Omega-3 and omega-6 fatty acids (FAs) comprise two families of polyunsaturated lipids required for normal growth and development and referred to as ‘essential’ in that they cannot be synthesized within the body and must be obtained from the diet. α-Linolenic acid (ALA) and linoleic acid are the parent molecules of the two respective FA families and are converted to form long-chain polyunsaturated FAs, including eicosapentaenoic acid (EPA; omega-3), docosahexaenoic acid (DHA; omega-3) and arachidonic acid (omega-6). These long-chain polyunsaturated FAs are incorporated into phospholipids that comprise cellular membranes throughout the body and mediate a range of physiological effects.
In 2006, we published a review  of studies suggesting a contributory aetiological role of omega-3 FA deficiency to depressive and bipolar disorders and overviewed a number of studies indicating that omega-3 FA supplementation (both as monotherapy and as an adjunct to formal antidepressant drugs) may be an effective treatment for depression. The then seemingly distinct ‘signal’ indicating a significant antidepressant role of omega-3 has, however, diminished over subsequent years as the published literature has expanded. We now overview the evolving story, highlighting studies published in the last 12–18 months. Of key significance, a narrowed ‘signal’ has emerged from recent meta-analyses.
EARLY EPIDEMIOLOGICAL DATA
In 1998, Hibbeln  reported a strong relationship between fish consumption (seafood being a major source of omega-3 FAs) and the prevalence of major depression in a large cross-national database. Subsequently, Hibbeln reported similar inverse correlations between seafood intake with rates of postnatal depression  and bipolar disorder  – especially with bipolar II disorder – and, as there was no such association with schizophrenia, such data indicated a dietary factor having specificity to mood disorders.
WHY MIGHT FATTY ACID ABNORMALITIES LINK WITH MOOD DISORDERS?
Omega-3 FAs confer numerous important biological advantages by their capacities to influence cellular metabolism and function . As illustrated in Fig. 1[6–9], mechanisms by which long-chain omega-3 FA modulate cellular functions include promoting membrane fluidity, so influencing transmembrane protein activity, and impacting on receptors, enzymes and ion channels; participating in intracellular metabolic pathways; and influencing gene expression.
DHA is highly concentrated in neuronal membranes, and animal studies show that an adequate supply of DHA is essential for normal neuronal development and behaviour [10▪]. More specifically, in relation to the mood disorders, adequate neuronal DHA is required for normal dopaminergic and serotonergic neurotransmission  and induces the expression of brain-derived neurotrophic factor (BDNF) , which impacts on neurogenesis, plasticity and synaptic transmission . The role of BDNF is particularly relevant when reduced brain and plasma BDNF levels have been quantified in patients suffering depressive and bipolar disorders, whereas antidepressant medications have been shown to stimulate BDNF expression and have positive effects on mood [14–16].
Further, both EPA and DHA suppress cytokine production and have anti-inflammatory effects [17,18▪,19], of relevance here, as there is increasing evidence implicating inflammatory processes in causing and advancing depressive episodes [20–23]. In essence, proinflammatory cytokines compromise neurotransmitter metabolism, stimulate the hypothalamic–pituitary–adrenal (HPA) axis and inhibit neuronal growth and plasticity [20–23]. Eicosanoid molecules mediate and modulate the acute inflammatory response. Those generated from omega-6 FAs are generally proinflammatory, whereas those generated from omega-3 FAs are either less inflammatory or anti-inflammatory . Moreover, omega-3 FAs are precursors to protectin and resolvin molecules, key to the resolution of inflammatory processes  and downregulate inflammatory genes . Such mechanisms – recently reviewed in much greater detail elsewhere [24–27] – advance the argument that a sufficient intake of the essential omega-3 FAs (DHA and EPA in particular) is required for normal brain functioning and immune system competency, and, more saliently, that insufficient omega-3 FAs may predispose to depression and other mood disorders.
