Omega-3 polyunsaturated fatty acids for major depressive disorder

Expert Opinion on Investigational Drugs

Volumn 22, Issue 12, 2013, Pages 1519-1534

  Su, Kuan Pin ^a,b   Wang, Sheng Min ^c   Pae, Chi Un ^c,d  

^a CHINA MEDICAL UNIVERSITY   (Taiwan)

^b CHINA MEDICAL UNIVERSITY HOSPITAL   (Taiwan)

^c The Catholic University of Korea College of Medicine   (South Korea)

^d DUKE UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Clinical trial; Efficacy; Major depressive disorder; Omega 3 polyunsaturated fatty acids; Safety

Indexed keywords

5 HYDROXYINDOLEACETIC ACID; ALPHA TOCOPHEROL; ANTIDEPRESSANT AGENT; ARACHIDONIC ACID; ARIPIPRAZOLE; BUSPIRONE; CENTRAL STIMULANT AGENT; CREATINE; CYTOCHROME P450 2D6; DOCOSAHEXAENOIC ACID; DOPAMINE RECEPTOR; DOPAMINE RECEPTOR STIMULATING AGENT; FLUOXETINE PLUS OLANZAPINE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; ICOSAPENTAENOIC ACID; INTERLEUKIN 6; LIOTHYRONINE; LITHIUM; NEUROTRANSMITTER; OMEGA 3 FATTY ACID; PLACEBO; QUETIAPINE; REACTIVE OXYGEN METABOLITE; S ADENOSYLMETHIONINE; SCOPOLAMINE; TUMOR NECROSIS FACTOR ALPHA;

ANTIDEPRESSANT ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; BEHAVIOR CHANGE; BIPOLAR DEPRESSION; BIPOLAR DISORDER; DIET SUPPLEMENTATION; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; DRUG TOLERABILITY; FRONTAL CORTEX; HAMILTON SCALE; HUMAN; HYPOMANIA; LIPID PEROXIDATION; MAJOR DEPRESSION; MANIA; META ANALYSIS (TOPIC); MONOTHERAPY; MONTGOMERY ASBERG DEPRESSION RATING SCALE; NERVE CELL PLASTICITY; OXIDATIVE STRESS; RANDOMIZED CONTROLLED TRIAL (TOPIC); RECEPTOR DENSITY; RECOMMENDED DRUG DOSE; REVIEW; SHELF LIFE; THERAPY EFFECT; TREATMENT OUTCOME; TREATMENT RESISTANT DEPRESSION; UPREGULATION;

ANIMALS; ANTIDEPRESSIVE AGENTS; DEPRESSIVE DISORDER, MAJOR; FATTY ACIDS, OMEGA-3; HUMANS;

EID: 84887641056     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2013.836487     Document Type: Review

References (175)

