CLINICAL STUDIES USING OMEGA-3 FATTY ACIDS TO COMBAT CENTRAL NERVOUS SYSTEM DISORDERS

Br J Psychiatry. 2006 Jan;188:46-50.

Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study.

University of Pittsburgh Medical Center

Omega 3 fatty acids influence mood, impulsivity and personality, study indicates.

In a study of 106 healthy volunteers, researchers found that participants who had lower blood levels of omega-3 polyunsaturated fatty acids were more likely to report mild or moderate symptoms of depression, a more negative outlook and be more impulsive. Conversely, those with higher blood levels of omega-3s were found to be more agreeable.

"A number of previous studies have linked low levels of omega-3 to clinically significant conditions such as major depressive disorder, bipolar disorder, schizophrenia, substance abuse and attention deficit disorder," said Sarah Conklin, Ph.D., a postdoctoral scholar with the Cardiovascular Behavioral Medicine Program in the department of psychiatry at the University of Pittsburgh School of Medicine. "However, few studies have shown that these relationships also occur in healthy adults. This study opens the door for future research looking at what effect increasing omega-3 intake, whether by eating omega-3 rich foods like salmon, or taking fish-oil supplements, has on people's mood."

The American Heart Association recommends that all Americans consume fish, which is high in omega-3 fatty acids, twice per week. This recommendation is based upon evidence that a diet high in fish s associated with improved heart health and reduced risk for heart-related problems. While the cardiovascular benefit of increasing omega-3 intake is well recognized, relatively little is known of the potential mental health effects among the general public.

Comparisons were made by analyzing levels of omega-3 fatty acids in participants' blood and comparing that data to the participants' scores on three accepted tests for depression, impulsiveness and personality. The amount of omega-3 circulating in blood reflects dietary intake of the fatty acid. The study did not require participants to make changes in their normal diet habits.

In addition to Dr. Conklin, co-authors of the study, which was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH), include: Jennifer I. Harris, M.D., psychiatry resident, department of psychiatry, Brown University; Stephen B. Manuck, Ph.D., University Professor of Health Psychology and Behavioral Medicine, department of psychology, University of Pittsburgh; Joseph R. Hibbeln, M.D., chief of outpatient clinic, Lab of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, NIH; and Matthew F. Muldoon, M.D., associate professor, department of medicine, University of Pittsburgh School of Medicine.

Neuropsychopharmacology. 2006 Jun 14; [Epub ahead of print]

Omega-3 Fatty Acid Ethyl-Eicosapentaenoate Attenuates IL-1beta-Induced Changes in Dopamine and Metabolites in the Shell of the Nucleus Accumbens: Involved with PLA2 Activity and Corticosterone Secretion.

Song C, Li X, Kang Z, Kadotomi Y.

[1] 1Department of Biomedical Sciences, AVC, University of Prince Edward Island, Charlottetown, PE, Canada [2] 2Canada National Institute for Nutrisciences and Health, Charlottetown, PE, Canada [3] 3Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada [4] 1Department of Biomedical Sciences, AVC, University of Prince Edward Island, Charlottetown, PE, Canada.