Animal studies have been integral in delineating the role of omega-3 FA in normal brain development and continue to provide insights into the relationship between omega-3 status, neuronal function and behaviour. For example, a recent study performed by McNamara et al. [28▪] provides evidence for the link between omega-3 FAs, inflammation and neuronal serotonin metabolism. Rats born to mothers fed an omega-3-deficient diet and maintained on an omega-3-deficient diet exhibited relationships between erythrocyte membrane DHA content, elevated plasma inflammatory markers and increased serotonin turnover in frontal cortex, hypothalamus and ventral striatum in adulthood. These abnormalities were normalized by reintroduction of dietary omega-3 FA postweaning [28▪]. A number of recent studies illustrate that omega-3 deprivation, particularly during the embryonic/preweaning period, exacerbates the HPA axis response to stress and increases anxious and depressive behaviours in adult life [29,30▪,31,32▪,33▪]. Lafourcade et al.[33▪] have shown that such behavioural effects are associated with ablated endocannabinoid modulation of synaptic plasticity in the prelimbic prefrontal cortex and nucleus accumbens. Further studies indicate that omega-3 supplementation ameliorates the physiological responses to stress and reduces depressive behaviours [34,35] in conjunction with increased central serotonin and BDNF levels [36▪,37] and reduced inflammatory cytokines . A study by Wietrzych-Schindler  indicated that antidepressant effects of DHA may be mediated, at least in part, through interaction with the retinoid X receptor γ transcription factor.
A POSTULATED IMPACT OF DIET ON THE PREVALENCE OF MOOD DISORDERS
It is commonly claimed that mood disorders have become prevalent in recent decades – a claim that may reflect less stigma and more people consequentially being prepared to admit to a mood condition and seek help, and/or a true increase in their prevalence. In considering the latter as a real possibility, one explanation is a dietary change. Jacka et al. [39▪] have quantified an association between a ‘western diet of processed or fried foods, refined grains, sugary products, and beer’ and an increased rate of depression. More specifically, changes in the dietary ratio of omega-3 and omega-6 may have contributed to increases in rates of mood disorders. It is claimed that our diet has changed from one rich in omega-3 (via fish, wild game and plants) to being more much more highly weighted in omega-6 polyunsaturated FAs (from vegetable oils and animal products), resulting in an increase in the omega-6/omega-3 intake ratio from 1 : 1 to more than 10 : 1 . It is argued that this results in a higher proportion of the omega-6 FA, arachadonic acid, rather than EPA in cellular membranes, potentially leading to a higher proportion of inflammatory eicosanoids and alterations in gene expression which may contribute to the increasing prevalence of chronic diseases [40,41].
The omega-3 FA ALA is present in leafy vegetables and certain plant oils (e.g. flaxseed, chia and canola), whereas the parent omega-6 FA linoleic acid is concentrated in many commonly used vegetable and nut oils (e.g. safflower, sunflower and corn) as well as meat, poultry and dairy products. ALA conversion to EPA and DHA is extremely low, so that provision of these long-chain omega-3 FAs is best achieved by direct consumption , with the best source of EPA and DHA being seafood (e.g. salmon, mackerel and trout). Whereas a US taskforce has recommended a daily intake of 250–500 mg of EPA + DHA , the modern western diet has been quantified as providing an average daily EPA + DHA intake in the order of 100–135 mg/day [42,43]. The western diet has, therefore, been implicated in contributing to a number of inflammatory diseases including depression, bipolar disorder and cardiovascular disease [22,41,44]. A candidate group at particularly high risk of omega-3 depletion is pregnant women, as during the last 3 months of a pregnancy the baby requires nearly 70 mg/day of DHA, in addition to maternal needs . As maternal omega-3 FA depletion occurs both during pregnancy (via placental transfer) and postnatally (via breast milk), such a dietary change is viewed as providing a depression risk to women both during late pregnancy and in the postnatal period . The importance of diet during pregnancy is highlighted by a recent prospective study of pregnant women , which found that adherence to a ‘health conscious’ diet, characterized by vegetables, fruit, pulses, nuts, dairy products, fish and olive oil, was associated with reduced risk for postnatal depression.
Since the initial epidemiological studies based on cross-national data [2–4] linking seafood intake with depression and bipolar disorder and indirectly positing a causal link, numerous studies have been reported. In essence, and perhaps reflecting most studies involving selected samples, associations between omega-3 FA dietary intake and depressive ‘symptoms’ have been less distinctive [48,49]. A recent large-scale 10-year longitudinal study reported that higher omega-3 FA intake in the form of ALA, along with lower linoleic acid intake, was associated with protection from major depressive disorder . Interestingly, however, no relationship was demonstrated between depression risk and intake of long-chain omega-3 from fish . This is likely to reflect the fact that diet is not the sole factor influencing omega-3 status [51▪]. Although EPA + DHA intake has been identified as the main predictor of the ‘omega-3 index’ (defined as the sum of EPA and DHA in erythrocyte membranes expressed as a percentage of total FAs), it has been estimated to account for only around 12% of variability in this measure . Other important factors influencing omega-3 status include age, lifestyle and genetic factors, including the expression of enzymes involved in polyunsaturated FA biosynthesis [51▪].
