omega-3 polyunsaturated fatty acids and depression a review of the evidence

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Current Pharmaceutical Design, 2009, 15, 4165-4172 416

1381-6128/09 $55.00+.00 2009 Bentham Science Publishers Ltd.

Omega-3 Polyunsaturated Fatty Acids and Depression: A Review of theEvidence

R. Liperoti*, F. Landi, O. Fusco, R. Bernabei and G. Onder

Centro di Medicina dellInvecchiamento, Dipartimento di Scienze Gerontologiche, Geriatriche e Fisiatriche, Universit

Cattolica del Sacro Cuore, Rome, I taly

Abstract: Brain lipids contain a high proportion of polyunsaturated fatty acids (PUFA), which are a main component of

cell membranes. Omega -3 (-3) PUFA eicosapentaeoic acid (EPA) and docosahexaenoic acid (DHA) are the most

common PUFA in the brain. The physiological roles of -3 PUFA in the brain include regulation of cell membrane

fluidity, dopaminergic and serotoninergic transmission, membrane-bound enzymes and cellular signal transduction. They

are also thought to play a role in brain glucose metabolism, eicosanoid synthesis, gene expression, cell growth and

protection from apoptosis. Increasing evidence from animal and human research shows -3 PUFA depletion may play an

etiological role in several inflammatory, autoimmune and neuropsychiatric disorders.In particular, an association between

-3 PUFA and depression was repeatedly suggested in observational and experimental studies on populations affected by

major depression, depressed mood or post-partum depression. Consistently, the potential therapeutic role of -3 PUFA

dietary supplementation was tested in clinical trials on depression.

The current review identifies and evaluates available epidemiological evidence of a negative relationship between -3

PUFA and depression and examines its biological plausibility.

Although current evidence increasingly supports an inverse association between -3 PUFA and depression, the validity of

findings from observational and experimental research is limited by several methodological issues. Further studies with

larger sample sizes and more sophisticated design are required to provide convincing evidence of a causal relationship

between -3 PUFA and depression.

Keywords:Omega-3 fatty acids, EPA, DHA, polyunsaturated fatty acids, depression.

INTRODUCTION

Fatty acids, an essential component of cell membranes inhumans and other mammals, are divided into three classes:saturated fatty acids, with all hydrogen atom positions filled;monounsaturated fatty acids, with a single carbon-carbon

double bond; polyunsaturated fatty acids (PUFA), withmultiple carbon-carbon double bonds. PUFA are classifiedaccording to the molecular position of the first double bond:omega-6 (-6) PUFA, a biosynthetic derivation of linoleicacid (LA), include arachidonic acid (AA) and dihomogam-malinoleic acid (DGLA) while omega-3 (-3) PUFA derivefrom alfa-linoleic acid (ALA) and include eicosapentaeoicacid (EPA) and docosahexaenoic acid (DHA). LA and ALAare defined as essential PUFA since human and mammalianscells are unable to synthesize them from precursors. Inhumans, conversion of LA and ALA into their metabolites isextremely low with an estimated rate of 2% in youngeradults[1] and several factors including age, gender, immunestate, alcohol and smoking, may influence LA and ALAmetabolism.[2,3] Therefore, for humans, diet is the majorsource of PUFA, including long chain PUFA such as AA,EPA and DHA. In the Western diet, -6 PUFA derivemainly from corn, soy, canola, safflower and sunflower oils

*Address correspondence to this author at the Centro di Medicina

dellInvecchiamento, Dipartimento di Scienze Gerontologiche, Geriatriche eFisiatriche, Universit Cattolica del Sacro Cuore, Largo A. Gemelli, 8 0168Rome, Italy; Tel: +39-06-3015-4341; Fax: +39-06-3051-911;E-mail: [email protected]

while the major sources of -3 PUFA are flaxseed oilwalnut oil and fish.