1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289:3095-105
2. Murray CJ, Lopez AD. Evidence-based health policy-lessons from the Global Burden of Disease Study. Science 1996;274:740-3
3. Murray CJL, Lopez AD. The global burden of disease: A comprehensive assessment of mortality and disability form diseases, injuries and risk factors in 1990 and projected to 2020. Global Burden of Disease and Injury Series, vol Harvard School of Public Health; Cambridge: 1996.
4. Pae CU, Wang SM, Lee SY, et al. Early switch strategy in patients with major depressive disorder. Expert Rev Neurother 2012;12:1185-8
5. Wisniewski SR, Rush AJ, Balasubramani GK, et al. Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract 2006;12:71-9
6. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: A meta-analysis of placebo-controlled randomized trials. Am J Psychiatry 2009;166(9):980-91
7. Pae CU, Forbes A, Patkar AA. Aripiprazole as adjunctive therapy for patients with major depressive disorder: overview and implications of clinical trial data. CNS Drugs 2011;25:109-27
8. Pae CU, Patkar AA. Clinical issues in use of atypical antipsychotics for depressed patients. CNS Drugs 2013;27(Suppl 1):39-45
9. Han C, Park GY, Wang SM, et al. Can botulinum toxin improve mood in depressed patients Expert Rev Neurother 2012;12:1049-51
10. Han C, Pae CU. Oral scopolamine augmentation for major depression. Expert Rev Neurother 2013;13:19-21
11. Horrobin DF, Bennett CN. 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. Prostaglandins Leukot Essent.Fatty Acids 1999;60:217-34
12. Lands WE. Biochemistry and physiology of n-3 fatty acids. FASEB J 1992;6:2530-6
13. Connor WE. Importance of n-3 fatty acids in health and disease. Am J Clin Nutr 2000;71:171S-5S
14. Su KP. Mind-body interface: The role of n-3 fatty acids in psychoneuroimmunology, somatic presentation, and medical illness comorbidity of depression. Asia Pac J Clin Nutr 2008;17(Suppl 1):151-7
15. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a mind-body interface Neurosignals 2009;17:144-52
16. Torpy JM, Lynm C, Glass RM. JAMA patient page. Eating fish: health benefits and risks. JAMA 2006;296:1926
17. Lin PY, Chiu CC, Huang SY, et al. A meta-analytic review of polyunsaturated fatty acid compositions in dementia. J Clin Psychiatry 2012; In Press
18. Chiu CC, Huang SY, Su KP, et al. Polyunsaturated fatty acid deficit in patients with bipolar mania. Eur Neuropsychopharmacol 2003;13:99-103
19. Lewis MD, Hibbeln JR, Johnson JE, et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status: A case-control comparison. J Clin Psychiatry 2011;72:1585-90
20. 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;67:1954-67
21. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry 2010;68:140-7
22. Freeman MP, Hibbeln JR, Silver M, et al. Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: A preliminary open trial. Menopause 2011;18:279-84
23. Lu DY, Tsao YY, Leung YM, et al. Docosahexaenoic acid suppresses neuroinflammatory responses and induces heme oxygenase-1 expression in BV-2 microglia: Implications of antidepressant effects for omega-3 fatty acids. Neuropsychopharmacology 2010;35:2238-48
24. 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;16:1627-38
25. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 2007;68:1056-61
26. Su KP, Huang SY, Chiu CC, et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267-71
27. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry 2002;159:477-9
28. Su KP, Huang SY, Chiu TH, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008;69:644-51.. The first placebo-controlled clinical trial of omega-3 pUFA in pregnant depressed woman as well as being the first one of monotherapeutic use of omega-3 OUFA for depression.
29. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Mol Psychiatry 2011;In press.. A recent meta-analysis showing negative effects of omega-3 PUFA.
30. Martins JG, Bentsen H, Puri BK. Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: A critique of Bloch and Hannestad and updated meta-analysis. Mol Psychiatry 2012
31. Lin PY, Mischoulon D, Freeman MP, et al. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. Mol Psychiatry 2012;In press.. A recent meta-analysis against the results from Bloch and Hannestad meta-analysis.
