Omega-3 Fatty Acids for the Prevention and Treatment of Depression
Eating fish at least weekly or taking fish oil supplements is now recommended by the American Heart Association for the prevention of heart disease. But two important fatty acids, EPA and DHA, which are especially high in fish, are vitally important to the human brain as well. There is growing evidence that the more fish a nation eats, the smaller the percentage of depressed citizens.
There are also now four double-blind studies (listed below) showing that patients with Major Depressive Disorder or Bipolar Disorder who add fish oil capsules to their daily medication regimen experience a significant decrease in depression. However, there are four more studies not finding benefit. Four for eight isn't a bad record for this type of research. It's like a team with four wins, four ties, and no losses. The benefit of fish oil treatment in the positive studies occurred within three weeks of starting the fish oil, although additional benefit very likely occurs after more extended periods. One of the first two studies used only four fish oil capsules per day while the other used fifteen. Since both had similar benefits, four capsules per day is probably all that is necessary in most cases.
There are many more epidemiologic studies (see below) suggesting the fish consumption reduces depression. In my opinion, fish oil very likely helps treat and prevent depression, but the magnitude of the effect is modest and may grow slowly over a period of months. Clarification of this issue awaits more research studies. In the meantime, if a person isn’t severely depressed, it appears acceptable to start fish oil along with other non-medication treatments (e.g. folic acid, selenium, vitamin D, exercise, bright light, counseling) for a three-four week trial. If benefit has not occurred, medication or rTMS should be added. Even if there was no evidence of benefit, fish oil should be continued, if for no other reason that for the heart, to prevent Alzheimer's Disease, and several other health benefits. The same is true for the other supplements.
In my opinion, all people should consume fish or take fish oil or an alternative source of omega-3 fatty acids starting in childhood. For children, one capsule a day is probably enough and for adults two capsules a day or eating fish two or more times a week is a healthy intake. Two to four capsules a day is probably enough for depression, at least until more research is available. Also, use canola oil, and eat nuts. Using flax seeds or flax oil is probably good, too.
The active ingredient in fish oil are two fatty acids called eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA). These are found in virtually all fish and seafood, although the levels are much higher in oily ocean fish such as salmon, mackerel, and sardines. To get the equivalent of 28 capsules per week from eating fish would require 1 ˝ cans of salmon per week or six standard cans of tuna. While concerns about mercury in tuna have been in the news recently, these concerns are much less well documented than the benefits of eating fish. In fact, people eating more fish have less heart disease, lower rates of Alzheimer’s Disease, and live longer.
I have found fish oil capsules for just 5.5 cents each at Walmart and 3.5 cents each when on sale on Osco's. While some of the fish oil comes from discarded parts of salmon, most comes from types of fish that are not popular with consumers and are otherwise used as animal feed, especially on fish farms. The capsules are quite large. I have found one source of smaller, more concentrated capsules for 9.0 cents each. These may be of use for children having a hard time swallowing larger capsules. Several different types of fish oil in liquid form are available. Unfortunately, the several I have tried with children are somewhat unpleasant tasting despite various flavoring used by manufacturers to disguise the strong taste. Cod liver oil is not a good substitute since the high levels of vitamin A in cod liver oil would be excessive if larger than recommended doses of cod liver oil were taken.
Vegan vegetarians have been found to have lower levels of omega-3 fatty acids than regular omnivores. Also, vegan mothers have been found to have low levels of omega-3 fatty acids in their breast milk. Vegans can get omega-3 fatty acids by eating flax seeds or flax oil every day, but only a small percentage do this. Also, the omega-3 fatty acid in flax seeds must be converted by the human body to EPA and DHA and the body has some difficulty in does this. A more reliable but more expensive non-animal animal source of EPA and DHA is from algae or phytoplanton. Indeed, this is were fish get their EPA and DHA since they don’t manufacture their own. Half size capsules of phytoplankton DHA are available for as little as $23.00 per hundred. Six to eight capsules per day would be necessary to equal the 3-4 fish oil capsules recommended for treating depression. Thus, the cost is also 10 times more than fish oil or about $1.50 per day. This is still less expensive than many popular anti-depressant medications, but also probably less effective.
Surprisingly, there is virtually no research on other dietary elements and moods. It would seem sensible to advocate fruits and vegetables often high in anti-oxidant flavonoids since these have been found to decrease Alzheimer’s Disease and well as heart disease, cancer, and stroke. Thus, blueberries, dark grape juice, spinach, greens, broccoli, tomatoes, strawberries, apples, and oranges would seem likely to help moods since they help maintain general brain health. A very small amount of research suggests that animal fats, especially from mammals (beef, pork, lamb, butter, cheese), are harmful for multiple sclerosis, schizophrenia, and Alzheimer’s Disease. Of course, they are also bad for the heart. Thus, avoiding these might also good for avoiding depression, but no one has studied this.
