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Omega-3 polyunsaturated fatty acids and anxiety disorders

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
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
&2009 Elsevier Ltd. All rights reserved.
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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Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 309–312
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
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
B.M. Ross / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 309–312310
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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B.M. Ross / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 309–312312
... In humans, PUFAs have positive effects on the pathophysiology of a wide range of stress-related disorders [32,34353637. Patients suffering major depression, a stress-related disorder, have shown reductions in the plasma levels of ω-3 PUFAs, without any change in fatty acid ω-6 levels38394041. These findings suggest that long-term ω-3 supplementation of the diet of post-weaning animals has two effects on chronically stressed rats: preventing the stress-induced learning impairment in a 2-AA test and decreasing plasma corticosterone levels and anxiety. ...
... Preclinical and clinical studies support the use of ω-3 supplementation in stress-related disorders such as depressive and anxiety disorders. For example, diets rich in ω-3 improve the effects of antidepressants in animal models of depressive-like behaviors [80,81], as well as in patients with major depression [82,83] and anxiety disor- ders [40]. In this context, we propose that due to its anxiolytic and anti-stress effects, ω-3 supplementation can improve the symptoms of patients with depressive and anxiety disorders. ...
Full-text available
Chronic stress leads to secretion of the adrenal steroid hormone corticosterone, inducing hippocampal atrophy and dendritic hypertrophy in the rat amygdala. Both alterations have been correlated with memory impairment and increased anxiety. Supplementation with omega-3 fatty acids improves memory and learning in rats. The aim of this study was to evaluate the effects of omega-3 supplementation on learning and major biological and behavioral stress markers. Male Sprague--Dawley rats were randomly assigned to three experimental groups: 1) Control, 2) Vehicle, animals supplemented with water, and 3) omega-3, rats supplemented with omega-3 (100 mg of DHA+25 mg of EPA). Each experimental group was divided into two subgroups: one of which was not subjected to stress while the other was subjected to a restraint stress paradigm. Afterwards, learning was analyzed by avoidance conditioning. As well, plasma corticosterone levels and anxiety were evaluated as stress markers, respectively by ELISA and the plus-maze test. Restraint stress impaired learning and increased both corticosterone levels and the number of entries into the open-arm (elevated plus-maze). These alterations were prevented by omega-3 supplementation. Thus, our results demonstrate that omega-3 supplementation had two beneficial effects on the stressed rats, a strong anti-stress effect and improved learning.
Chronic stress causes the release of glucocorticoids, which greatly influence cerebral function, especially glutamatergic transmission. These stress-induced changes in neurotransmission could be counteracted by increasing the dietary intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs). Numerous studies have described the capacity of n-3 PUFAs to help protect glutamatergic neurotransmission from damage induced by stress and glucocorticoids, possibly preventing the development of stress-related disorders such as depression or anxiety. The hippocampus contains glucocorticoid receptors and is involved in learning and memory. This makes it particularly sensitive to stress, which alters certain aspects of hippocampal function. In this review, the various ways in which n-3 PUFAs may prevent the harmful effects of chronic stress, particularly the alteration of glutamatergic synapses in the hippocampus, are summarized.
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Long-chain n-3 (ω3) polyunsaturated fatty acids exert beneficial effects in neuroendocrine dysfunctions in animal models and clinical trials. However, the mechanism(s) underlying the beneficial effects remains to be elucidated. We hypothesized that dietary treatment with fish oil (FO) could mitigate LPS-induced activation of hypothalamic-pituitary-adrenal (HPA) axis through inhibition of Toll-like receptor 4 and nucleotide-binding oligomerization domain protein signaling pathways. Twenty-four weaned pigs were used in a 2 × 2 factorial design, and the main factors consisted of diet (5% corn oil vs. 5% FO) and immunological challenge (saline vs. LPS). After 21 d of dietary treatment with 5% corn oil or FO diets, pigs were treated with saline or LPS. Blood samples were collected at 0 (preinjection), 2, and 4 h postinjection, and then pigs were humanely killed by intravenous injection of 40 mg/kg body weight sodium pentobarbital for tissue sample collection. FO led to enrichment of eicosapentaenoic acid and docosahexaenoic acid and total n-3 polyunsaturated fatty acids in hypothalamus, pituitary gland, adrenal gland, spleen, and thymus. FO decreased plasma adrenocorticotrophin and cortisol concentrations as well as mRNA expressions of hypothalamic corticotropin releasing hormone and pituitary proopiomelanocortin. FO also reduced mRNA expression of tumor necrosis factor-α in hypothalamus, adrenal gland, spleen, and thymus, and of cyclooxygenase 2 in hypothalamus. Moreover, FO downregulated the mRNA expressions of Toll-like receptor 4 and its downstream molecules, including cluster differentiation factor 14, myeloid differentiation factor 2, myeloid differentiation factor 88, interleukin-1 receptor-associated kinase 1, tumor necrosis factor-α receptor-associated factor 6, and nuclear factor kappa-light-chain-enhancer of activated B cells p65, and also decreased the mRNA expressions of nucleotide-binding oligomerization domain 1, nucleotide-binding oligomerization domain 2, and their adaptor molecule receptor-interacting serine/threonine-protein kinase 2. These results suggested that FO attenuates the activation of the HPA axis induced by LPS challenge. The beneficial effects of FO on the HPA axis may be associated with decreasing the production of brain or peripheral proinflammatory cytokines through inhibition of Toll-like receptor 4 and nucleotide-binding oligomerization domain protein signaling pathways.