STUDIES LINKING LOW OMEGA-3 FATTY ACID STATUS AND MOOD DISORDERS
Early studies identified ‘depressive patients’ as having lower omega-3 FA levels in erythrocyte membranes [53,54]. Not all subsequent studies have replicated these findings; however, a meta-analysis published in 2010 found that, considered overall, plasma/erythrocyte measures of omega-3 status including EPA, DHA and total omega-3 FA content are significantly lower in depressed patients compared with controls . A recent study adding to this literature reports a selective reduction in erythrocyte DHA in medication-free patients with major depression and bipolar disorder . The authors suggest that the selective nature of this deficit may be indicative of impairments in the peroxisomal reactions that comprise the final steps in conversion of short-chain omega-3 FA to DHA in these patients . Other recent studies have demonstrated reduced erythrocyte omega-3 status associated with adolescent depression , including depression linked to eating disorders , and a link between low plasma DHA and higher rates of suicide in the US military [59▪]. Another important study investigated the link between depression, omega-3 FA status and cardiovascular risk factors [60▪]. This study showed that, in addition to a lower omega-3 index compared with healthy controls, patients with major depressive disorder but no current cardiovascular disease were found to exhibit a range of cardiovascular risk factors, including increased plasma triglycerides, fasting glucose and interleukin 6 levels along with lower circulating high-density lipoproteins [60▪]. Another study  reported that low plasma omega-3 FA is a significant factor for reduced survival in heart failure patients with major depressive disorder. These studies provide additional evidence linking depression and cardiovascular disease, for which low omega-3 status is a shared risk factor .
Previous studies have demonstrated deficits in DHA content in the post-mortem brains of patients with mood disorders . Adding to this line of investigation, McNamara and Liu [64▪] report reduced mRNA expression of the enzymes involved in the biosynthesis of polyunsaturated FA in the post-mortem prefrontal cortex of patients diagnosed with major depressive disorder compared with controls. It appears that reductions in DHA are restricted to specific brain regions, given that Hamazaki et al.  report no DHA deficits in the amygdala of patients with schizophrenia, depressive and bipolar disorders.
IS OMEGA-3 SUPPLEMENTATION AN EFFECTIVE TREATMENT OF DEPRESSION?
In our 2006 review , we noted a number of positive intervention studies, supporting the role of fish oil (DHA and/or EPA) both as a beneficial monotherapy and as an adjunct to medication for those with clinical depression. Subsequently, there have been a significant number of studies carried out, investigating the use of assorted omega-3 preparations for various depressive disorders. The results – reflecting the studies themselves – have been variable, with some continuing to show beneficial effects and others demonstrating no advantage of omega-3 supplementation for the treatment of depression (as detailed previously ). A number of researchers have, thus, turned to meta-analyses with the hope that improved statistical power will clarify the outcome.
Three meta-analyses published in 2009–2010 provided qualified support for omega-3 supplementation for clinical depression [66–68]. In 2011, another two meta-analyses were published, reporting divergent conclusions [69▪▪,70▪▪]. Bloch and Hannestad [69▪▪] reported that omega-3 supplementation had no significant benefit for depression compared with placebo, and that any evidence of benefit was abolished after adjustment for publication bias. This study has attracted some criticism [71,72]; however, the authors stand by their general conclusions . In contrast to the findings of Bloch and Hannestad [69▪▪], Sublette et al. [70▪▪] reported a clear benefit of omega-3 supplementation for the amelioration of depressive symptoms; importantly, however, this effect was dependent upon the constituent omega-3 FA administered. As previously indicated by Ross et al. and Martins , the analyses of Sublette et al. identified EPA as the effective omega-3 component in treatment of depression. Sublette et al.[70▪▪] observed that such a finding was ‘in contrast to the greater validity of DHA’ – recognizing that DHA is the major brain omega-3 and has been shown to have a lower concentration in post-mortem studies of the brains of depressed patients. They offered several possible explanations, including EPA directly or indirectly facilitating an increase in brain DHA levels; EPA entering the brain and acting directly as the effector; and EPA having ‘nonbrain effects that cause secondary brain changes’. They further observed that not only did DHA appear ineffective, but it might ‘block beneficial effects of EPA at about a 1 : 1 dose ratio’. The authors added that such findings argue against any further trials of DHA for depression, that ‘the amount of EPA unopposed by DHA may be critical for effective polyunsaturated fatty acid supplementation in depressive episodes’, and that the knowledge base supports omega-3 supplementation in acute depression comprised of at least 60% EPA and with a ‘ceiling at around 2000 mg/day of EPA in excess of DHA’. The authors left open whether unopposed EPA doses should be tested in further trials.