32. Cipriani A, Geddes J. Comparison of systematic and narrative reviews: The example of the atypical antipsychotics. Epidemiol Psichiatr Soc 2003;12:146-53. A good review showing a difference between narrative and systematic review for clinicians.
33. Carlezon WA Jr, Mague SD, Parow AM, et al. Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats. Biol Psychiatry 2005;57:343-50
34. Lakhwani L, Tongia SK, Pal VS, et al. Omega-3 fatty acids have antidepressant activity in forced swimming test in Wistar rats. Acta Pol Pharm 2007;64:271-6
35. Huang SY, Yang HT, Chiu CC, et al. Omega-3 fatty acids on the forced-swimming test. J Psychiatr Res 2008;42:58-63
36. Song C, Zhang XY, Manku M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: Effects of chronic ethyl-eicosapentaenoate treatment. J Neurosci 2009;29:14-22
37. Delion S, Chalon S, Herault J, et al. Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotonergic neurotransmission in rats. J Nutr 1994;124:2466-75
38. Chalon S, Vancassel S, Zimmer L, et al. Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission. Lipids 2001;36:937-44
39. Berg KA, Maayani S, Clarke WP. 5-hydroxytryptamine2C receptor activation inhibits 5-hydroxytryptamine1B-like receptor function via arachidonic acid metabolism. Mol Pharmacol 1996;50:1017-23
40. Farooqui AA, Hirashima Y, Horrocks LA. Brain phospholipases and their role in signal transduction. Adv Exp Med Biol 1992;318:11-25
41. Chalon S, Delion-Vancassel S, Belzung C, et al. Dietary fish oil affects monoaminergic neurotransmission and behavior in rats. J Nutr 1998;128:2512-19
42. Delion S, Chalon S, Guilloteau D, et al. alpha-Linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex. J Neurochem 1996;66:1582-91
43. Maes M, Meltzer HYM. The serotonin hypothesis of major depression. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology, the fourth generation of progress. Raven Press; New York: 1995. p. 933-41
44. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213
45. Nizzo MC, Tegos S, Gallamini A, et al. Brain cortex phospholipids liposomes effects on CSF HVA, 5-HIAA and on prolactin and somatotropin secretion in man. J Neural Transm 1978;43:93-102
46. Dantzer R, OConnor JC, Freund GG, et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56
47. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24-31
48. Felger JC, Alagbe O, Hu F, et al. Effects of interferon-alpha on rhesus monkeys: A nonhuman primate model of cytokine-induced depression. Biol Psychiatry 2007;62:1324-33
49. Lu DY, Leung YM, Su KP. Interferon-alpha induces nitric oxide synthase expression and haem oxygenase-1 down-regulation in microglia: Implications of cellular mechanism of IFN-alpha-induced depression. Int J Neuropsychopharmacol 2012;1-12
50. Kumai T, Tateishi T, Tanaka M, et al. Effect of interferon-alpha on tyrosine hydroxylase and catecholamine levels in the brain of rats. Life Sci 2000;67:663-9
51. Su KP. Inflammation in psychopathology of depression: Clinical, biological, and therapeutic implications. Biomedicine 2012;2:68-74
52. McNamara RK, Jandacek R, Rider T, et al. Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover. Prostaglandins Leukot Essent Fatty Acids 2010;83:185-91
53. Kiecolt-Glaser JK, Belury MA, Andridge R, et al. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: A randomized controlled trial. Brain Behav Immun 2012;26:988-95
54. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999;46:1181-91
55. Perera TD, Coplan JD, Lisanby SH, et al. Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J Neurosci 2007;27:4894-901
56. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003;301:805-9
57. Frangou S, Lewis M, Wollard J, et al. Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol 2007;21:435-9
58. Beltz BS, Tlusty MF, Benton JL, et al. Omega-3 fatty acids upregulate adult neurogenesis. Neurosci Lett 2007;415:154-8
59. Dyall SC, Michael GJ, Michael-Titus AT. Omega-3 fatty acids reverse age-related decreases in nuclear receptors and increase neurogenesis in old rats. J Neurosci Res 2010;88:2091-102
60. Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 2006;139:991-7
61. Blondeau N, Nguemeni C, Debruyne DN, et al. Subchronic alpha-linolenic acid treatment enhances brain plasticity and exerts an antidepressant effect: A versatile potential therapy for stroke. Neuropsychopharmacology 2009;34:2548-59
