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Research -> Mental Neurological Health

Depression and Mood Disorders

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• Reviews the importance of omega-3 fats in various mental health conditions

MP Freeman. Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry 2000;12(3):159-165

Omega-3 fatty acids are long-chain, polyunsaturated fatty acids found in plant and marine sources. Unlike saturated fats, which have been shown to have negative health consequences, omega-3 fatty acids are polyunsaturated fatty acids that have been associated with many health benefits.

Omega-3 fatty acids may prove to be efficacious in a number of psychiatric disorders.

Mood disorders have been associated with abnormalities in fatty acid composition. Several lines of evidence suggest that diminished omega-3 fatty acid concentrations are associated with mood disorders.

Clinical data are not yet available regarding omega-3 fatty acids in the treatment of major depression. However, one double-blind treatment trial has been conducted in bipolar disorder. Also, substantial evidence does exist supporting a potential role of omega-3 fatty acids in schizophrenia, although treatment data are needed.

A case has been reported in which a patient with schizophrenia was successfully treated with omega-3 fatty acids. Controlled studies are necessary to explore the potential treatment of schizophrenia with omega-3 fatty acids. Omega-3 fatty acids may also be helpful in the treatment of dementia.

Furthermore, omega-3 fatty acids may prove to be a safe and efficacious treatment for psychiatric disorders in pregnancy and in breastfeeding.

• Depressed seniors have lower levels of omega-3s

Tiemeier H, van Tuijl HR, et al. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study. Am J Clinical Nutrition,2003;78(1): 40-46

Background: It has been hypothesized that n-3 polyunsaturated fatty acids (PUFAs) are involved in mood regulation, but epidemiologic evidence for such a link in the general population is lacking.

Objective: This study examined whether community-dwelling elderly persons with depression have a fatty acid composition that is different from that of nondepressed persons.

Design: We screened 3884 adults aged = 60 y for depressive symptoms as part of the Rotterdam Study. Subjects who screened positive had a psychiatric interview to diagnose depressive disorders. All eligible subjects had their blood drawn for measurement of plasma phospholipid concentrations.

We compared percentages of n-3 and n-6 PUFAs and their ratios between 264 subjects with depressive symptoms, including 106 subjects with depressive disorders, and 461 randomly selected reference subjects.

We also investigated whether atherosclerosis or the inflammatory response as measured by C-reactive protein underlies the relation between fatty acid composition and depression.

Results: Subjects with depressive disorders had a higher ratio of n-6 to n-3 PUFAs, but differences in individual PUFAs were mostly small.

However, depressed subjects with normal CRP concentrations (< 1.5 mg/L) had a substantially altered fatty acid composition; percentages of n-3 PUFAs and ratios of n-6 to n-3 PUFAs were significantly lower and higher, respectively, in subjects with depressive disorders than in control subjects [5.2% compared with 5.9% (P = 0.02) and 7.2 compared with 6.6 (P = 0.01), respectively]. This relation was not due to atherosclerosis.

Conclusions: In community-dwelling persons, fatty acid composition is related to depression. Because this relation was not secondary to inflammation, atherosclerosis, or possible confounders, it suggests a direct effect of fatty acid composition on mood.

• Low vitamin D levels associated with lower mood and worse cognitive performance in seniors

Wilkins CH, Sheline YI, et al. Vitamin D Deficiency Is Associated With Low Mood and Worse Cognitive Performance in Older Adults. Am J Geriatr Psychiatry,2006;14:1032-1040.

Background: Vitamin D deficiency is common in older adults and has been implicated in psychiatric and neurologic disorders. This study examined the relationship among vitamin D status, cognitive performance, mood, and physical performance in older adults.

Methods: A cross-sectional group of 80 participants, 40 with mild Alzheimer disease (AD) and 40 nondemented persons, were selected from a longitudinal study of memory and aging. Cognitive function was assessed using the Short Blessed Test (SBT), Mini-Mental State Exam (MMSE), Clinical Dementia Rating (CDR; a higher Sum of Boxes score indicates greater dementia severity), and a factor score from a neuropsychometric battery; mood was assessed using clinician's diagnosis and the depression symptoms inventory. The Physical Performance Test (PPT) was used to measure functional status. Serum 25-hydroxyvitamin D levels were measured for all participants.

Results: The mean vitamin D level in the total sample was 18.58 ng/mL (standard deviation: 7.59); 58% of the participants had abnormally low vitamin D levels defined as less than 20 ng/mL.

After adjusting for age, race, gender, and season of vitamin D determination, vitamin D deficiency was associated with presence of an active mood disorder (odds ratio: 11.69, 95% confidence interval: 2.04-66.86; Wald 2 = 7.66, df = 2, p = 0.022).

Using the same covariates in a linear regression model, vitamin D deficiency was associated with worse performance on the SBT (F = 5.22, df = [2, 77], p = 0.044) and higher CDR Sum of Box scores (F = 3.20, df = [2, 77], p = 0.047) in the vitamin D-deficient group. There was no difference in performance on the MMSE, PPT, or factor scores between the vitamin D groups.

Conclusions: In a cross-section of older adults, vitamin D deficiency was associated with low mood and with impairment on two of four measures of cognitive performance.

• Extensive review on need and benefit of EPA & DHA for mood disorders

Parker G, Gibson N, Brotchie H, et al. Omega-3 Fatty Acids and Mood Disorders. Am J Psychiatry, 2006;163:969-978.

OBJECTIVE: This article is an overview of epidemiological and treatment studies suggesting that deficits in dietary-based omega-3 polyunsaturated fatty acids may make an etiological contribution to mood disorders and that supplementation with omega-3 fatty acids may provide a therapeutic strategy.

METHOD: Relevant published studies are detailed and considered.

RESULTS: Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression.

CONCLUSIONS: Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach. This review identifies a number of hypotheses and studies for consideration.

In particular, the authors argue for studies clarifying the efficacy of omega-3 supplementation for unipolar and bipolar depressive disorders, both as individual and augmentation treatment strategies, and for studies pursuing which omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is likely to provide the greatest benefit.

• Study shows children with depression benefit from omega-3 supplementation

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.

OBJECTIVE: Major depressive disorder in children may be more common than previously thought, and its therapeutics are unclear. Because of success in a previous study on omega-3 fatty acids in adult major depressive disorder, the authors planned a pilot study of omega-3 fatty acids in childhood major depression.

