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

Int J Neuropsychopharmacol. 2004 Sep;7(3):341-9. Epub 2004 Mar 5.

Ethyl-eicosapentaenoate and dexamethasone resistance in therapy-refractory depression.

Murck H, Song C, Horrobin DF, Uhr M.

Laxdale Ltd, Stirling, Scotland, UK, FK7 9JQ. hmurck@laxdale.co.uk

Preliminary evidence shows that ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used as an adjunct in therapy-refractory depression. EPA belongs to the class of polyunsaturated omega-3 fatty acids. The mechanism of its action in depression is not fully understood. There are two related fields where the pathophysiology of refractory depression meets the effect of EPA. First, a general immunosuppressive effect of EPA meets a general immunoactivation in severe depression, especially an increase in CD4/CD8 ratio, neutrophilia, and an increase in interleukins (IL)-6 and IL-12 and of prostaglandin E2 (PGE2). Secondly, a resistance to dexamethasone (Dex) suppression of the HPA axis meets the effects of EPA on multidrug resistance reversing and HPA axis suppression. The effects of EPA on the immune system, the HPA axis, and multidrug resistance are connected through the action of a transport protein called p-glycoprotein (p-gp). Physiological and synthetic steroids such as cortisol and Dex are substrates of p-gp, and so Dex resistance in depression may be related to dysfunction of this protein. In addition, expression of p-gp is induced by PGE2, and EPA inhibits the synthesis of PGE2. The reversal of drug resistance by EPA may be mediated via this immunological mechanism and lead to its antidepressive efficacy. In addition, antidepressants such as amitriptyline, which have special efficacy in severe depression, decrease p-gp function. EPA may, furthermore, enhance the action of antidepressants, like many SSRIs that are p-gp substrates, which are actively transported out of the intracerebral space at the level of the blood-brain barrier.

PMID: 15003146 [PubMed - indexed for MEDLINE]

Arch Gen Psychiatry. 2002 Oct;59(10):913-9.

A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs.

Peet M, Horrobin DF.

Swallownest Court Hospital, Sheffield, England.

BACKGROUND: In depressed patients, low blood levels of eicosapentaenoic acid are seen. We tested the antidepressive effect of ethyl-eicosapentaenoate in these patients. METHODS: We included 70 patients with persistant depression despite ongoing treatment with an adequate dose of a standard antidepressant. Patients were randomized on a double-blind basis to placebo or ethyl-eicosapentaenoate at dosages of 1, 2, or 4 g/d for 12 weeks in addition to unchanged background medication. Patients underwent assessment using the 17-item Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, and the Beck Depression Inventory. RESULTS: Forty-six (88%) of 52 patients receiving ethyl-eicosapentaenoate and 14 (78%) of 18 patients receiving placebo completed the 12-week study with no serious adverse events. The 1-g/d group showed a significantly better outcome than the placebo group on all 3 rating scales. In the intention-to-treat group, 5 (29%) of 17 patients receiving placebo and 9 (53%) of 17 patients receiving 1 g/d of ethyl-eicosapentaenoate achieved a 50% reduction on the Hamilton Depression Rating Scale score. In the per-protocol group, the corresponding figures were 3 (25%) of 12 patients for placebo and 9 (69%) of 13 patients for the 1-g/d group. The 2-g/d group showed little evidence of efficacy, whereas the 4-g/d group showed nonsignificant trends toward improvement. All of the individual items on all 3 rating scales improved with the 1-g/d dosage of ethyl-eicosapentaenoate vs placebo, with strong beneficial effects on items rating depression, anxiety, sleep, lassitude, libido, and suicidality. CONCLUSION: Treatment with ethyl-eicosapentaenoate at a dosage of 1 g/d was effective in treating depression in patients who remained depressed despite adequate standard therapy.

PMID: 12365878 [PubMed - indexed for MEDLINE]

Am J Psychiatry 159:477-479, March 2002
© 2002 American Psychiatric Association

Addition of Omega-3 Fatty Acid to Maintenance Medication Treatment for Recurrent Unipolar Depressive Disorder.

Boris Nemets, M.D., Ziva Stahl, M.Sc., and R. H. Belmaker, M.D.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negrev, Beer-Sheva, Israel.

OBJECTIVE: Studies have reported that countries with high rates of fish oil consumption have low rates of depressive disorder. The authors studied a specific omega-3 fatty acid, the ethyl ester of eicosapentaenoic acid (E-EPA), as an adjunct to treatment for depressive episodes occurring in patients with recurrent unipolar depressive disorder who were receiving maintenance antidepressant therapy. METHOD: Twenty patients with a current diagnosis of major depressive disorder participated in a 4-week, parallel-group, double-blind addition of either placebo or E-EPA to ongoing antidepressant therapy. Seventeen of the patients were women, and three were men. RESULTS: Highly significant benefits of the addition of the omega-3 fatty acid compared with placebo were found by week 3 of treatment. CONCLUSIONS: It is not possible to distinguish whether E-EPA augments antidepressant action in the manner of lithium or has independent antidepressant properties of its own.

PMID: 11870016 [PubMed - indexed for MEDLINE]

Arch Gen Psychiatry. 2002 Jan;59(1)

Eicosapentaenoic Acid in Treatment-Resistant Depression

Puri B. K., Counsell S. J., Richardson A. J., Horrobin D. F.

Almost a third of patients with depression fail to respond to existing treatments, and new treatments are required. Epidemiological evidence about fish intake and blood levels of the relevant fatty acids suggests that increased intakes of 3 fatty acids such as eicosapentaenoic acid (EPA) may be helpful. A mixture of EPA and docosahexaenoic acid has been reported to improve depression and the course of illness in bipolar disorder, but to date; there are no reports of treatment of unipolar depression using this approach.

Int J Clin Pract. 2001 Oct;55(8):560-3.

Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover.

Puri BK, Counsell SJ, Hamilton G, Richardson AJ, Horrobin DF.

MRI Unit, Imperial College School of Medicine, Hammersmith Hospital, London, W12 0HS, UK.

The n-3 essential fatty acid eicosapentaenoic acid (EPA) was added to the conventional antidepressant treatment of a treatment-resistant severely depressed and suicidal male patient with a seven-year history of unremitting depressive symptoms. The niacin skin flush test and cerebral magnetic resonance scanning were carried out at baseline and nine months later. The addition of ethyl-EPA led to a dramatic and sustained clinical improvement in all the symptoms of depression, including a cessation of previously unremitting severe suicidal ideation, within one month. Symptoms of social phobia also improved dramatically. During the nine-month period the volumetric niacin response increased by 30%, the relative concentration of cerebral phosphomonesters increased by 53%, and the ratio of cerebral phosphomonesters to phosphodiesters increased by 79%, indicating reduced neuronal phospholipid turnover. Registered difference images showed that the EPA treatment was accompanied by structural brain changes including, in particular, a reduction in the lateral ventricular volume.

PMID: 11695079 [PubMed - indexed for MEDLINE]