Double Blind Studies
Helped Normals in DB: Omega-3 Help Mood and Attention in Normal Adults: In a 35-day DB PC study of healthy adults, the mood profile was improved after Omega-3 with increased vigor and reduced anger, anxiety and depression states. This was associated with an effect on reactivity with a reduction of reaction time. The latency of EMG activation was concomitantly. Omega-3 supplementation is associated with an improvement of attentional and physiological functions, particularly those involving complex cortical processing. Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Fontani G, et al. University of Siena , Italy . Eur J Clin Invest 2005; 35 (11): 691-699.
Fish Oil No Benefit in Small DB: In a 12-week DB PC study of 77 adults being treated for depression, 8 g of fish oil per day in addition to their existing therapy, there was no evidence that fish oil improved mood when compared to the placebo oil, despite an increase in circulating omega-3 polyunsaturated fatty acids. However, mood improved significantly in both groups within the first 2 weeks of the study (P<0.001) and this improvement was sustained throughout. In conclusion, fish oil was no more effective than the control as an add-on therapy for depression in this setting. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Silvers KM, et al. Christchurch, New Zealand. . Prostaglandins Leukot Essent Fatty Acids. 2005 Mar;72(3):211-8. Ed: This study was small and the sudden improvement in the olive oil group is odd. Maybe olive oil is too healthy and not a good control or maybe the large placebo improvement was just a coincidence. Soybean or corn oil may be better controls.
DB Fish Oil Helped Depression Again: A small PC DB study of 32 outpatients with Major Depression and HAM-D >17 despite 4 weeks on anti-depressant therapy. After a one week lead-in, the 28 who did not improve were treated for 8 weeks with the addition of 5 capsules twice a day of 440 mg EPA and 220 mg DHA (double potency). In the 22 patients completing the study, scores fell from 22 to 9 with fish oil and 22 to 16 with placebo (p=0.001). Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder: a preliminary double-blind, placebo-controlled trial. Europ Neuropsychopharm 2003;13:267-271. Taiwan. (Ed: This is a higher dose than used in other studies. The effect size in impressive, but the number of patients in the study is far too small to draw much of a conclusion. Still, it adds a little more evidence favoring fish oil.)
DB Shows Trend toward Improvement: 36 MDD patients treated in PC DB for 6 weeks with half on 2 g/day DHA. 28% responded on DHA vs. 23.5% on placebo. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. Am J Psychiatry. 2003 May;160(5):996-8
DB Fails to Find Benefit for Bipolars: A PC DB study of 59 bipolar patients failed to find any significant benefit to fish oil. Keck PE. Omega 3 fatty acids in bipolar disorder. Program and abstracts of the 3rd International Stanley Foundation Bipolar Conference; September 12-14, 2002; Freiberg, Germany.
DB Omega-3 Helps M-D in 4 Month Study: In a PC DB 4 month study of 30 bipolar patients, 14 had fish oil added to their usual treatment. 64% on fish oil improved vs. 18% on placebos. Patients received 7 high omega-3 fish oil capsules (440 EPA 240 DHA) twice a day (9.6 g/d). Benefit appeared for both depressive and manic symptoms. Four patients treated with no psych meds but fish oil did well vs. 3-4 on olive oil who did poorly. Stoll has used flax oil in open-label treatment. Starting dose=5g/d of omega-3 or alpha-linolenic with max dose to date 15 g/d. at over 10 g/d some diarrhea and oily stools. If patients take most fish oil HS, it decreases the aftertaste. Also, you can put fish oil in OJ. Perilla oil causes less GI distress. Most fish oil caps only 300 mg omega-3 so need 32 caps/d to equal study level. If flax seeds, 4 ˝ Tablespoons of 17.5 g flax oil = 9.6 g omega-3 equivalent. If flax oil caps, start with 10/d and 17.5/d=9.6 g. Stoll AL, Severus E, 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
DB Ethyl-EPA Highly Beneficial for Depression: 4-week, parallel-group, double-blind addition of either placebo or ethyl-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. Only 4 g/d used. Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. Am J Psychiatry 2002 Mar;159(3):477-9, B Nemets, Ben Gurion U.