METHOD: Children who entered the study were between the ages of 6 and 12. Ratings were performed at baseline and at 2, 4, 8, 12, and 16 weeks using Children's Depression Rating Scale (CDRS), Children's Depression Inventory (CDI), and Clinical Global Impression (CGI). Children were randomized to omega-3 fatty acids or placebo as pharmacologic monotherapy. Twenty-eight patients were randomized, and 20 completed at least 1 month's ratings.

RESULTS: Analysis of variance showed highly significant effects of omega-3 on symptoms using the CDRS, CDI, and CGI.

CONCLUSIONS: Omega-3 fatty acids may have therapeutic benefits in childhood depression.

• Low Omega-3 levels and suicide risk

Sublette M, Hibbeln J, Galfalvy H, et al. Omega-3 Polyunsaturated Essential Fatty Acid Status as a Predictor of Future Suicide Risk. Am J Psychiatry, 2006;163:1100-1102.

OBJECTIVE: Low levels of docosahexaenoic acid, a polyunsaturated fatty acid, and elevated ratios of omega-6/omega-3 fatty acids are associated with major depression and, possibly, suicidal behavior. Predicting risk of future suicidal behaviors by essential fatty acid status merits examination.

METHOD: Plasma polyunsaturated fatty acid levels in phospholipids were measured in 33 medication-free depressed subjects monitored for suicide attempt over a 2-year period. Survival analysis examined the association of plasma polyunsaturated fatty acid status and pathological outcome.

RESULTS: Seven subjects attempted suicide on follow-up. A lower docosahexaenoic acid percentage of total plasma polyunsaturated fatty acids and a higher omega-6/omega-3 ratio predicted suicide attempt.

CONCLUSIONS: A low docosahexaenoic acid percentage and low omega-3 proportions of lipid profile predicted risk of suicidal behavior among depressed patients over the 2-year period. If confirmed, this finding would have implications for the neurobiology of suicide and reduction of suicide risk.

• Low DHA levels measured in the brain, postmortem, in adults with depression; greater deficits in women

McNamara RK, Hahn CG, Jandacek R, et al. Selective Deficits in the Omega-3 Fatty Acid Docosahexaenoic Acid in the Postmortem Orbitofrontal Cortex of Patients with Major Depressive Disorder. Biol Psychiatry.2006; Epub ahead of print]

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls.

METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography.

RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables.

CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

PMID: 17188654

• Contribution by Dr. Lauren M. Bramley

Wake up to Omega-3
Dr. Lauren M. Bramley
Reprinted with permission

It is not news that most Americans eat too much fat and need to reduce their intake of saturated and trans fats, but there is at least one kind of fat that consumers do not generally get enough of - omega-3 fatty acids.

Dr. Lauren Bramley offers a professional insight into the wide range of health benefits that these good fats, found in oily fish, certain nuts, seeds and oils, can provide.

Most people are now aware of the benefits of omega-3 fatty acids in terms of heart disease and stroke. These fatty acids are essential for warding off heart attacks and stroke in that they lower LDL or bad cholesterol levels, thin the blood, lower blood pressure and stabilise heart rhythms.

The connection between omega-3 fatty acids and heart disease is most evident amongst the Eskimo and Japanese populations who have the highest fish intake in the world, in particular, deep, cold water fish. What most people are unaware of are the benefits of omega-3 for a whole range of other diseases, both physical and behavioural.

Omega-3 fatty acids were once known as ?Vitamin F? and are essential to health. Omega-6 fatty acids are also essential but are much more common, being found in animal fats, most cooking oils, margarine and soy.

What is critical to optimal functioning is the ratio of omega-3 to omega-6. Historically, omega-3 has been much more prevalent in the diet. Being found in algae, it was abundant up the food chain that fed on algae and in the animals and crops raised near the sea.

Since domestication and the altered diets of livestock, the quantity of omega-3 found naturally in the diet has reduced approximately 30 fold over the past 200 years. Consequently, the ratio of omega-3 to omega-6 fatty acids has shifted from the optimal 1:4 to as low as 1:20 in the typical American diet.

This shift is thought by many researchers to have contributed to the epidemic of heart disease, obesity, diabetes and insulin resistance, depression and anxiety as well as ADD, poor vision, osteoporosis, asthma, infertility and skin cancer.

Given that these essential fats are the precursors to hormones, a suboptimal amount will contribute to lower levels of thyroid hormone, sex hormones, insulin and serotonin. This results in a slower metabolism, weight gain and decreased well being and mood.

How does one restore the ratio to improve mood and well being, concentration and metabolism?

Change your oil. Just like a car, oil needs to be changed. Shift the ratio of omega-3 to omega-6 in your body back to the optimal 1:4 ratio. The brain is likely to function best at a 1:1 ratio instead of the 1:8 ratio seen today.

Firstly, increase your dietary intake by eating more fish, egg yolks, flax seed, nuts and canola oil. This will ensure that your cell membranes become more fluid, hormone levels are adequate, insulin works correctly to allow sugar to be used as fuel instead of stored as fat, serotonin levels stay up to keep you happy and calm, and the oil that insulates your skin doesn't sizzle in the sun and contribute to skin cancer.
As a powerful anti-inflammatory, omega-3 ensures that vessels are kept smooth and less likely to clog, that bones are kept dense and therefore less likely to break, and that the brain is insulated properly, making it easier to concentrate and learn.

Secondly, decrease omega-6 fatty acid intake. Unless you are a strict vegan, most of us are consuming too much of it. Throw out your corn oil, safflower oil, sunflower oil and margarine (except canola oil margarine which is high in omega-3). Switch to canola oil, olive oil and butter.
Be very aware of store bought baked goods and processed foods which have a very high content of the omega-6 oils which are often hydrogenated (trans fat) making them even worse.

Lastly consider a supplement. Unfortunately, eating enough omega-3 can be very difficult, especially for those who don't eat a lot of fish or are vegetarian.

Some people may be depleted of omega-3 especially during and after pregnancy when the developing foetus uses up the mother's omega-3 supply and afterwards it is used to make breast milk. Interestingly, some research explains post partum depression as mainly an omega-3 depleted state and some of the most convincing studies for mood and omega-3 have been seen in post partum depression.

In Australia, omega-3 is now put in some prenatal vitamins for its ability to improve foetal brain development and the IQ of the child, as well as to ward off post partum depression and improve weight loss after childbirth.

In Europe, and more recently in Canada and the US, omega-3 fatty acids are now often put in baby formula. To help treat conditions which may have already developed such as diabetes, heart disease, obesity and depression or simply to boost mood and well being, consider a supplement of omega-3.

