary in the nature, although the data are
certainly of great interest and sufficient to justify further experi-
mentation. It was also notable that the reduction in the symptoms
of anxiety was correlated with the degree of increase in plasma EPA
levels [57]. The possibility that raising EPA levels is responsible for
any clinical effect is similar to the hypothesis that EPA rather than
DHA is efficacious in the treatment of depression [23–25]. While
increased efficacy of EPA in ameliorating anxiety symptoms cannot
be ruled out, it is worth recalling that the test-anxiety trial
described above included no EPA in the supplement mix [51].
2. Conclusions
In summary, the comorbidity and pharmacological overlap
between mood and anxiety disorders provides a basis for
considering that the two classes of disorders may be partly
mechanistically related. The strong evidence now supporting the
efficacy of omega-3 PUFA supplementation for mood disorders
therefore makes a similar role in anxiety disorders plausible. The
data supporting such a hypothesis is limited although includes
biochemical, physiological and clinical findings. Further clinical
trials are required to conclusively determine whether omega-3
PUFA are useful in the treatment of these common disorders.
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