Previously, we have reported that interleukin-1 beta (IL-1) induces changes in dopaminergic (DA) and serotonergic systems in the core of nucleus accumbens (NAc). We have also demonstrated that n-3 fatty acid ethyl-eicosapentaenoate (EPA) can significantly reduce stress and anxiety-like behaviors, corticosterone concentration and peripheral inflammatory response induced by IL-1 administration. Compared to the core, the shell is involved more in emotion, stress and psychiatric diseases. However, the relationship between inflammation and the functions of DA system in the shell has not been studied. Since phospholipase (PL) A2 is a key enzyme in arachidonic acid (AA)- eicosanoids-prostaglandin (PG)E2 pathway, and the change in NAc dopaminergic system has been associated with glucocorticoid stimulation, therefore, the hypotheses of this study are (1) that IL-1 induced changes in DA neurotransmission in the shell may be through PLA2-PGE2-corticosterone pathway; (2) EPA may attenuate IL-1 effects via inhibiting PLA2 activities, which blocks PGE2 stimulation of corticosterone. Using an in vivo microdialysis method, the present study showed that IL-1 administration significantly increased extracellular levels of DA, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the shell of the NAc. IL-1 also increased blood concentration of corticosterone and PGE2, and increased the activities of cytosolic and sectory of PLA2. IL-1-induced changes were significantly attenuated by EPA treatment. Furthermore, glucorcoticoid receptor antagonist mifepristone (RU486) pretreatment significantly blocked IL-1-induced changes in DA and metabolites. Qquinacrine, a PLA2 antagonist significantly blocked IL-1 induced increase in PGE2 and corticosterone concentrations. These results demonstrated the hypotheses that IL-1 effects may be via PLA2-PGE2-corticosterone pathway and EPA attenuated IL-1 effects may be through the suppression of PLA2 expression, which then reduced PGE2 synthesis and corticosterone secretion.Neuropsychopharmacology advance online publication, 14 June 2006; doi:10.1038/sj.npp.1301117

PMID: 16794572 [PubMed - as supplied by publisher]

Biol Psychiatry. 2005 Feb 15;57(4):343-50.

Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats.

Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF.

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts, USA. carlezon@mclean.harvard.edu

BACKGROUND: Brain phospholipid metabolism and membrane fluidity may be involved in the pathophysiology of mood disorders. We showed previously that cytidine, which increases phospholipid synthesis, has antidepressant-like effects in the forced swim test (FST) in rats, a model used in depression research. Because cytidine and uridine both stimulate synthesis of cytidine 5'-diphosphocholine (CDP-choline, a critical substrate for phospholipid synthesis), we examined whether uridine would also produce antidepressant-like effects in rats. We also examined the effects of omega-3 fatty acids (OMG), which increase membrane fluidity and reportedly have antidepressant effects in humans, alone and in combination with uridine. METHODS: We first examined the effects of uridine injections alone and dietary supplementation with OMG alone in the FST. We then combined sub-effective treatment regimens of uridine and OMG to determine whether these agents would be more effective if administered together. RESULTS: Uridine dose-dependently reduced immobility in the FST, an antidepressant-like effect. Dietary supplementation with OMG reduced immobility when given for 30 days, but not for 3 or 10 days. A sub-effective dose of uridine reduced immobility in rats given sub-effective dietary supplementation with OMG. CONCLUSIONS: Uridine and OMG each have antidepressant-like effects in rats. Less of each agent is required for effectiveness when the treatments are administered together.

PMID: 15705349 [PubMed - in process]

Mol Psychiatry. 2004 Jun;9(6):630-8.

Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats.

Song C, Phillips AG, Leonard BE, Horrobin DF.

Department of Psychiatry, University of British Columbia, Vancouver, Canada. caisong@internchange.ubc.ca

Central or peripheral administration of the proinflammatory cytokine interleukin (IL)-1beta can impair performance on spatial memory tasks and also elevate circulating concentration of corticosterone. The present experiment provides independent confirmation that intracerebroventricular administration of 10 ng IL-1beta in the rat can have a selective effect on the retrieval of trial unique information about the location of food on an eight-arm radial maze. The probable involvement of corticosterone in IL-1beta-induced memory impairment was indicated by elevated corticosterone levels after IL-1beta administration. Further evidence comes from the blockade of the associated impairment in working memory by coadministration of the glucocorticoid receptor antagonist RU486. Ingestion of diet containing omega-3 fatty acid eicosapentaenoic acid (EPA) is known to antagonize the synthesis of prostaglandin (PG) E2 from aracadonic acid, and the present study confirmed that ethyl EPA (1%) reduced IL-1beta-elevated concentrations of PGE2 and corticosterone. Furthermore, rats given the ethyl-EPA diet for 8 weeks were unaffected by the disruptive effects of IL-1beta on working memory. IL-1beta-induced suppression of mitogen-stimulated release of the anti-inflammatory cytokine IL-10 was also blocked by treatment with ethyl-EPA. Collectively, these data demonstrate that IL-1beta can impair memory function by elevating the concentration of corticosterone and that prior consumption of 1% ethyl-EPA can block both the neuroendocrine and cognitive effects of IL-1beta. These findings in turn may indicate beneficial effects of ethyl-EPA in the treatment of cognitive and affective disorders in which inflammation and stress play a critical role.