Lipids constitute 36 - 60% of nervous tissue in the humanbrain [4] and of brain lipids, glycerophospholipids containthe highest proportion of PUFA. Specifically, DHA and AA

are the most common PUFA in the brain with the formeprevailing in grey matter and the latter in white matter.[4The fatty acid profile of brain cell membranes may be alteredby inducing a dietary deficiency of PUFA. Animal studieinvestigating the effect of dietary PUFA deficiencyparticularly the effects of brain -3 PUFA depletion, helpeddefine the physiological role of PUFA in human brains [621]. Far less is known about AA as dietary deficiency cannocause brain AA depletion. Some of the effects of DHAdietary deficiency include changes in cell membrane fluidityand stability [6], dopaminergic and serotoninergic transmission [7-9], and regulation of membrane-bound enzymesand cellular signal transduction; [10,11]. Metabolic effectsinclude reduced glucose uptake [12,13], altered regulation o

AA -derived eicosanoid synthesis [14,15], reduced levels odocosatrienes and 17S resolvins i.e. DHA metabolites whichare anti-inflammatory mediators; [16] changes in geneexpression; [17,18] alterations in neuronal cell and neuritegrowth [19,20], loss of cell protection from apoptosis [21].

More and more evidence from animal and humanresearch shows that -3 PUFA depletion may play anetiological role in several inflammatory, autoimmune andneuropsychiatric disorders [22,23]. An inverse association


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4166 Current Pharmaceutical Design, 2009, Vol. 15, No. 36 Liperoti et al

between -3 PUFA and depression was repeatedly suggestedin observational and experimental studies on populationsaffected by major depression, depressed mood or post-partum depression. Finally, the potential therapeutic role of

-3 PUFA dietary supplementation was tested in clinicaltrials on depression.

This review evaluates available evidence of a relationshipbetween -3 PUFA and depression and examines its

biological plausibility.

EPIDEMIOLOGICAL STUDIES OF -3 PUFA ANDDEPRESSION

An inverseassociation between low -3 PUFA status anddepression was postulated in the early 1980s after initialretrospective observations reported EPA and DHA concen-trations were lower in depressed than in non-depressedpatients [24,25]. Subsequently, several prospective studiesshowed that switching to a cholesterol-lowering and fish-enriching diet was associated with decreased depression andhostility [26-28]. In addition, correlation studies found thatlow -3 PUFA levels in serum phospholipids, cholesterylesters and erythrocyte membranes were associated withincreased risk of depression [29,30]. Since then, observa-tional studies have consistently documented lower -3PUFA levels in depressed patients than in non-depressed,with some reports suggesting a relationship between -3PUFA concentration and severity of disease. More recently,several therapeutic clinical trials consistently suggested -3PUFA might have an antidepressant effect, althoughevidence to date is limited and in some cases the validity offindings is questionable.

In the present review studies were collected by means ofa systematic Medline search from 1966 to September 2008,using the following keywords: (depression OR depressivedisorder OR mood disorder) AND (omega-3 OR polyun-

saturated fatty acids OR PUFA ORDHAOR EPA ORfish).Reference lists from identified articles were also scrutinizedfor pertinent studies that had not been indexed in theMedline electronic database. Inclusion criteria were: studydesign including case reports and case series, ecological,cross-sectional, case-control, cohort, pre post test,randomized controlled studies; published in English; pub-lished in peer-reviewed journals; description or evaluation ofthe association between -3 PUFA and depression orinvestigation of potential biological mechanisms as primarystudy objectives; independent studies (re-analysis of pub-lished data were not considered independent). Press articlesand unpublished studies were excluded from this review.Two authors independently reviewed the literature to identify

eligible studies and assess their suitability for inclusion,resolving disagreements in discussion. Two hundred andeighty-three studies were initially identified through theliterature search; eighty-six studies satisfied the inclusion/exclusion criteria and were included in this review.

OBSERVATIONAL STUDIES

Case Reports and Case Series

Several case reports indicated the beneficial effects of -3 PUFA treatment in adjunction to standard medical anti-depressant therapy. In 2001, Puri and colleagues described

the case of a treatment-resistant, severely depressed, suicidamale patient with a seven-year history of unremitting depressive symptoms who was treated with EPA in addition toconventional antidepressant therapy [31]. Permanent, markedclinical improvement was achieved in all symptoms odepression, including suicidal ideation. Neuro-radiologicaand biochemical markers indicated reduced neuronal phospholipid turnover during the nine-month follow-up. Anothe

case report described a pregnant patient with majodepression who was treated with EPA 4 g per day and DHA2 g per day [32].Clinical symptoms of depression improvedand suicidal ideation ceased. After delivery, the therapeuticregimen was integrated with paroxetine 20 mg per day andclinical benefits appeared to be stable. Supplementation o

-3 PUFA during pregnancy was demonstrated to be safe fothe newborn.