DB of Post-Partum Breast-Feeding Mothers No Impact: A four month PC DB study giving DHA 200mg/d found an 8% increase in blood DHA levels with supplementation vs. a 31% decrease with placebo. However, there was no difference in depression. Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing. Llorente AM, Jensen CL, Voigt RG, Fraley JK, Berretta MC, Heird WC. Am J Obstet Gynecol. 2003 May;188(5):1348-53 (Ed: 200 mg/d is a dose lower than what I would recommend. Also, depressed women would be more likely to show a decrease in depression than randomly selected women.)
Randomized Study of Angina Patients Finds No Impact on Moods: 452 men were randomized to advice to eat more fatty fish or no fish advice. Maxepa fish oil capsules were supplied to men who found the fish unpalatable. Fish intake and mood were assessed at baseline and six months using the Derogatis Stress Profile at baseline and follow-up. Self reported intake of fish was higher in the fish advice group at six months. There was, however, no difference in depression or anxiety in those allocated to receive fish advice. Advice to eat fish and mood: a randomised controlled trial in men with angina. Ness AR, Gallacher JE, Bennett PD, Gunnell DJ, Rogers PJ, Kessler D, Burr ML. Nutr Neurosci. 2003 Feb;6(1):63-5
Higher Body DHA From Fish Linked to Less Depression: In a cross-sectional study of 130 healthy adults from the island of Crete, fat tissue DHA was inversely related with depression. Multiple linear regression analysis taking into account the possible confounding effect of age, gender, body mass index, smoking and educational level confirmed this association. Higher long-term dietary intake of DHA from fish or fish oil is associated with a decreased risk for depression in adults. Depression and long chain n-3 fatty acids in adipose tissue in adults from Crete. Mamalakis G, et al. University of Crete, Iraklion, Crete, Greece. European Journal of Clinical Nutrition 8 February 2006
Higher Fish Consumption by Nation Lowers Bipolar Disease, But Not Schizophrenia: A new study has shown that the more seafood consumed in a country, the lower the rates of bipolar disease. Below 50 pounds consumption of seafood per year seemed to be a threshold level below which risk of bipolar II and bipolar spectrum disorder increased. Authors attribute the benefit to higher omega-3 fatty acid consumption. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Noaghiul S, Hibbeln JR. Am J Psychiatry. 2003 Dec;160(12):2222-7
Fish Eating Finnish Females Were Less Depressed: The Northern Finland 1966 Birth Cohort was followed up from pregnancy up to the age of 31 years. Questionnaires were completed by 5678 adults. After adjusting for body mass index, serum total cholesterol level and socioeconomic situation, females the risk of developing depression increased up to 2.6-fold 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. Fish consumption and depression: the Northern Finland 1966 birth cohort study. Timonen M, et al. University of Oulu, Finland. . J Affect Disord. 2004 Nov 1;82(3):447-52.
Suicide Attempts Less with High RBC EPA in Chinese: In a study of 100 suicide-attempt cases and another 100 control patients injured by accidents, eicosapentaenoic acid (EPA) levels in red blood cells (RBC) in the cases were significantly lower than those of the controls (.74% vs. 1.06%, p <.0001). When the highest and lowest quartiles of EPA in RBC were compared, the odds ratios of suicide attempt was 0.12 in the highest quartile (p =.0001) after adjustment for possible confounding factors. Suicide attempt and n-3 fatty acid levels in red blood cells: a case control study in China. Huan M, et al. Toyama Medical University, Japan. Biol Psychiatry. 2004 Oct 1;56(7):490-6.
Lower Omega-3s in Fat Tissue Linked to Higher Depression in Greek Elderly: In a study of 150 elderly males survivors of the Greek Seven Countries Study group with an average age of 84, depression correlated negatively with fat tissue alpha-linolenic acid (C18:3n-3). Depressed subjects had significantly lower (-10.5%) fat tissue C18:3n-3 levels than non-depressed subjects. This suggests that increased long-term dietary C18:3n-3 intakes lower the risk of depression. This agrees with findings of other studies indicating an inverse relation between depression and consumption of fish and n-3 polyunsaturated fatty acids. Depression has been linked to elevated cytokines, such as, IL-1, IL-2, IL-6, INF-gamma and INF-alpha. Fish oil and omega-3 fatty acids, on the other hand, have been reported to inhibit cytokine production. Depression and adipose polyunsaturated fatty acids in the survivors of the Seven Countries Study population of Crete. Mamalakis G, et al. University of Crete, Greece. . Prostaglandins Leukot Essent Fatty Acids. 2004 Jun;70(6):495-501.
