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Omega-3 polyunsaturated fatty acids and anxiety disorders

January 2008

Conference: Brain Lipids
Volume: Neurobiology of Lipids, 7, 1

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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.

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

ARTICLE IN PRESS

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/plefa

Prostaglandins, Leukotrienes and

Essential Fatty Acids

doi:10.1016/j.plefa.2009.10.004

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E-mail address: brian.ross@normed.ca

Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 309–312

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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

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

ARTICLE IN PRESS

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

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Sep 2013
J NUTR

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.

Anxiolytic-Like Actions of Fatty Acids Identified in Human Amniotic Fluid

Article

Full-text available

Apr 2013
TSWJ

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.

Omega 3 fatty acids in major depressive disorder: A preliminary double-blind, placebo-controlled trial

Conference Paper

Full-text available

Apr 2003
BIOL PSYCHIAT

Early diagnosis can decrease the social and economic burden of social anxiety disorder

Article

Full-text available

Jul 2005

Antonio E Nardi

Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and linolenic acids in young adult males

Article

Full-text available

Sep 1994
Biochim Biophys Acta

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.

Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes (vol 55, pg 891, 2004)

Article

Jun 2004
BIOL PSYCHIAT

Frasure-Smith

Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in the National Comorbidity Survey Replication

Article

Jul 2005

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.

The comorbidity of major depression and anxiety disorders: Recognition and management in primary care

Article

Jan 2001

Robert M A Hirschfeld

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.

Depletion of Omega3 Fatty Acid Levels in Red Blood Cell Membranes of Depressive Patients

Article

Mar 1998
BIOL PSYCHIAT

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.

Diagnostic and Statistical Manual of Mental Disorders: DSM-V

Book

Jan 1994

APA American Psychiatric Association

Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients

Article

Mar 1998
J AFFECT DISORDERS

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.

Identification of Skin as a Major Site on Prostaglandin D2 Release Following Oral Administration of Niacin in Humans

Article

Jun 1992

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.