Case reports are a useful resource for formulating but notesting hypotheses in epidemiology. Lack of controls in thistype of descriptive study implies inability to estimate anymeasure of association.

Ecological Studies

Large variations were reported in -3 PUFA intake andin the -6 to -3 PUFA dietary ratio across countries. Thesedifferences reflect marked variations in dietary habits andfish consumption across populations. In 1998, Hibbeln andcolleagues reported a significant inverse correlation betweenper capita fish consumption and national annual prevalenceof major depression across nine countries [33]. Subsequently, ecological data showed post-partum depression wainversely associated with fish consumption in 22 countriesand with DHA concentration in breast milk in 16 countries[34]. but did not document a relationship between EPA andAA breast milk levels and pos t-partum depression.

Ecological studies provide aggregate scientific evidencewhich can be very useful in generating hypotheses. Thimethodology does not permit drawing causal inference. Infact, finding an association in a population does not implythat the same relationship exists at the individual levelFinally, confounding is a serious methodological issue in thedesign of such studies since no individual data may beavailable to allow confounders to be checked.

Cross-Sectional Studies

Numerous cross-sectional studies investigated theassociation between depression and -3 PUFA body contenor fish consumption in individuals. In a small population omoderately to severely depressed patients Adams and

colleagues demonstrated a relationship between -3 PUFAlevels in plasma and erythrocyte phospholipids and severityof depression on the 21-item Hamilton depression ratingscale (HAM-D) [29] and reported a significant correlationbetween the AA to EPA ratio of erythrocyte phospholipidand severity of depression. Similarly, an inverse associationbetween -3 PUFA in serum phospholipids or adipose tissueand major depression was reported in later cross-sectionaobservations [30,35-38]. In a small study Edwards andcolleagues detected a significant -3 PUFA depletion in redblood cell membranes in depressed patients compared withhealthy controls and observed that severity of depression


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Omega-3 Polyunsaturated Fatty Acids and Depression Current Pharmaceutical Design, 2009, Vol. 15, No. 36 416

correlated negatively with -3 PUFA membrane levels anddietary intake [39]. In a study investigating the associationbetween depression and -3 PUFA serum levels in patientsrecovering from acute coronary syndrome, depressedpatients had lower total -3 and DHA concentrations andhigher AA to DHA and AA to EPA ratios than controls [40].These findings were subsequently confirmed in a populationof patients who were hospitalized for acute coronary

syndrome and a major depressive episode [41]. Depressedpatients showed significantly lower -3 PUFA and DHAserum levels than controls and severity of depression, asassessed by the 18-item Depression in the Medically Ill(DMI-18), correlated with -3 PUFA levels. One obser-vational study has investigated to date the relationshipbetween depression and fatty acid plasma composition in apopulation of community-dwelling elderly individuals [42],thus providing the results of a cross-sectional analysis of datacollected within the Rotterdam Study cohort study. Afteradjusting for several potential confounders, depressedpatients had a h igher serum ratio

of -6 to -3 PUFAs and

lower -3 PUFA levels than controls. Although inflam-mation and atherosclerosis were hypothesized to be

intermediate factors between PUFA and depression, the C-reactive protein (CRP) and intima-media thickness, markersof inflammation and atherosclerosis, respectively, were noteffect modifiers of the association. In a large New Zealandpopulation enrolled in the 1997 National Nutrition Survey,Crowe and colleagues investigated the association betweenserum phospholipid fatty acid composition and physical andmental well-being, as assessed using the short-form 36 healthquestionnaire [43]. Unlike previous data, a positive asso-ciation was found between -3 PUFA levels and physical,but not mental, well-being, suggesting -3 PUFA could playa significant role as mood stabilizers. Finally, cross-nationalcomparisons repeatedly reported an inverse relationshipbetween fish consumption and depressive symptoms, pre-

valence of major depression and self-reported mental status,even after taking into account potential confounders such asage, gender, socio-economic status, eating patterns, alcoholuse and smoking habit [44,45]. One study on 771 Japanesepatients with lung cancer failed to show significant diffe-rences in EPA and DHA dietary intake in depressed and non-depressed participants, although a trend emerged toward aninverse relationship between fish consumption anddepression [46].