62. Venna VR, Deplanque D, Allet C, et al. PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus. Psychoneuroendocrinology 2009;34:199-211
63. Levant B, Ozias MK, Davis PF, et al. Decreased brain docosahexaenoic acid content produces neurobiological effects associated with depression: Interactions with reproductive status in female rats. Psychoneuroendocrinology 2008;33:1279-92
64. Rao JS, Ertley RN, Lee HJ, et al. n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Mol Psychiatry 2007;12:36-46
65. Wu A, Ying Z, Gomez-Pinilla F. Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. J Neurotrauma 2004;21:1457-67
66. Rapoport SI, Bosetti F. Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder Arch Gen Psychiatry 2002;59:592-6
67. Maes M, Christophe A, Delanghe J, et al. Lowered omega3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 1999;85:275-91
68. Maes M, Smith R, Christophe A, 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;38:35-46
69. Noponen M, Sanfilipo M, Samanich K, et al. Elevated PLA2 activity in schizophrenics and other psychiatric patients. Biol Psychiatry 1993;34:641-9
70. Su KP, Huang SY, Peng CY, et al. Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels. Biol Psychiatry 2010;67:550-7
71. Chang MC, Contreras MA, Rosenberger TA, et al. Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: A possible common effect of mood stabilizers. J Neurochem 2001;77:796-803
72. Rintala J, Seemann R, Chandrasekaran K, et al. 85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain. Neuroreport 1999;10:3887-90
73. Chang MC, Jones CR. Chronic lithium treatment decreases brain phospholipase A2 activity. Neurochem Res 1998;23:887-92
74. Ghelardoni S, Tomita YA, Bell JM, et al. Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry 2004;56:248-54
75. Su KP, Shen WW, Huang SY. Are omega3 fatty acids beneficial in depression but not mania Arch Gen Psychiatry 2000;57:716-17
76. Mahadik SP, Mukherjee S, Horrobin DF, et al. Plasma membrane phospholipid fatty acid composition of cultured skin fibroblasts from schizophrenic patients: Comparison with bipolar patients and normal subjects. Psychiatry Res 1996;63:133-42
77. Lee SY LS, Han C, Patkar AA, et al. Oxidative/nitrosative stress and antidepressants: Targets for novel antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2013;46:224-35
78. Mori TA, Woodman RJ, Burke V, et al. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Radic Biol Med 2003;35:772-81
79. Chen LY, Lawson DL, Mehta JL. Reduction in human neutrophil superoxide anion generation by n-3 polyunsaturated fatty acids: role of cyclooxygenase products and endothelium-derived relaxing factor. Thromb Res 1994;76:317-22
80. von Schacky C, Baumann K, Angerer P. The effect of n-3 fatty acids on coronary atherosclerosis: Results from SCIMO, an angiographic study, background and implications. Lipids 2001;36(Suppl):S99-102
81. Hajianfar H, Paknahad Z, Bahonar A. The effect of omega-3 supplements on antioxidant capacity in patients with type 2 diabetes. Int J Prevent Med 2013;4:S234-8
82. Kesavulu MM, Kameswararao B, Apparao C, et al. Effect of omega-3 fatty acids on lipid peroxidation and antioxidant enzyme status in type 2 diabetic patients. Diabetes Metab 2002;28:20-6
83. Mori TA, Puddey IB, Burke V, et al. Effect of omega 3 fatty acids on oxidative stress in humans: GC-MS measurement of urinary F2-isoprostane excretion. Redox Rep 2000;5:45-6
84. Mori TA, Woodman RJ, Burke V, et al. Effect of eicosapentaenoic acid and docosahexaenoic acid on oxidative stress and inflammatory markers in treated-hypertensive type 2 diabetic subjects. Free Radic Biol Med 2003;35(7):772-81
85. Meyer BJ, Grenyer BF, Crowe T, et al. Improvement of major depression is associated with increased erythrocyte DHA. Lipids 2013;In press
86. Hibbeln JR, Linnoila M, Umhau JC, et al. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early-and late-onset alcoholics. Biol Psychiatry 1998;44:235-42
87. Hibbeln JR, Nieminen LR, Blasbalg TL, et al. Healthy intakes of n-3 and n-6 fatty acids: Estimations considering worldwide diversity. Am J Clin Nutr 2006;83:1483S-93S
88. Kotwal S, Jun M, Sullivan D, et al. Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2012;5:808-18
89. De Vriese SR, Christophe AB, Maes M. Lowered serum n-3 polyunsaturated fatty acid (PUFA) levels predict the occurrence of postpartum depression: further evidence that lowered n-PUFAs are related to major depression. Life Sci 2003;73:3181-7