Interestingly, omega-3 supplementation has also been shown to markedly reduce the withdrawal symptoms of coming off SSRI antidepressants such as electric shocks, headaches and agitation. Some antidepressants currently being developed will contain omega-3, thus making them more effective and making it easier to stop them when the time is right.

Unless you are a strict vegan it is not necessary to supplement with omega-6 or omega-9, so avoid the Omega 3-6-9 supplement. Most omega-3 supplements also contain GLA (which is the least inflammatory of the omega-6s, also known as evening primrose oil), but they should not contain other omega-6s.

Most supplements will list EPA, DHA and GLA in the ingredients. In pregnancy, however, GLA/evening primrose is not recommended.

It is also advised to stop intake of omega-3 two weeks before and after surgery to lower the risk of bleeding due to its blood thinning properties. People on blood thinners (not including aspirin) are advised not to take omega-3.

Make sure your supplement has been tested for mercury and PCBs. Some brands are far less likely to cause a fish aftertaste than others, as this often signifies the freshness of the oil. Doses and ratios of the fatty acids vary depending on the condition.

Take it earlier in the day as omega-3 can be so energising it keeps some people awake. More randomised controlled trials are needed before claims for omega-3 can be undisputed. In my practice I have seen dramatic improvements in depression and overall mood through using high dose EPA and DHA.

I have also seen dramatic improvements in pre-diabetes and insulin resistance and weight loss using omega-3 and GLA, and I have seen acne and psoriasis improve greatly.

I have also heard from parents that their child's concentration, immunity and happiness improved with a better diet and/or omega-3 supplementation. I have seen far less post-natal depression since we started recommending DHA in pregnancy. I have watched patients avoid needing an antidepressant medication or finding it easier to come off one with omega-3.

Try it and you just may feel it in your hair, skin, physique and outlook. No one thing can be a cure-all but if it can help and do no harm it is worth a try.

Resources: The Omega 3 Connection The groundbreaking antidepression diet and brain program. Andrew L. Stoll, M.D. Simon and Schuster. 2002 ISBN 0684871394 http://www.nordicnaturals.com/
All the latest omega research news: http://www.omega-research.com/

• Study shows benefit from fish oil in people with depression

Su K, Huang S, Chiu C, et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13(4):267-271.

Patients with depression have been extensively reported to be associated with the abnormality of omega-3 polyunsaturated fatty acids (PUFAs), including significantly low eicosapentaenoic acid and docosahexaenoic acid in cell tissue contents (red blood cell membrane, plasma, etc.) and dietary intake. However, more evidence is needed to support its relation.

In this study, we conducted an 8-week, double-blind, placebo-controlled trial, comparing omega-3 PUFAs (6.6 g/day) [corrected] with placebo, on the top of the usual treatment, in 28 patients with major depressive disorder.

Patients in the omega-3 PUFA group had a significantly decreased score on the 21-item Hamilton Rating Scale for Depression than those in the placebo group (P < 0.001).

From the preliminary findings in this study, omega-3 PUFAs could improve the short-term course of illness and were well tolerated in patients with major depressive disorder.

Erratum in Eur Neuropsychopharmacol. 2004 Mar;14(2):173

PMID: 12888186

• Less risk for depression found in women who regularly eat fish

Timonen M, Horrobin D, et al. Fish consumption and depression: the Northern Finland 1966 birth cohort study. J Affect Disord, 2004;82(3):447-452

BACKGROUND: Since low fish consumption and omega-3 fatty acids have recently been linked with depression, we investigated by means of a large, general population database, whether a low fish consumption is associated with increased risk of developing depression.

METHODS: The Northern Finland 1966 Birth Cohort was followed up prospectively from pregnancy up to the age of 31 years. The data on HSCL-25 depression subscale, doctor-diagnosed life-time depression and fish consumption (during the previous 6 months) of cohort members were obtained by postal questionnaires at the age of 31. The final number of cohort members, whose completed variable information was available in multivariate logistic analyses, was 2721 males and 2968 females.

RESULTS: After adjusting for body mass index, serum total cholesterol level and socioeconomic situation, logistic regression analyses showed that among females the risk of developing depression increased up to 2.6-fold (95%CI 1.4-5.1) among rare fish eaters when compared with regular eaters. In males, there were no significant differences between rare and regular fish eaters for any of the estimates of depression.

LIMITATIONS: The data on life-time fish consumption of cohort members were not available.

CONCLUSIONS: A low frequency of fish consumption was statistically significantly associated with depression in women, but not in men. Possible background-theories behind the gender difference are discussed.

• Regular intake of cod liver oil associated with few symptoms of depression

Raeder MB, Steen VM, Vollset SE, Bjelland I. Associations between cod liver oil use and symptoms of depression: The Hordaland Health Study. J Affect Disord. 2006; [Epub ahead of print]

BACKGROUND: Clinical trials suggest that omega-3 fatty acids improve the outcome of depression.

This study aimed to evaluate the association between intake of cod liver oil, rich in omega-3 fatty acids, and high levels of symptoms of depression and anxiety in the general population.

METHODS: We used data from the "The Hordaland Health Study '97-'99" (HUSK), a population based cross-sectional health survey from Norway including 21,835 subjects aged 40-49 and 70-74 years. Symptoms of depression and anxiety were measured by The Hospital Anxiety and Depression Scale (HADS). We used logistic regression to study associations.

RESULTS: Among the participants, 8.9% used cod liver oil daily. A total of 3.6% had high levels of depressive symptoms. The prevalence of such depressive symptoms among the subjects who used cod liver oil daily was 2.5%, as compared to 3.8% in the rest of the population.

The users of cod liver oil were significantly less likely to have depressive symptoms than non-users after adjusting for multiple possible confounding factors (odds ratio=0.71, 95% confidence interval 0.52 to 0.97). These factors included age, gender, smoking habits, coffee consumption, alcohol consumption, physical activity, and education.

In addition, we found that the prevalence of high levels of depressive symptoms decreased with increasing duration (0-12 months) of cod liver oil use (multivariate adjusted test for trend, P=0.04). We were only able to study this latter association in a subset of the population aged 40-46 years.

LIMITATIONS: Data are cross sectional.

CONCLUSIONS: The findings indicate that regular use of cod liver oil is negatively associated with high levels of depressive symptoms in the general population.

• Study shows that depressed individuals have lower levels of omega-3s

Maes M, Smith R, et al. Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids.
J Affect Disord, 1996;38(1):35-46

Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and omega 3 essential fatty acid levels and by an increased C20: 4 omega 6/C20: 5 omega 3, i.e., arachidonic acid/eicosapentaenoic, ratio.