Omega-3 Low in Dutch Depressed: As part of the Rotterdam heart study, 3884 adults were screened for depression. 264 with depressive symptoms, including 106 with depressive disorders, and 461 random controls studied. 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]. Differences not due to inflammation or atherosclerosis. Suggests direct effect on mood. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study. Tiemeier H, van Tuijl HR, Hofman A, Kiliaan AJ, Breteler MM. Am J Clin Nutr. 2003 Jul;78(1):40-6
DHA Lower in RBCs of Depressed: Omega-3s, especially DHA, decreased in RBCs of young depressed and schizophrenic patients as well. Biol Psychiatry 2001 Mar 15;49(6):510-22
Omega-3 Low in Suicide Attempters: Hibbeln found non-depressed have high blood EPA & strikingly lower scores on 6 psych rating scales related to suicide risk. Another study = diet of EPA & DHA may influence serotonin function in brain. Synatic membranes have large proportion essential fatty acids which derive entirely from diet. In last century, western diet much less omega-3 and big increase in depression, maybe 100-fold. Link fish consumption by country with low depression. (NY Reuters 9/3/98). Ed: Hibbeln is prone to exaggeration.
Less Fish, More Depression in Finland: Large study found people who ate fish less than weekly had 31% more depression than those who ate more. Antti Tanskanen, U Kuopio, Chic AP 5/17/00. Finnish study of 3,024 adults found higher fish intake linked to lower Beck Depression Inventory scores. Psychiatr Serv 2001 Apr;52(4):529-31. Suicidality also decreased. Frequent fish consumer considered twice a week or more. OR 0.63 for being depressed (BDI>10) and 0.57 for suicidal thoughts.
Fish Not Linked to Depression in Larger Finland Study: 29,133 men ages 50 to 69 years participated in a population-based trial in Finland. Self-reported depressed mood was recorded three times annually, data on hospital treatments due to a major depressive disorder were derived from the National Hospital Discharge Register, and suicides were identified from death certificates. There were no associations between the dietary intake of omega-3 fatty acids or fish consumption and depressed mood, major depressive episodes, or suicide. Is low dietary intake of omega-3 Fatty acids associated with depression? Hakkarainen R, Partonen T, Haukka J, Virtamo J, Albanes D, Lonnqvist J. Am J Psychiatry. 2004 Mar;161(3):567-9
Less Post-Partum Depression with Higher Fish and Higher Breast Milk DHA: 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. J Affect Disord 2002 May;69(1-3):15-29, Hibbelm, NIAAA
More Fish, Less Depression for Japanese: Study of 265,000 with 17 year follow-up found those with daily fish intake decreased suicide. (Hirayama T. Life-Style and Mortality: A Large Census-Based Cohort Study in Japan. Basel, Switzerland: Karger, 1990.
More Fish, Less Seasonal Affective Disorder in Iceland: Iceland has far lower rates of seasonal affective disorder (SAD) than expected based on latitude. Some think the decrease is due to high fish intake. Am J Psychiatry 2000;157:234-8 & 2001;158:328. (SAD has hypersomnia and weight gain).
Omega-3 Depleted in Depression: Membrane lipid abnormalities occur in major depression. Curr Opinion in Psychiatry 10:477-80 11/97 Malcolm Peet. 10 depressed vs. 14 controls found depletion n-3 polyunsaturated fatty acids (PUFAs) in red blood cell (RBC) membranes and decreased dietary intake correlated negatively with severity of depression. J Affect Disord 1998 Mar;48:149-55, Edwards R, Peet M, U Sheffield. RBC membrane omega–6(n-6) tended to increase risk of depression. Joel Simon, Am J Epid 9/1/95;142:469-76%. High n-6 in depressives show evidence oxidative damage and n-3 may be protective. Peet M, Biol Psychiatry 1998 Mar;43:315-9. Maes M of U Antwerp in J Affect Disord 1996 Apr; 38:35-46 found shift from n-3 to n-6 in serum cholesteryl esters and phopholipids of 36 severely depressed vs. 14 minor depressed and 24 normals. Also, Adams PB of Queensland in Lipids 1996 Mar;31 Suppl:S157-61 found 20 depressed had RBC arachidonic acid (AA) to EPA ratio increased with their depression. But Ohio State med students showed more stress and less esterified AA and linoleic acid than control lab workers. Low AA could be from depletion of plasma stores by immunoregulatory prostenoids or cytokines. No diff in the n-3 DHA. In Prostaglandins Leukot Essent Fatty Acids 1992 Oct;47:165-70.