90. Green P, Hermesh H, Monselise A, et al. Red cell membrane omega-3 fatty acids are decreased in nondepressed patients with social anxiety disorder. Eur Neuropsychopharmacol 2006;16:107-13
91. Mischoulon D, Best-Popescu C, Laposata M, et al. A double-blind dosefinding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. Eur Neuropsychopharmacol 2008;18:639-45
92. Mischoulon D, Papakostas GI, Dording CM, et al. A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J Clin Psychiatry 2009;70:1636-44
93. Nemets H, Nemets B, Apter A, et al. Omega-3 treatment of childhood depression: A controlled, double-blind pilot study. Am J Psychiatry 2006;163:1098-100
94. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59:913-19
95. Gertsik L, Poland RE, Bresee C, et al. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clin Psychopharmacol 2012;32:61-4
96. Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust NZ J Psychiatry 2008;42:192-8
97. da Silva TM, Munhoz RP, Alvarez C, et al. Depression in Parkinsons disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J Affect Disord 2008;111:351-9
98. Khajehnasiri F, Mortazavi SB, Allameh A, et al. Effect of omega-3 and ascorbic acid on inflammation markers in depressed shift workers in Shahid Tondgoyan Oil Refinery, Iran: A randomized double-blind placebo-controlled study. J Clin Biochem Nutr 2013;53:36-40
99. Mozurkewich EL, Clinton CM, Chilimigras JL, et al. The Mothers, Omega-3, and Mental Health Study: A double-blind, randomized controlled trial. Am J Obstet Gynecol 2013;208:313, e1-9
100. Freeman MP, Davis M, Sinha P, et al. Omega-3 fatty acids and supportive psychotherapy for perinatal depression: A randomized placebo-controlled study. J Affect Disord 2008;110:142-8
101. Lesperance F, Frasure-Smith N, St-Andre E, et al. The efficacy of omega-3 supplementation for major depression: A randomized controlled trial. J Clin Psychiatry 2011;72:1054-62
102. Lucas M, Asselin G, Merette C, et al. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: A double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr 2009;89:641-51
103. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry 2003;160:996-8
104. Rogers PJ, Appleton KM, Kessler D, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: A randomised controlled trial. Br J Nutr 2008;99:421-31
105. Bot M, Pouwer F, Assies J, et al. Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: A randomized, double-blind placebo-controlled study. J Affect Disord 2010;126:282-6
106. Carney RM, Freedland KE, Rubin EH, et al. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: A randomized controlled trial. JAMA 2009;302:1651-7
107. Grenyer BF, Crowe T, Meyer B, et al. Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1393-6
108. Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: Randomized double-blind placebo-controlled trial. Aust NZ J Psychiatry 2008;42:199-205
109. Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011
110. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;84:1308-16
111. Richardson AJ. n-3 Fatty acids and mood: The devil is in the detail. Br J Nutr 2008;99:221-3
112. Stoll AL Severus WE, Freeman MP, et al. Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407-12
113. Chiu CC, Huang SY, Chen CC, et al. Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry 2005;66:1613-14
114. Murphy BL, Stoll AL, Harris PQ, et al. Omega-3 fatty acid treatment, with or without cytidine, fails to show therapeutic properties in bipolar disorder: A double-blind, randomized add-on clinical trial. J Clin Psychopharmacol 2012;32:699-703
115. Bays HE. Safety considerations with omega-3 fatty acid therapy. Am J Cardiol 2007;99:35C-43C
116. 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;75:291-7
117. Bays H. Clinical overview of Omacor: A concentrated formulation of omega-3 polyunsaturated fatty acids. Am J Cardiol 2006;98:71i-6i
118. Harris WS. Expert opinion: omega-3 fatty acids and bleeding-cause for concern Am J Cardiol 2007;99:44C-6C
119. Matsuo N. Studies on the toxicity of fish oil. V. Toxicity of oxidized commercial cod-liver oil. Tokushima J Exp Med 1961;8:96-100
120. Palozza P, Sgarlata E, Luberto C, et al. n-3 fatty acids induce oxidative modifications in human erythrocytes depending on dose and duration of dietary supplementation. Am J Clin Nutr 1996;64:297-304