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Eight fatty acids (C12-C18) were previously identified in human amniotic fluid, colostrum, and milk in similar proportions but different amounts. Amniotic fluid is well known to be the natural environment for development in mammals. Interestingly, amniotic fluid and an artificial mixture of fatty acids contained in amniotic fluid produce similar anxiolytic-like actions in Wistar rats. We explored whether the lowest amount of fatty acids contained in amniotic fluid with respect to colostrum and milk produces such anxiolytic-like effects. Although a trend toward a dose-response effect was observed, only an amount of fatty acids that was similar to amniotic fluid fully mimicked the effect of diazepam (2 mg/kg, i.p.) in the defensive burying test, an action devoid of effects on locomotor activity and motor coordination. Our results confirm that the amount of fatty acids contained in amniotic fluid is sufficient to produce anxiolytic-like effects, suggesting similar actions during intrauterine development.
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The purpose of this study was to investigate the effect of dietary linoleic acid (18:2(n - 6)) on the conversion of 18:2(n - 6) and 18:3(n - 3) to their respective n - 6 and n - 3 metabolites; to compare the incorporation of these fatty acids into human plasma lipids; to evaluate the importance of dietary 18:3(n - 3) as a precursor for the biosynthesis of long-chain length n - 3 fatty acids. The approach used was to feed young adult male subjects (n = 7) diets containing 2 levels of linoleic acid (SAT diet, 15 g/day; PUFA diet, 30 g/day) for 12 days. A mixture of triacylglycerols containing deuterated linolenic (18:3(n - 3)) and linoleic (18:2(n - 6)) acids was fed and blood samples were drawn over a 48 h period. Concentrations of deuterated 18:3(n - 3) in plasma total lipid ranged from 309.2 to 606.4 microgram/ml and concentrations of 18:2(n - 6) ranged from 949.2 to 1743.3 micrograms/ml. The sum of the deuterated n - 3 long-chain length fatty acid metabolites in plasma total lipid were 116 +/- 4.3 micrograms/ml (SAT diet) and 41.6 +/- 12.4 micrograms/ml (PUFA diet). The total deuterated n - 6 fatty acid metabolites were 34.6 +/- 12.2 micrograms/ml (SAT diet) and 9.8 +/- 5.9 micrograms/ml (PUFA diet). The total percent conversion of deuterated 18:3(n - 3) to n - 3 fatty acid metabolites and deuterated 18:2(n - 6) to n - 6 fatty acid metabolites were 11-18.5% and 1.0-2.2%, respectively. The percentages for deuterated 20:5(n - 3), 22:5(n - 3) and 22:6(n - 3) (6.0%, 3.5%, and 3.8%) were much higher than for 20:3(n - 6) and 20:4(n - 6) (0.9% and 0.5%). Overall, conversion of deuterated 18:3(n - 3) and 18:2(n - 6) was reduced by 40-54% when dietary intake of 18:2(n - 6) was increased from 15 to 30 g/day. Comparison of the deuterated 18:3(n - 3) and 18:2(n - 6) data for plasma triacylglycerol and phosphatidylcholine (PC) indicated that 18:2(n - 6) was preferentially incorporated into PC. Dietary 18:2(n - 6) intake did not alter acyltransferase selectivity but activity was reduced when 18:2(n - 6) intake was increased. Based on these results, conversion of the 18:3(n - 3) in the US diet (2 g) is estimated to provide 75-85% of the long-chain length n - 3 fatty acids needed to meet daily requirements for some (but not all) adults.