Cross-sectional studies provide evidence for an inverseassociation between depression and -3 PUFA and permitthe strength of the relationship to be estimated. Cross-sectional data cannot assess causality because, by their very

nature, they cannot assess the temporal relationship betweenexposure and outcome. In other words, it is not possible tounderstand whether depression is due to -3 PUFA dietarydeficiency or whether depression actually causes thedeficiency by influencing dietary habits and lifestyle.Misclassification of outcome and exposure may be a concernwhen self-reported information is used to assess -3 PUFAdietary intake, fish consumption and depressive status.Finally, although most of the cross-sectional studies citedabove attempted to control for potential confounders,residual confounding may still have affected the validity offindings.

Cohort Studies

A limited number of prospective studies presentedconflicting findings on the relationship between depressionand -3 PUFA. Sublette and colleagues recently documentedthat DHA levels and the -3 to -6 PUFA ratio may predicsuicide attempts in depressed patients over a 2-year followup [47]. Although a large study of 29,133 Finnish adulmales failed to observe an association between dietary intake

of -3 PUFA and depression [48], the validity of thesefindings was questioned since misclassification of exposureand outcome appeared to have occurred. Indeed, -3 PUFAdietary intake was assumed to be constant over the entirefollow-up (median 6 years) and self-reported informationfrom participants was used to assess depressed mood. Earlyobservations suggested fish consumption during pregnancymight be related to post-partum depression [49,50]. Browneand colleagues found that self-reported fish consumptionduring pregnancy correlated with maternal -3 PUFA levelpost-partum but did not predict post-partum depression [51]These findings were confirmed in a large longitudinal studyof 865 Japanese women participating in the Osaka Maternaand Child Health Study [52]. According to the authors, thehigh level of fish consumption in the Japanese populationmay have contributed to the lack of association. Veryrecently, fatty fish consumption and a long-chain n-3 PUFAintake of over 0.10% of total energy intake were associatedwith a significantly reduced risk of recurrent depression in a8-year follow-up [53]. The association was markedly strongamong men and non-smokers.

EXPERIMENTAL STUDIES

Findings from observational research provided evidencefor a growing number of interventional studies on thebeneficial role of -3 PUFA in major depression, bipoladisorder and post-partum depression.

Omega-3 PUFA and Major Depression

In one of the early intervention studies investigating theantidepressant effect of -3 PUFA, Peet and Horrobinconducted a double-blind randomized clinical trial (RCT) on70 adult patients with persistent depression [54]. Participantwere randomized to receive 1, 2 or 4 g of ethyl-EPA per dayor placebo for 12 weeks in addition to their standard anti-depressant therapy. The 17-item HAM-D, the MontgomeryAsberg Depression Rating Scale (MADRS), and the BeckDepression Inventory (BDI) were used to assess patientsdepressive status. Only study participants receiving ethylEPA 1 g per day experienced a significant beneficial effec

with a 50% reduction on the HAM-D score relative toplacebo. A small placebo-controlled study on 20 patientwith recurrent major depression on antidepressant medications showed ethyl-EPA 2 g per day exerted a markedlybetter antidepressant effect than placebo after 3 weektreatment [55]. Similarly, an 8-week, double-blind, placebocontrolled RCT, evaluating the effect of EPA and DHA 6.6 gper day, as add-on therapy in 22 patients with majordepression, showed -3 PUFA was associated with asignificant improvement on the 21-item HAM-D [56]. Incontrast with these findings, Marangell and colleagueshowed that, compared with placebo, DHA 2 g per day for 6