The present study aimed to examine fatty acid composition of serum cholesteryl esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects.

Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2, C20:4) fatty acids in phospholipid and cholesteryl ester fractions were assayed and the sums of the percentages of omega 6 and omega 3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios omega 6/omega 3 and C20:4 omega 6/C20:5 omega 3 were calculated.

Major depressed subjects had significantly higher C20:4 omega 6/C20:5 omega 3 ratio in both serum cholesteryl esters and phospholipids and a significantly increased omega 6/omega 3 ratio in cholesteryl ester fraction than healthy volunteers and minor depressed subjects.

Major depressed subjects had significantly lower C18:3 omega 3 in cholesteryl esters than normal controls.

Major depressed subjects showed significantly lower total omega 3 polyunsaturated fatty acids in cholesteryl esters and significantly lower C20:5 omega 3 in serum cholesteryl esters and phospholipids than minor depressed subjects and healthy controls.

These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of cholesteryl esters in major depression.

• Study shows, low DHA levels and low seafood consumption is associated with postpartum depression

Hibbeln JR. Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord,2002;69(1-3):15-29

BACKGROUND: Mothers selectively transfer docosahexaenoic acid (DHA) to their fetuses to support optimal neurological development during pregnancy.
Without sufficient dietary intake, mothers become depleted of DHA and may increase their risk of suffering major depressive symptoms in the postpartum period. We postulated that the DHA content of mothers' milk and seafood consumption would both predict prevalence rates of postpartum depression across countries.

METHODS: Published prevalence data for postpartum depression were included that used the Edinburgh Postpartum Depression Scale (n=14532 subjects in 41 studies). These data were compared to the DHA, eicosapentaenoic acid (EPA) and arachidonic acid (AA) content in mothers' milk and to seafood consumption rates in published reports from 23 countries.

RESULTS: Higher concentrations of DHA in mothers' milk (r=-0.84, p<0.0001, n=16 countries) and greater seafood consumption (r=-0.81, p<0.0001, n=22 countries) both predicted lower prevalence rates of postpartum depression in simple and logarithmic models, respectively. The AA and EPA content of mothers' milk were unrelated to postpartum depression prevalence.

LIMITATIONS: These findings do not prove that higher omega-3 status cause lower prevalence rates of postpartum depression. Data on potentially confounding factors were not uniformly available for all countries.

CONCLUSIONS: Both lower DHA content in mothers' milk and lower seafood consumption were associated with higher rates of postpartum depression.

These results do not appear to be an artifact of cross-national differences in well-established risk factors for postpartum depression. Interventional studies are needed to determine if omega-3 fatty acids can reduce major postpartum depressive symptoms.

• Omega-3 Subcommittee recommendations for use of EPA and DHA in psychiatric disorders

Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 Fatty Acids: Evidence Basis for Treatment and Future Research in Psychiatry. J Clin Psychiatry, 2006;67(12):1954-1967.

Omega-3 Fatty Acid Subcommittee Recommendations*

+All adults should eat fish at least or more than 2 times per week

+Patients with mood, impulse-control, or psychotic disorders should consume 1 g EPA + DHA per day

+A supplement may be useful in patients with mood disorders (1-9 g per day). Use of > 3 g per day should be monitored by physician.

*Adapted from the American Heart Association recommendations to provide guidelines on omega-3 fatty acid use in the context of treating psychiatric disorders.

Abbreviations: DHA = docosahexaenoic acid, EPA = eicosapentaenoic acid

Note: The Omega-3 Fatty Acids Subcommittee was assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA).

• Summary of evidence for use and treatment of EPA and DHA for mental health

Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 Fatty Acids: Evidence Basis for Treatment and Future Research in Psychiatry. J Clin Psychiatry, 2006;67(12):1954-1967.

Objective: To determine if the available data support the use of omega-3 essential fatty acids (EFA) for clinical use in the prevention and/or treatment of psychiatric disorders.

Participants: The authors of this article were invited participants in the Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association (APA).

Evidence: Published literature and data presented at scientific meetings were reviewed. Specific disorders reviewed included major depressive disorder, bipolar disorder, schizophrenia, dementia, borderline personality disorder and impulsivity, and attention -deficit/hyperactivity disorder. Meta-analyses were conducted on major depressive disorder and bipolar disorders and schizophrenia, as sufficient data were available to conduct such analysis in these areas of interest.

Consensus process: The subcommittee prepared the manuscript, which was reviewed and approved by the following APA committees: the Committee on Research and Psychiatric Treatments, the Council on Research, and the Joint Reference Committee.

Conclusions: The preponderance of epidemiological and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in mood disorders. Meta-analysis of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p =.02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry. Treatment recommendations and directions for future research are described. Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications.

• Branded fish oil blend shown to significantly reduce anxiety scores in adults with history of substance abuse

Buydens-Branchey L, Branchey M. n-3 Polyunsaturated Fatty Acids Decrease Anxiety Feelings in a Population of Substance Abusers. J Clin Psychopharmacol,2006;26(6):661-665.

There is mounting evidence that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of a number of psychiatric disorders.

Preclinical studies have shown that n-3 PUFAs decrease anxietylike behaviors, but there is a paucity of information about their effects on anxiety in humans. In light of our observation that substance abusers have poor dietary habits and the strong association between anxiety disorders and substance use disorders, the possibility that the administration of supplements of n-3 PUFAs would decrease the anxiety level of a group of substance abusers was explored.

Thirteen patients were given on a daily basis capsules containing 3 g of n-3 PUFAS (eicosapentaenoic acid + docosahexaenoic acid). Eleven patients received similarly looking placebo capsules containing vegetable oil.

The trial was double-blind, randomized, and lasted 3 months. A scale assessing anxiety feelings was administered at baseline and on a monthly basis thereafter. Six PUFA group patients and 8 placebo group patients were followed for an additional 3 months after treatment discontinuation and administered the same questionnaire monthly.

Patients who received n-3 PUFAs for 3 months showed a progressive decline in anxiety scores. This was not the case for patients who received placebos. A comparison of the 2 groups was significant (P = 0.010). Anxiety scores remained significantly decreased in the PUFA group for 3 months after treatment discontinuation. A comparison of the 2 groups followed for 6 months was also significant (P = 0.042).

In conclusion, these preliminary data indicate that n-3 PUFA supplementation could be beneficial in the treatment of some patients with anxiety disorders.

