Ethyl eicosapentaenoic acid

Ethyl eicosapentaenoic acid
File:Ethyl eicosapentaenoate.png
IUPAC name Ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate
Other names Eicosapentaenoic acid ethyl ester; Ethyl eicosapentaenoate; Epadel; Icosapent; Ethyl icosapentate; EPA ethyl ester
style="background: #F8EABA; text-align: center;" colspan="2" | Identifiers
CAS number	86227-47-6
PubChem	9831415
SMILES
style="background: #F8EABA; text-align: center;" colspan="2" | Properties
Molecular formula	C22H34O2
Molar mass	330.5 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Ethyl eicosapentaenoic acid (E-EPA) is a synthetic derivative of derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). In Japan E-EPA is often called EPA-E.

Only EPA is considered to exihibit antipsychotic and antidepressive effects. E-EPA is a psychotropic omega-3 fatty acid and it is therefore of special interest in psychiatry.

Cardiovascular diseases, diabetes

The Japan Eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) tested the effects of long-term use of E-EPA (1800 mg/day) in addition to a statin in Japanese patients with hypercholesterolemia. The results suggest that the addition of E-EPA to statin therapy prevents major coronary events, angina pectoris and clinical myocardial infarctions, apparently through mechanisms independent from regulation of the lipid metabolism. It has been suggested that the cardioprotective action of E-EPA is probably mediated by its anti-inflammatory properties. In addition, E-EPA may improve the clinical outcome in type 2 diabetes and its cardiovascular complications, such as coronary artery disease and thickening of carotid arteries. E-EPA may on the one hand reduce the platelet-derived microparticles (PDMP) and on the other enhance the cardioprotective hormone adiponectin in hyperlipidemic, diabetic patients. According to Japanese mice studies, E-EPA may prevent and correct non-alcoholic fatty liver.

Mental health

Acute psychosis

As adjuct therapy, E-EPA has been tested in first-episode psychosis. The daily dosage of E-EPA given in these trials, i.e., 2 gram per day, corresponds to 10 to 15 helpings of Atlantic salmon.

In schizophrenia, the trials are based on the so-called membrane theory of the disease. According to the Omega-3 Subcommittee of the American Psychiatric Association (APA), the evidence of the effects is still too weak to recommend the use of E-EPA, but more studies are currently in progress.

Clinical depression

Omega-3 fatty acids have been investigated as adjunct therapy for depression as they are anti-inflammatory agents and chronic low-grade inflammation has been linked to the disease. Moreover, omega-3 content in the cell membranes of depressive persons is often decreased, and supplementation with omega-3 may correct this deficiency and improve the clinical outcome. . This hypothesis has been tested in a number of clinical trials using E-EPA, mostly 1 gram daily.

Most (but not all) trials have yielded positive results. In one study E-EPA boosted the effect of an antidepressive drug, fluoxetine. According to a new report from Massachusetts General Hospital in Boston, E-EPA seems to be more effective than placebo as monotherapy in major depressive disorder.

Bipolar depression

The first placebo-controlled study with ethyl esterized fish oil was carried out at Harvard University by professor Andrew L. Stoll, published in 1999. His team later demonstrated that rigid cell mebranes in test subjects were smoothed by omega-3 fatty acids. Subsequent studies at London's King's College Institute of Psychiatry have demonstrated the efficacy of E-EPA in bipolar patients. One of the biochemical mechanisms seem to be enhancement of an amino acid called N-acetyl aspartate (NAA) in the brain. E-EPA seems to exert similar effect on the NAA concentration as lithium which has been used for bipolar depression for decades.

Borderline personality disorder

So far one small clinical trial conducted on women has been published yielding promising results.

Psychological stress

Animal tests demonstrate that E-EPA balances the metabolism of glucocorticoids (cortisol and cortisone) and may thus alleviate stress symptoms and attenuate interleukine 1-beta (IL-1b) induced changes in dopamine and it's metabolites in the shell of the Nucleus accumbens. The fatty acid EPA may confer neuroprotection in the amyloid-ß challenged aged hippocampus.

Other conditions

E-EPA has been tested and found beneficial in anorexia nervosa, hepatitis C, in children with ulcerative colitis, nonalcoholic fatty liver (steatohepatisis) in psychological distress in postmenopausal middle-aged women, and in women suffering from menopausal hot flushes.

Safety aspects

E-EPA 2 g/day is generally well tolerated. Clinicians should be aware of possible increases in bleeding time, as well as changes in weight and lipid metabolism.

External links

• Function of E-EPA on the nerve cell membrane. Animationfi:E-EPA

Horrobin D. The Madness of Adam and Eve. How schizophrenia shaped humanity. Bantam Press 2001

Horrobin DF (2002). "A new category of psychotropic drugs: neuroactive lipids as exemplified by ethyl eicosapentaenoate (E-E)". Prog Drug Res. 59: 171–99. PMID 12458967. 