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weeks had no significant effect in a sample of 35 patientswith major depression, rated on the HAM-D and MADRS[57]. In 77 patients with depression who received 8 g of fishoil per day for 12 weeks and were assessed using the ShortForm HAM-D and the Beck Depression Inventory II (BDIII), Silvers and colleagues failed to observe an advantage offish oil over placebo as add-on antidepressant therapyrelative [58] Moreover, -3 PUFA was not found to be any

better than placebo in a group of 83 outpatients with majordepression who received tuna fish oil in addition toconventional medical treatment over a four-month period[59]. Interestingly, the authors interpreted these negativefindings as suggesting that a beneficial effect of -3 PUFAmight be manifest only in patients with pre-existing -3PUFA deficiency. Very recently, Rogers and colleaguesconducted a double-blind placebo-controlled RCT evaluatingthe effect of EPA plus DHA supplementation at 1.5 g perday for 12 weeks on mood and cognition of 190 patientswith mild to moderate depression [60]. Although compliancewith -3 PUFA supplementation was discrete, the study didnot detect any differences in the two groups on the primarydepression outcome measure on the depression subscale of

the Depression Anxiety and Stress Scales (DASS). Finally,Jazaiery and colleagues compared the effects of EPA 1 g perday, fluoxetine 20 mg per day and their combination in an 8-week trial in 48 patients with major depression.[61]

Depressive symptoms were assessed using the 17-itemHAM-D. Response rates expressed as decrease in baselineHAM-D were 50%, 56% and 81% in the fluoxetine, EPAand combination groups respectively, suggesting that EPAand fluoxetine exerted an equally beneficial effect and theircombination provided a therapeutic advantage.

Omega-3 PUFA and Bipolar Disorder

To date, few RCTs have investigated the therapeutic role

of

-3 PUFA in bipolar disorder. Stoll and colleagues foundthat, among 30 patients with bipolar disorder on standardmedications, those treated with EPA plus DHA 9.6 g per dayhad longer periods of remission compared with placebo [62].A small, open label, add-on trial on 12 bipolar outpatientswith depressive symptoms treated with EPA 1.5 to 2 g perday for 6 months documented a beneficial effect in 8 out of10 patients who completed 1 month of treatment.[63]

Frangou and colleagues compared the efficacy of EPA 1 gper day and 2 g per day versus placebo as add-on treatmentfor a 12 week period in 75 patients with bipolar disorder.[64]EPA had a significantly better therapeutic effect thanplacebo although no dose-response was evident.In contrast,Keck and colleagues did not find any evidence of efficacy

over placebo of EPA 6 g per day administered as add-ontreatment for 4 months to outpatients with bipolar depressionor rapid cycling bipolar disorder [65].

Omega-3 PUFA and Post-Partum Depression

Most interventional studies evaluating the role of -3PUFA in preventing and treating post-partum depressionfailed to confirm the association. In a double-blind study ofbreast-feeding mothers who were randomly assigned toreceive either DHA 200 mg per day or placebo for the first 4months after the delivery, Llorente and colleagues measured

major depression outcome using a self-rating questionnaireof current depression symptoms [66]. Although serum DHAcontent was higher in the supplemented group than in theplacebo group, no inter-group difference emerged in selfrating post-partum depression. Similarly, a small open-labestudy did not find a preventive antidepressant effect of amixture of DHA plus EPA administered, between the 34th to36th week of pregnancy, as fish oil to women with a history

of post-partum depression [67]. More recently, an 8-weekdouble-blind, placebo-controlled RCT comparing -3 PUFA3.4 g per day with placebo in 24 pregnant women with majordepressive disorders found significantly lower scores on theHAM-D at weeks 6 and 8, as well as higher response andremission rates in the supplemented group [68]. The studyalso showed a good tolerability of -3 PUFA in mothers andsafety for newborns. In contrast with these findings, Reeand colleagues reported no difference in the depressionscores of women with major depression during the perinataperiod who were treated with either fish oil or p lacebo for sixweeks [69] but suggested the study was too underpowered todetect any effect. Finally, a large study evaluated the efficacyand safety of EPA and DHA 1.9 g per day versus placebo fo

8 weeks in a sample of 51 women with perinatal majodepressive disorder [70]. Omega-3 PUFA was well toleratedAlthough all participants had significant improvements onthe HAM-D and Edinburgh Postnatal Depression Scale(EPDS), no difference was detected between the -3 PUFAand placebo groups.Limitations of Experimental Studies