Such interpretations assist consideration of an important study published by Makrides [75▪], reporting a large multicentre placebo-controlled randomized controlled trial (RCT) investigating the impact of DHA supplementation across the latter half of pregnancy on the incidence of postnatal depression. Those authors reported that DHA-rich omega-3 supplementation (800 mg DHA + 100 mg EPA/day) did not reduce the risk of postnatal depression. This finding could be interpreted as a null result and arguing against any omega-3 supplementation as a strategy for preempting postnatal depression. The conclusions from the meta-analysis by Sublette et al.[70▪▪] suggest, however, that we should encourage further perinatal prophylactic studies but with omega-3 preparations having an EPA weighting, and perhaps that such a conclusion should not be limited to perinatal depression studies.
Studies that have been published too recently to have been included in the above meta-analyses include a study by Gertsik et al.[76▪] that EPA-rich omega-3 FA given as an adjunct to citalopram for treatment of major depressive disorder resulted in significantly greater improvement in depressive symptoms compared with citalopram and placebo (paraffin oil). No advantage in terms of onset of antidepressant effect was evident. A number of RCTs have also indicated a beneficial effect of omega-3 supplementation for depressive symptoms in the elderly [77,78,79▪]. Rondanelli et al.[79▪] report that 2.5 g/day of omega-3 FA (including 1670 mg EPA and 830 mg DHA) over 2 months led to significant reductions in depressive symptoms along with improvements in the physical and mental components of the Short-Form 36 – Item Health Survey in a group of depressed/dysthymic elderly female nursing home residents. Sinn et al. performed their study in a group of elderly people with mild cognitive impairment and report that participants administered approximately 2 g of either DHA-rich or EPA-rich omega-3 supplements each day over 6 months demonstrated improvements in depression scores compared with participants receiving approximately 2 g of linoleic acid per day. These results should, however, be interpreted with caution given that linoleic acid is an omega-6 FA that may potentially have deleterious effects on mood; thus, it is not clear whether DHA and EPA were having a beneficial effect or whether linoleic acid was making mood worse. Tajalizadekhoob et al. found that low-dose omega-3 supplementation (180 mg EPA + 120 mg DHA/day) had a small effect in reducing Geriatric Depression Scale scores in a group of elderly participants exhibiting mild-to-moderate depressive symptoms. Giltay et al. found that ALA (2 g/day) and/or EPA–DHA (400 mg/day, EPA : DHA 3 : 2) did not reduce depressive symptoms in patients who had suffered myocardial infarction.
Finally, another recent RCT with encouraging results demonstrated that, in comparison to placebo (comprising a mixture of commonly used plant oils), 12 weeks of EPA-rich omega-3 supplementation (2085 mg EPA + 348 mg DHA) reduced anxiety in a group of healthy young medical students, in association with a reduction in inflammatory markers [18▪].
IS OMEGA-3 SUPPLEMENTATION AN EFFECTIVE TREATMENT FOR BIPOLAR DISORDER?
As we overviewed previously , Stoll et al.  undertook a 4-month double-blind placebo-controlled augmentation trial (as most were receiving a mood stabilizer) of patients with a bipolar condition. Although a difficult study to evaluate, there was the suggestion of some antidepressant benefit but no clear impact on mania or hypomania. Two subsequent RCTs [82,83] reported similar findings, whereas another  found no impact on either depressive or manic symptoms. Considered overall, a recent meta-analysis reports a significant advantage of long-chain omega-3 FA supplementation over placebo for the adjunctive treatment of bipolar depression [85▪] but no benefit of omega-3 on mood elevation in bipolar patients. Of relevance, there has been a single case report of omega-3 FAs inducing switching , as can occur with all antidepressant drugs.