• Jean Carper on 5 Ways Fish Oil Manages the Brain

Fights Depression:
Skimping on fish may depress you. Norman Salem Jr., a researcher at the National Institutes of Health, notes that populations consuming large amounts of fish have low rates of major depression. A lack of fish oil is linked to depression in alcoholics, people with multiple sclerosis and women with postpartum depression. Further, he says, some dieters who reduce overall fat, including fish fat, tend to get depressed.

A recent Australian study of 21 depressed patients confirmed that the most severely depressed had imbalances of fatty acids in their blood and cell membranes. Evidence suggests DHA-type fish oil helps regulate serotonin, a neurotransmitter known for its "feel-good" qualities. Depressed people often have low levels of serotonin.

Reduces Aggression:
You are less likely to express stress-induced aggression if your brain is under the influence of fish oil, according to Japanese researchers. In a new double-blind test of 41 adult students, those taking 1.5 to 1.8 daily grams of DHA fish oil for three months did not become more socially aggressive at a time of severe mental stress: final exams. In contrast, students taking a dummy look-alike capsule showed significant jumps in social aggression, as measured by psychological tests. This effect on stress may help explain how fish oil prevents heart disease. Stress hormones triggered by hostility and anger can constrict arteries and accelerate the formation of blockages, research shows; fish oil may suppress the release of those hormones.

Stimulates young minds:
Fetuses and infants must get sufficient omega-3 oils for optimal brain development, says William Connor, Oregon Health Sciences University. In one telling study of premature infants, those fed breast milk had 8 points higher IQ at age 8 than those fed standard infant formula. Connor credits breast milk's higher amounts of DHA for that superior intelligence. In infant rhesus monkeys deprived of omega-3-type oils, Connor found severely impaired visual acuity and behavior indicative of a neurological defect. Autopsies revealed abnormalities in brain cells. Connor advises pregnant women to eat fish a couple of times a week, especially during the last trimester, the time of greatest fetal brain growth. And breast-feeding is preferable to infant formula, he says.

Blunts Brain Damage?
Fish oil may eventually be proved to lessen alcohol-induced brain damage, Salem says. He explains that excessive alcohol depletes brain levels of omega-3's -- DHA in particular -- which leads to neurological damage and impaired vision. He put experimental animals on high-alcohol, low omega-3 diets for six months to three years. They suffered severe losses of DHA in brain cells and detrimental changes in brain functioning. Some scientists speculate that fish oil also may have a protective role in degenerative brain diseases leading to memory loss and dementia. The brains of deceased Alzheimer's sufferers, for example, show low levels of omega-3 fats.

Influences Behavior:
Children deficient in omega-3 oils may be more likely to have behavioral and learning problems known as attention deficit hyperactivity disorder or ADHD, according to new research at Purdue University. John R. Burgess, assistant professor of foods and nutrition, tested the omega-3 blood levels of 96 boys, ages 6-12; about half had been identified as having ADHD. Clearly, Burgess says, "boys with lower levels of the omega-3 fat scored higher in frequency of behavioral problems," such as hyperactivity, impulsivity, anxiety, temper tantrums and sleep problems.

The big question:
Does taking more omega-3 and other appropriate fats cure the deficiency and improve ADHD behavior? That's what Burgess is trying to find out in a follow-up study. He cautions that only 40 percent of kids with ADHD in his study had low omega-3, so obviously it wouldn't work in most cases. Burgess also says it's unclear how much of what type of oils each individual child may need. Whatever you do, he advises working with health professionals and not stopping other treatments or medications for ADHD without proper medical advice.

Smart tips:
Restrict omega-6 oils (corn oil, regular safflower and sunflower seed oils, and most margarines), which tend to negate the benefits of omega-3. Recommended: canola and olive oils.

WARNING:
Pregnant women should avoid freshwater sports fish, which may be contaminated with environmental chemicals. One of the safest and best for everybody: sardines.

Jean Carper's current best-selling book is Stop Aging Now!

Source: http://www.usaweekend.com/food/carper_archive/961117carper_eatsmart.html

• Changes of omega-3 levels, within one generation, significantly impacts depression and aggression, shown in rats

DeMar, JC, Ma K, Bell JM, et al. One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J of Lipid Research, 2006;47:172-180.

Male rat pups at weaning (21 days of age) were subjected to a diet deficient or adequate in n-3 polyunsaturated fatty acids (n-3 PUFAs) for 15 weeks.

Performance on tests of locomotor activity, depression, and aggression was measured in that order during the ensuing 3 weeks, after which brain lipid composition was determined.

In the n-3 PUFA-deprived rats, compared with n-3 PUFA-adequate rats, docosahexaenoic acid (22:6n-3) in brain phospholipid was reduced by 36% and docosapentaenoic acid (22:5n-6) was elevated by 90%, whereas brain phospholipid concentrations were unchanged.

N-3 PUFA-deprived rats had a significantly increased (P = 0.03) score on the Porsolt forced-swim test for depression, and increased blocking time (P = 0.03) and blocking number (P = 0.04) scores (uncorrected for multiple comparisons) on the isolation-induced resident-intruder test for aggression.

Large effect sizes (d > 0.8) were found on the depression score and on the blocking time score of the aggression test. Scores on the open-field test for locomotor activity did not differ significantly between groups, and had only small to medium effect sizes.

This single-generational n-3 PUFA-deprived rat model, which demonstrated significant changes in brain lipid composition and in test scores for depression and aggression, may be useful for elucidating the contribution of disturbed brain PUFA metabolism to human depression, aggression, and bipolar disorder.

• Higher brain levels of arachidonic acid, an omega-6 fat, seen in depression

Green P, Gispan-Herman I, Yadid G. Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression. Journal of Lipid Res, 2005; 46:1093 -1096.

Depression may be associated with impaired membrane PUFA composition, especially decreased n-3 PUFA.
This assumption has not been tested at the level of brain tissue. Moreover, most studies were confounded by dietary variability.

We examined the FA composition of selected brain areas in an animal model of depression, the Flinders Sensitive Line (FSL) rat, and compared the findings with those in controls fed identical diets.

In all brain regions studied, the concentration of arachidonic acid (AA) was significantly higher in the FSL rats: in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. No significant differences were observed for n-3 PUFA or for the saturated and monounsaturated FAs.

Our results confirm the existence of altered brain PUFA composition in an animal model of depression.

The finding of increased AA, an n-6 PUFA, rather than decreased n-3 PUFA, emphasizes the importance of both PUFA families in the pathophysiological processes underlying depression.

The FSL rat is a useful tool for further elucidation of the FA disturbances in depression.