Two recent meta-analyses of published RCTs evaluatedexperimental evidence of the effect of -3 PUFA ondepression. Appleton and colleagues estimated a pooledeffect size of 0.13 (95% Confidence Intervals (CI) 0.01-0.25from 12 RCTs included in the meta-analysis [71]. Strong

evidence of heterogeneity was reported, with publicationbias being deemed the most likely source. The authorsconcluded that experimental data provided little support for abeneficial effect of -3 PUFA treatment in depressedpatients and that available evidence was limited and difficulto summarize due to heterogeneity. A second meta-analysisof 10 randomized double-blind placebo-controlled trialshowed -3 PUFA treatment exerted significant antidepressant efficacy in patients with major depression or bipoladisorder (pooled effect size 0.61; 95% CI 0.21-1.01) [72]High-dose EPA (but not medium- or low-dose EPA) wassignificantly more efficacious than placebo in decreasingdepressive symptoms, suggesting an EPA dose-dependenantidepressant effect. Nonetheless, the authors questioned

the validity of their findings because of significant studyheterogeneity and publication bias. Three negative RCTs andone positive on patients with major depression and postpartum depression were subsequently published but were noincluded in the above mentioned meta-analyses [60, 69, 70].

Methodological issues in clinical trials investigating the-3 PUFA antidepressant efficacy were repeatedlyhighlighted [72,73]. Criteria for the definition of depressionappeared to be very heterogeneous and were often poorlydescribed, which may have led to outcome misclassificationand reports of negative findings. It may also have seriouslythreatened the validity of comparing different studies. Large


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heterogeneity in clinical trials was also documented in termsof severity of depression, psychiatric comorbidity, -3PUFA baseline levels, concomitant antidepressant medi-cation use, individual acid used as active treatment. Eventhough current data seem to support the hypothesis that high-dose EPA exerts an antidepressant effect, there is notsufficient evidence for concluding that EPA is moreefficacious than DHA, for identifying the most effective dose

and length of treatment or for determining whether -3PUFAs interact with antidepressant medications. Sincesmall sample size characterizes many of the published RCTs,lack of statistical power may explain negative findings inseveral cases. Finally, study blinding may not be preserveddue to the fishy aftertaste which characterizes activetreatment. Unblinding is one of the principle threats tovalidity, especially since high placebo response rates werereported in trials on antidepressant treatments [74].

Finally, although depressive symptoms are highly pre-valent in elderly individuals and the incidence increases withage, experimental evidence on the potential benefit of -3PUFA supplementation in the geriatric population is verylimited. One RCT investigated the effect of 26 weeks fish-oilor placebo supplements on the mental well-being of a large,non-depressed, elderly population (mean age 70 years) [75].Daily supplementation with low- or high- dose EPA plusDHA had no effect compared with placebo on mental well-being, assessed using the Center for Epidemiologic StudiesDepression Scale (CES-D), the MADRS, the 15-itemGeriatric Depression Scale (GDS) and the subscale of theHospital Anxiety and Depression Scale (HADS-A). Futureresearch should be directed towards investigating therelationship between -3 PUFA and depressive symptoms inthe elderly and exploring any particular mechanisms under-lying this association in the ageing brain.

BIOLOGICAL MECHANISMS

Even though the pathogenetic mechanisms underlyingdepression, which is thought to result from genetic andenvironmental components, are still not completely known,several mechanisms were proposed to explain the negativerelationship between -3 PUFA and depression.

Several neural systems were found to be dysfunctional indepression and in -3 PUFA deficiency. Evidence fromanimal and human studies showed that -3 PUFA deficiencywas linked to altered neurotransmission, decreased glucosemetabolism, increased production of pro-inflammatorycytokines, reduced levels of brain-derived neurotrophicfactor (BDNF) and neuronal atrophy, which are also asso-

ciated with depression. In rats with

-3 PUFA deficiencyaltered regulation of serotonergic and dopaminergic neuro-transmitters was observed [76], particularly reduced expres-sion of dopamine receptor D2R in the frontal cortex, alongwith a significant decrease in dopamine release [7].Dopamine levels increased in the frontal cortex of ratsfollowing dietary supplementation with -3 PUFA [77].Glucose uptake, transport and utilization were reduced in thebrains of rats deficient in -3 PUFA [10,12,13]. Similarly,neuronal functional activity, measured through cerebralblood flow and glucose metabolism, was decreased indepressed patients [78,79]. Major depression was repeatedly