Rees and Parker  recently reported an overview of fish oil for those with a bipolar II disorder, considering the few research studies but concluding that the addition of fish oil to mood-stabilizing medication appeared warranted even although the clinical ‘signal’ was not distinctive.
There is some support – principally from the meta-analysis by Sublette et al.[70▪▪] – for EPA-weighted omega-3 as a treatment (both as a monotherapy and as an augmenter of orthodox antidepressant drugs) for clinical depression; however, optimal dosage remains to be clarified. The more equivocal findings from analyzing studies involving multiple omega-3 preparations may reflect ‘overriding’ an EPA specificity effect, failure to have studied appropriate EPA/DHA constituent ratios, failure to study only those with a low omega-3 status, failure of studies to calibrate individual differences in omega-3 absorption and metabolism, and failure to recognize that relevant FAs may have quite varying therapeutic relevance to differing depressive (e.g. melancholic versus nonmelancholic) conditions, with their varying biological and psychosocial aetiologies.
Although evidence-based support is limited, fish oil has high acceptability to patients, who view it as ‘natural’ and generally failing to invite the antipathy or resistance shown to recommendations to initiate formal antidepressant drugs. Its beneficial effects on cardiovascular disease have led to the recommendation that adults should consume at least 200–500 mg of EPA + DHA/day [42,88] or 1000 mg/day for those with documented cardiovascular disease [42,88], of relevance when the overlap between cardiovascular disease and depression has been widely documented.
As it emerged as highly beneficial in the trial reported by Nemets et al.[89▪] in children and in adolescents and showed a clear benefit in reducing the rate of conversion to schizophrenia in a high-risk group of young people [90▪], it is worthy of closer research and perhaps clinical application in young people in whom brain maturation is still distinctly evolving and in whom the risk of illness onset is at its highest, respecting its neuroprotective propensities. These clinical application recommendations move somewhat beyond the empirical evidence but are supported by the reality that omega-3 has a minimal risk profile. In light of the research evidence, we currently favour an omega-3 preparation that has a higher proportion of EPA to DHA (EPA ≥ 60%), and a dose of 1–2 g EPA + DHA per day.
This study was supported by an NHMRC Program Grant (510135), an Infrastructure Grant from NSW Health and a grant from the Australian Federal Government, Department of Health and Aging.
We thank Amelia Paterson for assistance in article preparation.
Conflicts of interest
Both G.P. and B.H. have received fish oil capsules at no cost from manufacturers to undertake evaluative research studies.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 126–127).
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Important study demonstrating a functional relationship between omega-3 FA deficiency, alterations in immune functioning and serotonin metabolism in rats.
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Interesting study providing evidence as to how dietary deficiency during development can impact upon stress responsivity.
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Interesting study providing evidence as to how diet and stress during early development can impact upon behaviour in later life.
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Fascinating insights into mechanisms underlying the detrimental effects of omega-3 deficiency.
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Key study linking omega-3 FA, BDNF expression and serotonin signalling in rat brain.
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A study that broadens consideration of dietary impacts on mood disorders.
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Provides insights into factors affecting omega-3 status and its relationship to cardiovascular health.
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59▪. Lewis MD, Hibbeln JR, Johnson JE, et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status. J Clin Psychiatry 2011; 72:1585–1590.
Important study demonstrating a link between low omega-3 fatty acid status and increased risk of suicide in the military.
60▪. Baghai TC, Varallo-Bedarida G, Born C, et al. Major depressive disorder is associated with cardiovascular risk factors and low omega-3 index. J Clin Psychiatry 2011; 72:1242–1247.
Study demonstrating association between depression, low omega-3 status and cardiovascular risk factors.
61. Jiang W, Oken H, Fiuzat M, et al. Plasma omega-3 polyunsaturated fatty acids and survival in patients with chronic heart failure and major depressive disorder. J Cardiovasc Transl Res 2012; 5:92–99.
62. Maes M, Ruckoanich P, Chang YS, et al. Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:769–783.
63. McNamara RK. DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders. J Nutr 2010; 140:864–868.
64▪. McNamara RK, Liu Y. Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder. J Affect Disord 2011; 129:359–363.
Another in a series of studies by this group investigating abnormalities in brain omega-3 FA in people with mood disorders.
65. Hamazaki K, Hamazaki T, Inadera H. Fatty acid composition in the postmortem amygdala of patients with schizophrenia, bipolar disorder, and major depressive disorder. J Psychiatr Res 2012; 46:1024–1028.