PMID: 14699427 [PubMed - indexed for MEDLINE]

Effects of fish oil on the central nervous system: a new potential antidepressant?

Naliwaiko K, Araujo RL, da Fonseca RV, Castilho JC, Andreatini R, Bellissimo MI, Oliveira BH, Martins EF, Curi R, Fernandes LC, Ferraz AC.

Laboratorio de Fisiologia e Farmacologia do Sistema Nervoso Central, Departamento de Fisiologia e Farmacologia, Universidade Federal do Parana, 81.531-990 Curitiba, PR, Brazil.

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.

PMID: 15279495 [PubMed - indexed for MEDLINE]

Altern Med Rev. 2003 Nov;8(4):410-25. 

Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression.

Logan AC.

CAM Research Consulting, 13 Stonewall Court, Mahwah New Jersey 07430, USA. aclnd@cfs-fm.org

Omega-3 fatty acids have been the subject of volumes of international research, the results of which indicate these substances may have therapeutic value in a number of medical conditions. An emerging area of research is examining the neurobehavioral aspects of omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and the critical role of these essential fats in the functioning of the central nervous system. Investigations have linked omega-3 fatty acids to a number of neuropsychiatric disorders, including depression. The purpose of this article is to examine the possible mechanisms of action and potential clinical value of omega-3 fatty acids in major depression. A novel mechanism involving omega-3 modulation of cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) is proposed.

PMID: 14653768 [PubMed - indexed for MEDLINE]

Lipid Res. 2003 Oct;44(10):1984-91. Epub 2003 Jul 1.

Effects of dietary n-3 or n-6 fatty acids on interleukin-1beta-induced anxiety, stress, and inflammatory responses in rats.

Song C, Li X, Leonard BE, Horrobin DF.

Department of Psychiatry, University of British Columbia, Canada. caisong@interchange.ubc.ca

The present study demonstrated that an omega (n)-3 fatty acid, ethyl-eicosapentaenoic acid (ethyl-EPA), supplemented diet significantly attenuated the stress/anxiety behavior of rats in the "open field" and elevated plus maze, which was induced by subchronic intracerebroventricular administration of proinflammatory cytokine interleukin (IL)-1beta. Ethyl-EPA also reduced the rise in serum corticosterone induced by IL-1. The n-6 fatty acid ethyl-gamma-linolenic acid (ethyl-GLA) had little effect on the IL-1-induced changes in behavior and the corticosterone concentration. Following IL-1beta administration, ethyl-EPA reduced the elevated prostaglandin (PG) E2 secretion and increased the secretion of antiinflammatory cytokine IL-10 from whole blood cells. Ethyl-GLA showed a similar antiinflammatory effect to ethyl-EPA. By contrast, n-6 fatty acid arachidonic acid (AA) had no effect on the behavior, immune, and endocrine changes induced by IL-1. AA alone enhanced the basal inflammatory response, raised serum corticosterone concentrations, and induced anxiety behavior in the elevated plus maze. The reduced growth rates of rats following the administration of IL-1 was attenuated by ethyl-EPA, and to a greater extent by ethyl-EPA plus ethyl-GLA, but not by AA alone or in combination with ethyl-EPA. Thus, ethyl-EPA would appear to antagonise the endocrine, immune, and behavioral effects of subchronic IL-1 administration. Ethyl-GLA only antagonised IL-1-induced inflammatory changes, whereas AA caused an increase in the secretion of corticosterone and PGE2, and induced anxiety-like behavior without enhancing the effects of IL-1.