Errors in Byline, Author Affiliations, and Acknowledgment. In the Original Article titled “Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication,” published in the June issue of the ARCHIVES (2005;62:617-627), an author’s name was inadvertently omitted from the byline on page 617. The byline should have appeared as follows: “Ronald C. Kessler, PhD; Wai Tat Chiu, AM; Olga Demler, MA, MS; Kathleen R. Merikangas, PhD; Ellen E. Walters, MS.” Also on that page, the affiliations paragraph should have appeared as follows: Department of Health Care Policy, Harvard Medical School, Boston, Mass (Drs Kessler, Chiu, Demler, and Walters); Section on Developmental Genetic Epidemiology, National Institute of Mental Health, Bethesda, Md (Dr Merikangas). On page 626, the acknowledgment paragraph should have appeared as follows: We thank Jerry Garcia, BA, Sara Belopavlovich, BA, Eric Bourke, BA, and Todd Strauss, MAT, for assistance with manuscript preparation and the staff of the WMH Data Collection and Data Analysis Coordination Centres for assistance with instrumentation, fieldwork, and consultation on the data analysis. We appreciate the helpful comments of William Eaton, PhD, Michael Von Korff, ScD, and Hans-Ulrich Wittchen, PhD, on earlier manuscripts. Online versions of this article on the Archives of General Psychiatry Web site were corrected on June 10, 2005.
Background: Depressive and anxiety disorders commonly occur together in patients presenting in the primary care setting. Although recognition of individual depressive and anxiety disorders has increased substantially in the past decade, recognition of comorbidity still lags. The current report reviews the epidemiology, clinical implications, and management of comorbidity in the primary care setting. Method: Literature was reviewed by 2 methods: (1) a MEDLINE search (1980-2001) using the key words depression, depressive disorders, and anxiety disorders; comorbidity was also searched with individual anxiety diagnoses; and (2) direct search of psychiatry, primary care, and internal medicine journals over the past 5 years. Results: Between 10% and 20% of adults in any given 12-month period will visit their primary care physician during an anxiety or depressive disorder episode (although typically for a nonpsychiatric complaint); more than 50% of these patients suffer from a comorbid second depressive or anxiety disorder. The presence of depressive/anxiety comorbidity substantially increases medical utilization and is associated with greater chronicity, slower recovery, increased rates of recurrence, and greater psychosocial disability. Typically, long-term treatment is indicated, although far less research is available to guide treatment decisions. Selective serotonin reuptake inhibitor antidepressants are the preferred treatment based on efficacy, safety, and tolerability criteria. Knowledge of their differential clinical and pharmacokinetic profiles can assist in optimizing treatment. Conclusion: Increased recognition of the high prevalence and negative psychosocial impact of depression and anxiety disorder comorbidity will lead to more effective treatment. While it is hoped that early and effective intervention will yield long-term benefits, research is needed to confirm this.
Background: It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression. Methods: We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects. Results: Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls. Conclusions: These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed.
There is a hypothesis that lack of n-3 polyunsaturated fatty acids (PUFAs) is of aetiological importance in depression. Docosahexaenoic acid, a member of the n-3 PUFA family, is a crucial component of synaptic cell membranes. The aim of this study was to measure RBC membrane fatty acids in a group of depressed patients relative to a well matched healthy control group. Red blood cell (RBC) membrane levels, and dietary PUFA intake were measured in 10 depressed patients and 14 matched healthy control subjects. There was a significant depletion of RBC membrane n-3 PUFAs in the depressed subjects which was not due to reduced calorie intake. Severity of depression correlated negatively with RBC membrane levels and with dietary intake of n-3 PUFAs. Lower RBC membrane n-3 PUFAs are associated with the severity of depression. Although patient numbers were small, confounding factors were well controlled for and the results were highly significant. Results of the dietary data would tend to be weakened due to the limitations associated with dietary assessment. The findings raise the possibility that depressive symptoms may be alleviated by n-3 PUFA supplementation.
Oral administration of niacin (nicotinic acid) at pharmacologic doses that reduce serum colestrol levels induces intense flushing in humans. We have recently shown that the vasodilation following ingestion of niacin is due to the release of prostaglandin (PG) D2. However, the site from which PGD2 is released is not known. It has previously been shown that topical application of methylnicotinate causes local cutaneous erythema. Thus, we investigated whether topical methylnicotinate causes a release of PGD2 locally from skin and the possibility that skin may be a major contributor to the release of PGD2 when niacin is administered by mouth. Topical administration of methylnicotinate (10⁻¹ M) to the forearms of human volunteers resulted in 58- to 122- times increases in levels of the PGD2 and 9α,11β-PGF2 were not found in blood drawn simultaneously from veins in the contralateral arm, indicating that the PGD2 was released from the site of methylnicotinate application. The release of PGD2 in response to topically applied methylnicotinate occurred in a dose-dependent manner over the concentration range of 10⁻³ to 10⁻¹ M. The release of PGD2 was not accompanied by a release of histamine, suggesting that the release of PGD2 was not from the mast cell. Following oral ingestion niacin, levels of PGD2 in superficial venous blood draining the skin were 14 to 1200 times higher than the level in arterial blood supplying the skin is a major site from which PGD2 is released following oral ingestion of niacin. These studies thus indicate that the cutaneous vasodilation that occurs following oral administration of niacin is primarily due to a release of PGD2 from a niacin responsive cell that resides in the skin.