• News - Heart-healthy omega-3s may also be good for your brain

Some Fish Fats Protect the Heart. What If They Could Also Treat Your Brain?
BY SALLY SQUIRES
Washington Post Service

They occur naturally in fish, flaxseed, canola oil, nuts and avocados and are sold in dozens of dietary supplements. Increasingly, they are added to bread, dairy products, margarine, baby food and cereal.

Omega-3 fatty acids are already prized by cardiologists for protecting the heart against blocked arteries and for thwarting irregular, often fatal, heartbeats. Now psychiatrists are taking a closer look.
Omega-3s, dubbed the ''happy'' fats in some quarters, are under investigation for treating depression, bipolar disease and the so-called baby blues, or postpartum depression. Earlier this year, the American Psychiatric Association formed a committee to review the findings to make treatment recommendations for the use of omega-3s.

There's hope that omega-3s may help bridge the treatment gap in mental disorders -- up to 30 percent of people being treated for depression, for example, find drugs inadequate in controlling their symptoms.

''The main problem we have with depression is that we do not have treatment that [dependably] provides complete recovery,'' says David Kupfer, head of psychiatry at the University of Pittsburgh's Western Psychiatric Institute and Clinic. "We're still leaving people mildly depressed or unable to function well. It's like trying to make the last 10 yards when you're in field-goal range. . . .''

The idea that omega-3 fatty acids might help treat mental disorders dawned on Joseph R. Hibbeln in an anatomy lab in 1984. ''I had cut open the brain, and it just very much struck me that it is mostly fat,'' says Hibbeln, chief of the outpatient clinic at the Laboratory of Membrane Biochemistry and Biophysics at the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in Bethesda, Md.

Essential fatty acids can't be produced by the body but are required for good health. Playing key roles in brain cell structure, they're vital for each neuron's membrane, both its outer protection and its means of accessing key nutrients. It is these essential fats that regulate the growth of long tendrils called axons that enable neurons to communicate with each other.

One is an omega-3 fatty acid called alpha linolenic acid, which is found in fish, canola oil and flaxseed. The other is an omega-6 fatty acid, which is found in soybean, safflower and corn oils, as well as in meat, poultry, fish and processed foods. Omega-3s and omega-6s are close enough in chemical structure to be able to compete for the same molecular machinery that allows entry into the brain.

In 1909, Americans got most of their fat from free-range animals, which have higher levels of omega-3s than most of the meat and chicken eaten today. They also consumed about 0.02 pounds per year of soybean oil -- a number that increased gradually until about 1960, when ''soybean oil took over the U.S. food chain,'' says William Lands, a retired biochemist with NIAAA.

OMEGA-6 FACTOR
By 1999, per-capita consumption of soybean oil -- a major ingredient in crackers, bread, salad dressings, baked goods and processed food -- reached 25 pounds per year, according to the U.S. Department of Agriculture. ''That means that there has been a 1,000-fold increase in [consumption of] omega-6 fatty acids'' over 100 years, says Hibbeln. ``So we have literally changed the composition of people's bodies and their brains. A very interesting question, which we don't know the answer to yet, is to what degree the dietary change has changed overall behavior in our society.''

Flooding brains and bodies with a diet rich in omega-6 fatty acids theoretically could allow them to block omega-3s from getting inside cells and replenishing stores in the brain and elsewhere in the body.

Intrigued by this possibility, Hibbeln charted fish consumption worldwide and compared those figures to rates of depression. In a paper published in 1998 in The Lancet, he showed that nations with the highest fish consumption -- Japan, Taiwan and Korea -- had the lowest rates of depression. Nations with the lowest fish consumption -- New Zealand, Canada, Germany, France and the United States -- had the highest rates of depression.

VIOLENCE PATTERNS
Next, he took a look at homicide, suicide and aggression rates and compared them to seafood consumption. Similar patterns emerged. Using World Health Organization statistics, for example, Hibbeln found that men living in land-locked Hungary, Bulgaria and Austria had the lowest fish consumption and the highest suicide rates, while their counterparts in Japan, Portugal, Hong Kong, Korea and Norway ate the most fish and had the lowest suicide rates.
Since then, Hibbeln has examined patterns of postpartum depression. During pregnancy, mothers are the sole source of an omega-3 fatty acid known as docosahenaenoic acid (DHA) to the fetus. So key is this substance to fetal brain development that the mother's stores are depleted if she doesn't consume enough DHA. In a 2002 study in the Journal of Affective Disorders, Hibbeln reported that ''rates of postpartum depression are 50 times higher in countries where women don't eat fish,'' he says.
Of course, results from such population studies -- known as epidemiology -- can at best show only associations and trends, not cause and effect. Nailing down a new scientific theory requires both basic science and clinical trials.

As director of a Boston-area psychopharmacology research lab, psychiatrist Andrew Stoll often gets the most difficult patients to treat, the ones for whom standard therapy has failed.

DEPRESSION
In the late 1990s, research had already shown that depressed people seem to have lower levels of DHA in their brains than healthy people. Studies by Hussein Manji at the National Institute of Mental Health also found that people who respond well to antidepressants have neurons that exhibit greater plasticity, meaning that they are more receptive to changes that help them grow. Other laboratory work suggested that omega-3 fatty acids could help neurons be more plastic. Stoll put all these elements together in a study of 30 people suffering from bipolar disorder, also known as manic depression. During the four-month study, published in 1999 in the Archives of General Psychiatry, he randomly assigned participants to receive either fish oil capsules containing omega-3 fatty acids along with their standard treatment or a placebo of olive oil plus the standard treatment. The study found that the omega-3s significantly lengthened the period of remission.
Since then, a handful of other small, short-term studies have also found benefits to omega-3s. In England, Malcolm Peet and his colleagues at the Swallownest Court Hospital in Sheffield gave another type of omega-3 -- eicosapentaenoic acid (EPA) -- in varying doses to people with ongoing depression that was not well controlled with antidepressants. Peet found in this 12-week study that one gram per day of EPA was significantly better than a placebo in improving mood. (Both groups also received standard antidepressant medication.) Other studies found omega-3s helpful in controlling postpartum depression, impulsivity and even antisocial behavior in prisoners.

MANY QUESTIONS
But the story is still unfolding. Exactly how omega-3s may work and which dosage of omega-3s may be most effective is not known, ''although it's probably going to be in the range of one to three grams per day,'' says Marlene Freeman, lead investigator of two studies examining the use of omega-3s in pregnant women at high risk for postpartum depression. ``It's all kind of theoretical, but then we don't truly know how antidepressants work, either.''