associated with over-production of pro-inflammatorycytokines [80,81] in speculating on the pathogenetic role o-3 PUFA in depression, one might hypothesize that -3PUFA deficiency was associated with over-reaction of theimmune system leading to a neuro-inflammatory statusIndeed, -3 PUFA inhibited production of pro-inflammatorycytokines [15] due to reduced AA metabolism and lessproduction of pro-inflammatory prostaglandins and

leukotrienes. Decreased DHA levels in the frontal cortex andaltered expression of enzymes related to the AA cascadewere found in the brain of rats fed a -3 PUFA deficient diefor 15 weeks [18]. Similarly, tryciclic antidepressantinhibited release of pro-inflammatory cytokines includingIL-6, IL-1beta, IL-2, TNF-alpha and interferon-gamma fromhuman monocytes and T cells [82]. Evidence from animastudies increasingly points to a relationship between thebrain derived neurotrophic factor (BDNF) and depression[83,84]. BDNF, a brain trophic factor, is involved inneuronal growth and plasticity [84,85] and cerebral levels arthought to correlate with development of depressionCerebral atrophy of specific brain areas such as the prefrontal cortex and hippocampus was found in major depres

sion [86]. Lifestyle factors such as stress, exercise and diemay influence BDNF expression in the brain [87-89]. SerumBDNF levels correlated with the severity of depression andwere higher in patients on antidepressants than in non-treatedpatients [83]. There is evidence that BDNF levels may beincreased by dietary supplementation with -3 PUFA andreduced by saturated fat and refined sugar [87,89]. An -3PUFA deficiency appeared to reduce BDNF expression in rafrontal cortex; adding DHA to rat astrocyte cultures inducedBDNF expression [90].

According to a recent interesting hypothesis, the linkbetween -3 PUFA deficiency and depression may be due toa combination of dietary and genetic components [91]. Alow dietary intake only partially explains low -3 PUFAavailability in the brains of depressed patients. Reduced -3PUFA levels in patients with depression could also be due toan altered -3 PUFA uptake mechanism with specificimpairments to the enzyme Type IV cytosolic phospholipasA2 and the fatty acid CoA ligase 4. Recent moleculafindings provided evidence to support the hypothesis ogenetically determined abnormal phospholipid syntheticpathway functioning in major depression [91-94]. If thipathogenetic model is confirmed by further evidence, agentssuch as citicoline and cytidine which enhance phospholipidsynthesis may prove to be efficacious antidepressants.

Finally, animal studies and observational evidencesuggested -3 PUFA plasma levels or dietary intake were

linked to risk of dementia development and progression[95,96] Depression is a frequent comorbidity in patients withdementia as well as a risk factor for incident dementia[97,98] Similarly, cognitive decline may affect patients withdepression [99]. Consequently, one may hypothesize that theeffect of -3 PUFA levels on mood is mediated by a direceffect of -3 PUFA on cognition. Depression could in turnmediate the effect of -3 PUFA on cognition in dementiapatients. Further research is needed for a better understanding of the independent effect of -3 PUFA on mood andcognition.


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CONCLUSIONS

Accumulating evidence over the past decade indicates alink between -3 PUFA deficiency and depression.Following initial observations of reduced -3 PUFA plasmaconcentrations in patients with major depression, bipolardisorder and post-partum depression, several RCTs sugges-ted that dietary supplementation with EPA and DHA exertedan antidepressant effect As, however, most observational

studies on -3 PUFA and depression had a cross- sectionaldesign, it was not possible to exclude that the associationwas due to a direct effect of depression on -3 PUFA levels.The validity of observational findings was limited by severalmethodological issues such as exposure or outcomemisclassification and inadequate control for confounders.Similarly, RCTs were often limited by small samples andinadequate statistical power. Finally, very limited data areavailable on the relationship between -3 PUFA and depres-sion in the elderly, despite the high prevalence of mooddisorders and depressive symptoms in the geriatricpopulation.

In conclusion, although epidemiological findings increa-

singly suggest an inverse association between -3 PUFA anddepression and support its biological plausibility, currentevidence is not conclusive. Further studies with largersample size and more sophisticated design need toinvestigate the interaction between -3 PUFA and antide-pressant medications, the antidepressant properties ofdifferent fatty acids and the most effective dose and durationof treatment in order to provide convincing evidence of acausal relationship.

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Received: August 6,2009 Accepted: August 19,2009


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