PMID: 12837849 [PubMed - indexed for MEDLINE]

Am J Psychiatry 160:996-998, May 2003
© 2003 American Psychiatric Association

A Double-Blind, Placebo-Controlled Study of the Omega-3 Fatty Acid Docosahexaenoic Acid in the Treatment of Major Depression.

Lauren B. Marangell, M.D., James M. Martinez, M.D., Holly A. Zboyan, B.A., Barbara Kertz, M.A., H. Florence Seung Kim, M.D., and Lucy J. Puryear, M.D.

Mood Disorders Center, Department of Psychiatry, Baylor College of Medicine, Suite 560, 6655 Travis Road, Houston, TX 77030, USA. laurenm@bcm.tmc.edu

OBJECTIVE: This study was an evaluation of the omega-3 fatty acid docosahexaenoic acid (DHA) for the treatment of major depression. METHOD: Thirty-six depressed patients were randomly assigned to receive DHA, 2 g/day, or placebo for 6 weeks. Response was defined a priori as a 50% reduction in the score on the Montgomery-Åsberg Depression Rating Scale. Thirty-five participants were evaluable; 18 received DHA, and 17 received placebo. RESULTS: Response rates were 27.8% in the DHA group and 23.5% in the placebo group. The difference in response rates between groups did not reach statistical significance. CONCLUSIONS: This trial failed to show a significant effect of DHA monotherapy in subjects with major depression.

PMID: 12727707 [PubMed - indexed for MEDLINE]

Arch Gen Psychiatry. 1999 May;56(5):407-12.

Comment in:

Arch Gen Psychiatry. 1999 May;56(5):413-4; discussion 415-6.

Arch Gen Psychiatry. 2000 Jul;57(7):715.

Arch Gen Psychiatry. 2000 Jul;57(7):716-7.

Arch Gen Psychiatry. 2001 May;58(5):512-3.

Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.
Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.

Brigham and Women's Hospital, Department of Psychiatry, Harvard Medical School, Boston, Mass, USA. alstoll@mclean.harvard.edu

BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

PMID: 10232294 [PubMed - indexed for MEDLINE]

Prostaglandins Leukot Essent Fatty Acids. 1999 Mar;60(3):141-67. 

New gene targets related to schizophrenia and other psychiatric disorders: enzymes, binding proteins and transport proteins involved in phospholipid and fatty acid metabolism.

Horrobin DF, Bennett CN.

Laxdale Research, Kings Park House, Laurelhill Business Park, Stirling, UK.

Phospholipids make up about 60% of the brain's dry weight. In spite of this, phospholipid metabolism has received relatively little attention from those seeking genetic factors involved in psychiatric and neurological disorders. However, there is now increasing evidence from many quarters that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. To date the possible specific proteins and genes involved have been relatively ill-defined. This paper reviews the main pathways of phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C series in signal transduction processes. It identifies some likely protein candidates for involvement in psychiatric and neurological disorders. It also reviews the chromosomal locations of regions likely to be involved in these disorders, and relates these to the known locations of genes directly or indirectly involved in phospholipid and fatty acid metabolism.

PMID: 10359017 [PubMed - indexed for MEDLINE]

Prostaglandins Leukot Essent Fatty Acids. 1999 Apr;60(4):217-34.

Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes.

Horrobin DF, Bennett CN.

Laxdale Research, Stirling, UK.

Depression and bipolar disorder are two of the commonest illnesses in the developed world. While some patients can be treated effectively with available drugs, many do not respond, especially in the depression related to bipolar disorder. Depression is associated with diabetes, cardiovascular disease, immunological abnormalities, multiple sclerosis, cancer, osteoporosis and ageing: in each case depressed individuals have a worse outcome than non-depressed individuals. In all of these conditions there is now evidence of impaired phospholipid metabolism and impaired fatty acid-related signal transduction processes. Impaired fatty acid and phospholipid metabolism may be a primary cause of depression in many patients and may explain the interactions with other diseases. Several novel gene candidates for involvement in depression and bipolar disorder are proposed.

PMID: 10397403 [PubMed - indexed for MEDLINE]