66. Kraguljac NV, Montori VM, Pavuluri M, et al. Efficacy of omega-3 fatty acids in mood disorders-a systematic review and metaanalysis. Psychopharmacol Bull 2009; 42:39.
67. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 2009; 28:525–542.
68. Appleton KM, Rogers PJ, Ness AR. Updated systematic review and meta-analysis of the effects of n − 3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010; 91:757–770.
69▪▪. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol Psychiatry 2011. doi: 10.1038/mp.2011.100. [Epub ahead of print]
Meta-analysis concluding that omega-3 supplementation is not of benefit for depressive disorders.
70▪▪. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011; 72:1577–1584.
A key study which is likely to shape future intervention studies due to its findings indicating that DHA-weighted preparations may be ineffective, whereas EPA-rich preparations generate a distinct antidepressant effect.
71. Martins JG, Bentsen H, Puri BK. Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: a critique of Bloch and Hannestad and updated meta-analysis. Mol Psychiatry 2012. doi:10.1038/mp.2012.25. [Epub ahead of print]
72. Lin P-Y, Mischoulon D, Freeman MP, et al.
Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. Mol Psychiatry 2012. doi:10.1038/mp.2012.111. [Epub ahead of print]
73. Bloch MH, Hannestad J. Response to critiques on ‘Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis’. Mol Psychiatry 2012. doi:10.1038/mp.2012.116. [Epub ahead of print]
74. Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis 2007; 6:21.
75▪. Makrides M. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. JAMA 2010; 304:1675.
Important large-scale study showing no benefit of DHA supplementation throughout pregnancy for postnatal depression.
76▪. Gertsik L, Poland RE, Bresee C, Rapaport MH. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012; 32:61–64.
Important study demonstrating the benefit of omega-3 as an adjunct to formal antidepressants.
77. Tajalizadekhoob Y, Sharifi F, Fakhrzadeh H, et al. The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: a double-blind, randomized, placebo-controlled study. Eur Arch Psychiatry Clin Neurosci 2011; 261:539–549.
78. Sinn N, Milte CM, Street SJ, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr 2011; 107:1682–1693.
79▪. Rondanelli M, Giacosa A, Opizzi A, et al. Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly depression: effects on depressive symptoms, on phospholipids fatty acids profile and on health-related quality of life. J Nutr Health Aging 2011; 15:37–44.
An RCT showing a clear benefit of omega-3 for both depressive symptoms and some aspects of quality of life in elderly patients.
80. Giltay EJ, Geleijnse JM, Kromhout D. Effects of n-3 fatty acids on depressive symptoms and dispositional optimism after myocardial infarction. Am J Clin Nutr 2011; 94:1442–1450.
81. Stoll AL, Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999; 56:407–412.
82. Chiu C-C, Huang S-Y, Chen C-C, Su K-P. Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry 2005; 66:1613–1614.
83. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 2006; 188:46–50.
84. Keck PE Jr, Mintz J, McElroy SL, et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 2006; 60:1020–1022.
85▪. Sarris J, Mischoulon D, Schweitzer I. Omega-3 for bipolar disorder. J Clin Psychiatry 2011; 73:81–86.
A meta-analysis demonstrating benefit of omega-3 supplementation for bipolar depression but having no significant effect on mania.
86. Kinrys G. Hypomania associated with omega3 fatty acids. Arch Gen Psychiatry 2000; 57:715–716.
87. Rees A-M, Parker G. Parker G. The role of fish oil in managing bipolar II disorder. Bipolar II Disorder. Modelling, Measuring and Managing 2nd ed.Cambridge:Cambridge University Press; 2012. 133–144.
88. Heart Foundation of Australia (2008). Fish, fish oils, n-3 polyunsaturated fatty acids and cardiovascular health. Position Statement. Downloaded from http://www.heartfoundation.org.au
89▪. Nemets H, Nemets B, Apter A, et al. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry 2006; 163:1098–1100.
An intriguing study in that the separation between fish oil and placebo was more distinctive than for any placebo-controlled trial of a formal antidepressant.
90▪. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2010; 67:146–154.
The differentiation between omega-3 and placebo was higher than in equivalent placebo-controlled studies of antipsychotic drugs. It invites replication studies. If replicated with such a level of differentiation as quantified here, this will be one of the major psychiatric therapeutic stories of the last decade.