Fish Intake Negatively Correlates with Depression around the world according to Jos R Hibbeln at NIH. Japanese, the nationality who eat the most fish, are least depressed. Says humans evolved on 1:1 diet of n-6:n-3 fatty acids. Speculates depressions which accompany alcoholism, MS, and postpartum depression may be due to lack of DHA and can be corrected by dietary DHA from fish or linolenic acid as in flax. Am J Clin Nutr 7/95;62:1-9.
Decreased DHA in Bipolar Manics: Red blood cell membranes were compared in 20 bipolars and 20 normal controls. The bipolar RBCs were markedly lower in arachidonic acid and DHA by not total omega-6 or omega-3. Taiwan Med. Univ. Polyunsaturated fatty acid deficit in patients with bipolar mania. Chiu CC, Huang SY, Su KP, Lu ML, Huang MC, Chen CC, Shen WW. Eur Neuropsychopharmacol. 2003 Mar;13(2):99-103
Decreased DHA with Depression: Less DHA in RBCs of depressed patients. Biol Psych ’98 43:315-9.
More Recent Depression: Cohorts born before 1934 had one fifth to one twentieth the level of depr as those after 1945 (Klerman & Weissman, 1989)(Ed: Maybe due in part to increased bottle feeding?). In this century, PUFA consumption has decreased and saturated increased. Omega-6 up has increased, omega-3 decreased. www.shef.ac.uk
Mechanism and Details of Stoll Study: Lithium and valproate inhibit neuronal signal transduction systems. Overactive cell-signal pathways may be part of the cause of bipolar disorder. High omega-3 dampens signal transduction associated with phosphatidylinosital, arachidonic acid, and other systems. Study found omega-3 benefited both depressive and manic symptoms. High drop out in olive oil group and almost none from omega-e group. Rapid cycling and type I and II all did well although numbers were small. 61% mild GI with omega-3 and 53% with olive oil. HAM-D decr 48% in omega-3 but incr 24% in olive oil, Young Mania RS both groups showed big drop. CGI and GAS both considerable improved in omega-3 and some deterioration in olive oil. The two that deteriorated on omega-3 both had manic upswings.
Studies show high omega-3 diet incorp into RBCs membrane phospholipids crucial for cell-signaling. High omega-3 in membrane phospholipids suppresses phosphatidylinosital-associated signal transduction. May make membr more resistant to hydrolysis by phospholipases reducing generation of second messenger diacylglycerol (DAG) and inositol triphosphate (IP3) and thus less activation of downstrean intracellular signaling molecules as protein kinase C and calcium ions. Omega-3 highly incorporated in neuronal phospholipids in animals. Thus, suppresses aberrant signal transduction pathways.
Omega-3 Deprived Rats More Depressed and Aggressive: Male rat at weaning (21 days of age) were put of diets deficient or adequate in n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks. In the n-3 PUFA deprived compared with adequate rats, docosahexaenoic acid (DHA)(22:6n-3) in brain phospholipid was reduced by 36% and docosapentaenoic acid (DPA)(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 on the Isolation Induced Resident Intruder test for aggression. Large "effect sizes" (d > 0.8) were found on the depression score and blocking time score of the aggression test. Scores on the Open Field Test for locomotor activity did not differ significantly. Dietary N-3 polyunsaturated fatty acid deprivation in rats following weaning increases their behavioral depression and aggression test scores. Demar JC Jr, et al. NIMH. J Lipid Res. 2005 Oct 6
Lithium, Carbamazepine, Valproic Acid All Decrease Arachidonic Acid But Not DHA Incorporation Into Brain; Topiramate Doesn't: Similar to lithium and valproic acid, chronic carbamazepine, compared with vehicle, decreased the rate of incorporation of arachidonic acid-CoA (27%-29%) and turnover of arachidonic acid (25%-27%) but not of DHA-CoA or DHA in brain phospholipids. Chronic Carbamazepine Decreases the Incorporation Rate and Turnover of Arachidonic Acid but Not Docosahexaenoic Acid in Brain Phospholipids of the Unanesthetized Rat: Relevance to Bipolar Disorder. Bazinet RP, et al. National Institute on Aging, National Institutes of Health, Bethesda, Maryland. Biol Psychiatry. 2005 Sep 20. However, topiramate, which does not help Bipolar Disorder, does not have this effect on arachidonic acid. Lee, HJ, et al NIMH. Neurochem Res. 2005 May;30(5):677-83.