And at least one trial, published earlier this year in the American Journal of Psychiatry by researchers at Baylor College of Medicine, found no significant effect of adding DHA to treatment for major depression.

Such findings explain why plenty of people -- even experts in the field -- are cautious about overbilling the benefits of omega-3 fatty acids.
''The biggest risk is for someone to try to treat themselves with these over the counter when what they really need is an evaluation,'' says Freeman. ``It scares me a little to have this in the media.''

''Is the evidence strong enough to use [omega-3s] for depression?'' asks Alice H. Lichtenstein, professor of nutrition at Tufts University. ``It's sufficient evidence to do human trials, but not to make dietary recommendations.''

Stoll is so convinced of the benefits of omega-3s that he jokes he nearly force-feeds food rich in omega-3s to his three children.
As Stoll says, ``Anything good for the heart seems to be good for the brain.''

• News - High levels of omega-6 from diet associated with more depression

Bethesda, MD A group of researchers from Israel has discovered that rats exhibiting the signs of depression have increased levels of the omega-6 fatty acid, arachidonic acid, in their brains.

The details of their findings appear in the June issue of the Journal of Lipid Research, an American Society for Biochemistry and Molecular Biology journal.

During recent years, omega-3 fatty acids have enjoyed increased popularity as numerous studies have shown that supplementing diets with fish oil (a natural source of this polyunsaturated fatty acid) does everything from reducing the risk of heart disease to preventing arthritis.

There is also evidence that depression may be associated with a dietary deficiency in omega-3 fatty acids. This "phospholipid hypothesis" of depression has been supported by research showing that omega-3 fatty acid concentration in the blood of depressed patients is lower than that in control patients.

"The "phospholipid hypothesis" of depression postulates that decreased omega-3 fatty acid intake, and hence, perhaps decreased brain omega-3 fatty acid content, could be responsible for the disease," explains Dr. Pnina Green of Tel Aviv University. "In humans, because of high dietary variability and the obvious inability to examine brain tissue, the theory is backed up mainly by indirect evidence. The availability of the Flinders Sensitive Line rat, an animal model of depression, overcomes both these obstacles."

In the Journal of Lipid Research study, Dr. Green in collaboration with Dr Gal Yadid of Bar-Ilan University, Ramat Gan, used the Flinders Sensitive Line rats to investigate the link between omega-3 fatty acids and depression. They examined the brains of the depressed rats and compared them with brains from normal rats. Surprisingly, they found that the main difference between the two types of rats was in omega-6 fatty acid levels and not omega-3 fatty acid levels.

Specifically, they discovered that brains from rats with depression had higher concentrations of arachidonic acid, a long-chain unsaturated metabolite of omega-6 fatty acid.

Arachidonic acid is found throughout the body and is essential for the proper functioning of almost every body organ, including the brain. It serves a wide variety of purposes, from being a purely structural element in phospholipids to being involved in signal transduction and being a substrate for a host of derivatives involved in second messenger function.

"The finding that in the depressive rats the omega-3 fatty acid levels were not decreased, but arachidonic acid was substantially increased as compared to controls is somewhat unexpected," admits Dr. Green. "But the finding lends itself nicely to the theory that increased omega-3 fatty acid intake may shift the balance between the two fatty acid families in the brain, since it has been demonstrated in animal studies that increased omega-3 fatty acid intake may result in decreased brain arachidonic acid."

Although far less attention has been paid to dietary requirements for omega-6 fatty acids, which can be found in most edible oils and meat, perhaps in the future depression may be controlled by increasing omega-3 fatty acid intake and decreasing omega-6 fatty acid intake.

Source: http://www.eurekalert.org/pub_releases/2005-05/asfb-slb052505.php

• Preliminary results suggest that fish oil supplementation may reduce depression in pregnancy

Naliwaiko K, Araujo R, et al. Effects of fish oil on the central nervous system: a new potential antidepressant? Nutr Neurosci, 2004;7(2):91-99

In the last 100 years major depression has increased worldwide. In this study we provided coconut fat (CF, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids) to female rats throughout pregnancy and lactation and then to their offspring post-weaning and examined lipid brain profile and the possible effect of FO as antidepressant agent in the offspring in adulthood (F1).

Rats were submitted to forced swimming test, elevated plus maze, Morris water maze and open field. Peroxidation rate in the cerebral cortex and hippocampus were measured.

Docosahexaenoic acid (DHA) concentration in dam's milk, eicosapentaenoic acid (EPA) and DHA concentration in hippocampus and cerebral cortex from F1 rats FO supplemented increased significantly when compared to control (C) and CF rats. Arachidonic acid/EPA ratio in the cerebral cortex and hippocampus decreased in rats submitted to forced swimming test. Peroxidation rate were not different between the groups. Immobility time in the forced swimming test in FO group was reduced (p < 0.01) when compared to C and CF rats.

We conclude that lifelong intake of FO was able to induce an antidepressant effect with EPA and DHA concentration increased in the cerebral cortex and hippocampus.

• Considering benefits of fish oil omega-3s for postpartum depression

Freeman MP. Omega-3 fatty acids and perinatal depression: a review of the literature and recommendations for future research. Prostaglandins Leukot Essent Fatty Acids,2006;75(4-5):291-297.

INTRODUCTION: Perinatal depression refers to major depression in the context of pregnancy and postpartum. In consideration of its prevalence and consequences, the treatment and prevention of perinatal depression should be important public health priorities. Omega-3 fatty acids are attractive for consideration in perinatal women, due to known health benefits for the mother and baby. Antidepressant medications may pose risks in utero and in breastfeeding.

METHODS: MEDLINE and manual searches were conducted.

RESULTS: Epidemiological and preclinical data support a role of omega-3 fatty acids in perinatal depression. Two studies failed to support a role of omega-3 fatty acids for postpartum depression prophylaxis, although one included a small sample, and the other utilized a low dosage. Two pilot studies suggest good tolerability and potential efficacy in the acute treatment of perinatal depression.

CONCLUSIONS: Further research studies are warranted to determine the role of omega-3 fatty acids in the treatment of perinatal depression.

• Study shows that depressed individuals have less DHA in adipose tissue

Mamalakis G, Tornaritis M, and A Kafatos. Depression and adipose essential polyunsaturated fatty acids. Prosta, Leukot, Essent Fatty Acids 2002;67(5):311-318

The objective of the present study was to investigate the relation between adipose tissue polyunsaturated fatty acids, an index of long-term or habitual fatty acid dietary intake, and depression.