Yokoyama M, Origasa H, Matzunaki M. et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomized open-label, blinded endpoit analysis. The Lancet 2007;369:1090-8 Abstract

Tanaka K, Ishikawa Y, Yokoyama M, et al. for the JELIS Investigators, Japan. Reduction in the Recurrence of Stroke by Eicosapentaenoic Acid for Hypercholesterolemic Patients. Subanalysis of the JELIS Trial. Stroke. 2008;39:2052-2058[1]

King A. Does treatment with eicosapentaenoic acid prevent major coronary events in patients with hypercholesterolemia? Editorial. Commentary by William S. Harris Nat Clin Pract Cardiovasc Med. 2007 Aug 14; Free Full Text

Harris WS. Omega-3 fatty acids. The "Japanese" factor. Journal of the American College of Cardiology 2008;52(6)425–7JAAC

Westerveld HT, de Graaf JC, van Breugel HH, et al. Effects of low-dose EPA-E on glycemic control, lipid profile, lipoprotein(a), platelet aggregation, viscosity, and platelet and vessel wall interaction in NIDDM. Diabetes Care. 1993; 16(5) 683-688 Abstract

Satoh N, Shimatsu AS, Kotani, K et al. Purified Eicosapentaenoic Acid Reduces Small Dense LDL, Remnant Lipoprotein Particles, and C-reactive Protein in Metabolic Syndrome Diabetes Care 2007;30: 144-146 Full Free Text

Oikawa S, Yokoyama M, Origasa H. et al. Jelis Investigators, Japan. (Oct 2009) "Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study." Atherosclerosis 2009;206(2):535-9. Abstract

Nemoto E, Suzuki S, Kikuchi H, et al. (Sept 2009)"Ethyl-eicosapentaenoic Acid Reduces Liver Lipids and Lowers Plasma Levels of Lipids in Mice Fed a High-fat Diet." In Vivo 23:685-689 Abstract

Kajikawa S, Harada T, Kawashima A, et al. (2009) "Suppression of hepatic fat accumulation by highly purified eicosapentaenoic acid prevents the progression of d-galactosamine-induced hepatitis in mice fed with a high-fat/high-sucrose diet." Biochim Biophys Acta. 1791(4):281-8. PubMed

Wood SJ, Cocchi L, Proffitt TM, et al. Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: a longitudinal T2 relaxometry pilot study. Psychiatry Res. 2010 (May);182(2):180-2.Free Full Text

Berger GE, Proffit TM, McConchie M, et al. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry 2007;68:1867-1875 Free Full Text

Peet M. Essential fatty acids: theoretical aspects and treatment implications for schizophrenia and depression. Advances in Psychiatric Treatment (2002) 8: 223-229 Free Full Text

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Emsley R, Myburgh C, Oosthuizen P et al. Randomized, Placebo-Controlled Study of Ethyl-Eicosapentaenoic Acid as Supplemental Treatment in Schizophrenia. Am J Psychiatry 2002;159:1596-1598 Full Free Text

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Peet M, Horrobin DF (2002). "A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms". J Psychiatr Res. 36 (1): 7–18. doi:10.1016/S0022-3956(01)00048-6. PMID 11755456. 

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Clinical Trials

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Kiecolt-Glaser JK, Belury MA, Porter K, et al. Depressive Symptoms, omega-6:omega-3 Fatty Acids, and Inflammation in Older Adults Psychosom Med, 2007; 69(3): 217 - 224 Abstract

Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 2006;27(1) 24-31 Free Full Text

Song C, Li X, Kang Z, Kadotomi Y. 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. Neuropsychopharmacology 2007;32(5):1207 Free Full Text

McNamara RK. The emerging role of omega-3 fatty acids in psychiatry. Prostaglandins Leukot Essent Fatty Acids. 2006 Aug 22 Free Full Text

McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fatty Acids. 2006 Aug 29 Free Full Text

Nemets B, Oscher Y, Belmaker RH. Omega-3 fatty acids and augmentation strategies in treating resistant depression. Essent Psychopharmacol. 2004;6(1):59-64

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Mischoulon D, Papakostas GI, Dording CM, et al. (August 2009) “A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder.” J Clin Psychiatry. Abstract

Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry 1999;56(5):407-12 Free Full Text

Frangou S, Lewis M, McCrohe P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. British Journal of Psychiatry 2006;188: 46-50 Free Full Text

Frangou S, Lewis M, Wollard J, Simmons A. Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol. 2006 Aug 4 Free Full Text

Zanarini MC, Frankenburg FR. Omega-3 Fatty Acid treatment of women with borderline personality disorder: a double-blind, placebo-controlled pilot study. Am J Psychiatry. 2003;160(1):167-9 Free Full Text

Taepavarapruk P, Song C. (Dec 2009) "Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin-1beta administrations: effects of omega-3 fatty acid EPA treatment." J Neurochem. Free Full Text

Song C, Li X, Kang Z, Kadotomi Y. 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. Neuropsychopharmacology 2007;32(5):1207 Free Ful Text

Song C, Li X, Kang Z, Kadotomi Y. 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. Neuropsychopharmacology 2006 Jun 14; Free Full Text

Song C, Zhao S Omega-3 fatty acid eicosapentaenoic acid. A new treatment for psychiatric and neurodegenerative diseases: a review of clinical investigations. Expert Opin Investig Drugs. 2007;16(10):1627-1638 PubMed

Lynch AM, Loane DJ, Minogue AM et al. Eicosapentaenoic acid confers neuroprotection in the amyloid-ß challenged aged hippocampus. Neurobiology of aging 2007; 28(6) 845-855

Lynch AM, Lynch MA. The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. European Journal of Neuroscience 2002;15 (11), 1779–1788 Abstract

Ayton AK, Azaz A, Horrobin DF. Rapid improvement of severe anorexia nervosa during treatment with ethyl-eicosapentaenoate and micronutrients. Eur Psychiatry. 200419(5):317-9 Free Full Text

Ayton AK, Azaz A, Horrobin DF. A pilot open case series of Ethyl-EPA supplementation in the treatment of anorexia nervosa. Prostaglandins Leukot Essent Fatty Acids. 2004:71(4):205-9 Free Full Text

Lucas M, Asselin G, Mérette C, Poulin MJ, Dodin S. Effects of ethyl-eicosapentaenoic acid omega-3 fatty acid supplementation on hot flashes and quality of life among middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Menopause. 2008 Nov 20 Abstract