The sample consisted of 247 healthy adults (146 males, 101 females) from the island of Crete. The number of subjects with complete data on all variables studied was 139. Subjects were examined at the Preventive Medicine and Nutrition Clinic of the University of Crete.

Depression was assessed through the use of the Zung Self-rating Depression Scale.

Mildly depressed subjects had significantly reduced (-34.6%) adipose tissue docosahexaenoic acid (DHA) levels than non-depressed subjects.

Multiple linear regression analysis indicated that depression related negatively to adipose tissue DHA levels. In line with the findings of other studies, the observed negative relation between adipose tissue DHA and depression, in the present study, appears to indicate increasing long-term dietary DHA intakes with decreasing depression.

This is the first literature report of a relation between adipose tissue DHA and depression. Depression has been reported to be associated with increased cytokine production, such as IL-1, IL-2, IL-6, INF-gamma and INF-alpha.

On the other hand, fish oil and omega-3 fatty acids have been reported to inhibit cytokine synthesis. The observed negative relation between adipose DHA and depression, therefore, may stem from the inhibiting effect of DHA on cytokine synthesis.

• DHA for depression

Mischoulon D, Fava M. DHA and omega-3 fatty acids in depression. Psychiatr Clin North Am 2000; 23(4):785-794.

Abstract: Geographic areas where consumption of DHA is high are associated with decreased rates of depression. DHA deficiency states, such as alcoholism and the postpartum period, also are linked with depression. Individuals with major depression have marked depletion in omega-3 EFAs (especially DHA) in erythrocyte phospholipids compared with controls. These data suggest that DHA may be associated with depression, and the limited data available on supplementation with DHA or other omega-3 FAs seem to support the hypothesis that DHA may have psychotropic effects. Overall, the use of EFAs is promising, particularly in view of the many illnesses potentially treatable with these substances; however, larger, carefully designed studies are needed to establish whether DHA is an effective and safe antidepressant, mood stabilizer, or antipsychotic.

A few preliminary trials of DHA are in progress, but no studies comparing DHA against placebo or against an established antidepressant have been carried out. Studies to address this issue are being developed at the Massachusetts General Hospital. Studies likely will require escalating doses of DHA, eventually reaching high levels so as to ensure that patients will avoid a potentially ineffective subclinical dose. Careful monitoring of dietary intake among subjects also will necessary because a high intake of omega-3-rich foods may confound results. Finally, large-scale, placebo-controlled, double-blind trials comparing the efficacy and safety of DHA against standard antidepressants are required before psychiatrists can recommend DHA therapy as effective and safe for the treatment of depression and other mood disorders.

Given the popularity of self-medication by patients who already are taking marketed antidepressants, studies examining the use of DHA as an augmentor to standard antidepressants may answer whether DHA can occupy a niche as an augmenting agent for patients who have made a partial response or have not responded to conventional antidepressants. Considering that natural medications generally seem best for treating mild to moderate illness, the role of DHA as a therapy for minor and subsyndromal depression also should be considered. It is hoped that studies of these types will help to clarify some of the knowledge gaps outlined in this article.

• Low DHA levels associated with cardiovascular health and depression

Parker G, Heruc G, Hilton T, et al. Low levels of docosahexaenoic acid identified in acute coronary syndrome patients with depression. Psychiatry Res, 2006; 141(3): 279-86.

As deficiencies in n-3 PUFAs have been linked separately to depression and to cardiovascular disease, they could act as a higher order variable contributing to the established link between depression and cardiovascular disease.

We therefore examine the relationship between depression and omega-3 polyunsaturated fatty acids (n-3 PUFA), including total n-3 PUFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in patients with acute coronary syndrome (ACS).

Plasma phospholipid levels of n-3 PUFA were measured in 100 patients hospitalized with ACS. Current major depressive episode was assessed by the Composite International Diagnostic Interview (CIDI). Depression severity was assessed by the 18-item Depression in the Medically Ill (DMI-18) measure.

Patients clinically diagnosed with current depression had significantly lower mean total n-3 PUFA and DHA levels. Higher DMI-18 depression severity scores were significantly associated with lower DHA levels, with similar but non-significant trends observed for EPA and total n-3 PUFA levels.

The finding that low DHA levels were associated with depression variables in ACS patients may explain links demonstrated between cardiovascular health and depression, and may have prophylactic and treatment implications.

• Low levels of omega-3 found in serum phospholipids and cholesterol esters of depressed patients.

Maes, M, Christophe, A et al. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res, 1999; 85(3):275-91

Depression is associated with a lowered degree of esterification of serum cholesterol, an increased C20:4omega6/C20:5omega3 ratio and decreases in omega3 fractions in fatty acids (FAs) or in the red blood cell membrane.

The aims of the present study were to examine: (i) serum phospholipid and cholesteryl ester compositions of individual saturated fatty acids (SFAs), monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) in major depressed patients vs. healthy volunteers; (ii) the relationships between the above FAs and lowered serum zinc (Zn), a marker of the inflammatory response in depression; and (iii) the effects of subchronic treatment with antidepressants on FAs in depression.

The composition of the FAs was determined by means of thin layer chromatography in conjunction with gas chromatography. Lipid concentrations were assayed by enzymatic colorimetric methods. The oxidative potential index (OPI) of FAs was computed in 34 major depressed inpatients and 14 normal volunteers.

Major depression was associated with: increased MUFA and C22:5omega3 proportions and increased C20:4omega6/C20:5omega3 and C22:5omega6/C22:6omega3 ratios; lower C22:4omega6, C20:5omega3 and C22:5omega3 fractions in phospholipids; lower C18:3omega3, C20:5omega3 and total (sigma)omega3 FAs, and higher C20:4omega6/C20:5omega3 and sigmaomega6/sigmaomega3 ratios in cholesteryl esters; lower serum concentrations of phospholipids and cholesteryl esters; and a decreased OPI.

In depression, there were significant and positive correlations between serum Zn and C20:5omega3 and C22:6omega3 fractions in phospholipids; and significant inverse correlations between serum Zn and the sigmaomega6/sigmaomega3, C20:4omega6/C20:5omega3, and C22:5omega6/C22:6omega3 ratios in phospholipids.

There was no significant effect of antidepressive treatment on any of the FAs. The results show that, in major depression, there is a deficiency of omega3 PUFAs and a compensatory increase in MUFAs and C22:5omega6 in phospholipids.

The results suggest that: (i) there is an abnormal metabolism of omega 3 PUFAs in depression; (ii) the FA alterations in depression are related to the inflammatory response in that illness; and (iii) the disorders may persist despite successful antidepressant treatment.

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