121. Stalenhoef AF, de Graaf J, Wittekoek ME, et al. The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia. Atherosclerosis 2000;153:129-38
122. Grundt H, Nilsen DW, Mansoor MA, et al. Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction. Eur J Clin Nutr 2003;57:793-800
123. Turini ME, Crozier GL, Donnet-Hughes A, et al. Short-term fish oil supplementation improved innate immunity, but increased ex vivo oxidation of LDL in man-a pilot study. Eur J Nutr 2001;40:56-65
124. Nair PP, Judd JT, Berlin E, et al. Dietary fish oil-induced changes in the distribution of alpha-tocopherol, retinol, and beta-carotene in plasma, red blood cells, and platelets: modulation by vitamin E. Am J Clin Nutr 1993;58:98-102
125. Valk EE, Hornstra G. Relationship between vitamin E requirement and polyunsaturated fatty acid intake in man: A review. Int J Vitam Nutr Res 2000;70:31-42
126. Turley E, Wallace JM, Gilmore WS, et al. Fish oil supplementation with and without added vitamin E differentially modulates plasma antioxidant concentrations in healthy women. Lipids 1998;33:1163-7
127. Wander RC, Du SH, Ketchum SO, et al. alpha-Tocopherol influences in vivo indices of lipid peroxidation in postmenopausal women given fish oil. J Nutr 1996;126:643-52
128. Halvorsen B, Almendingen K, Nenseter MS, et al. Effects of partially hydrogenated fish oil, partially hydrogenated soybean oil and butter on the susceptibility of low density lipoprotein to oxidative modification in men. Eur J Clin Nutr 1996;50:364-70
129. Higdon JV, Du SH, Lee YS, et al. Supplementation of postmenopausal women with fish oil does not increase overall oxidation of LDL ex vivo compared to dietary oils rich in oleate and linoleate. J Lipid Res 2001;42:407-18
130. Higgins S, Carroll YL, McCarthy SN, et al. Susceptibility of LDL to oxidative modification in healthy volunteers supplemented with low doses of n-3 polyunsaturated fatty acids. Br J Nutr 2001;85:23-31
131. Linseisen J, Hoffmann J, Lienhard S, et al. Antioxidant status of surgical patients receiving TPN with an omega-3-fatty acid-containing lipid emulsion supplemented with alpha-tocopherol. Clin Nutr 2000;19:177-84
132. Rhodes LE, Shahbakhti H, Azurdia RM, et al. Effect of eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, on UVR-related cancer risk in humans. An assessment of early genotoxic markers. Carcinogenesis 2003;24:919-25
133. Tholstrup T, Hellgren LI, Petersen M, et al. A solid dietary fat containing fish oil redistributes lipoprotein subclasses without increasing oxidative stress in men. J Nutr 2004;134:1051-7
134. Calviello G, Palozza P, Franceschelli P, et al. Low-dose eicosapentaenoic or docosahexaenoic acid administration modifies fatty acid composition and does not affect susceptibility to oxidative stress in rat erythrocytes and tissues. Lipids 1997;32:1075-83
135. Wheaton DH, Hoffman DR, Locke KG, et al. Biological safety assessment of docosahexaenoic acid supplementation in a randomized clinical trial for X-linked retinitis pigmentosa. Arch Ophthalmol 2003;121:1269-78
136. Barbosa DS, Cecchini R, El Kadri MZ, et al. Decreased oxidative stress in patients with ulcerative colitis supplemented with fish oil omega-3 fatty acids. Nutrition 2003;19:837-42
137. Jain S, Gaiha M, Bhattacharjee J, et al. Effects of low-dose omega-3 fatty acid substitution in type-2 diabetes mellitus with special reference to oxidative stress-a prospective preliminary study. J Assoc Physicians India 2002;50:1028-33
138. Parinyasiri U, Ong-Ajyooth L, Parichatikanond P, et al. Effect of fish oil on oxidative stress, lipid profile and renal function in IgA nephropathy. J Med Assoc Thai 2004;87:143-9
139. Vericel E, Calzada C, Chapuy P, et al. The influence of low intake of n-3 fatty acids on platelets in elderly people. Atherosclerosis 1999;147:187-92
140. Abel S, De Kock M, Smuts CM, et al. Dietary modulation of fatty acid profiles and oxidative status of rat hepatocyte nodules: Effect of different n-6/n-3 fatty acid ratios. Lipids 2004;39:963-76
141. Mohan IK, Das UN. Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus. Prostaglandins Leukot.Essent.Fatty Acids 1997;56:193-8
142. Ramirez-Tortosa MC, Suarez A, Gomez MC, et al. Effect of extra-virgin olive oil and fish-oil supplementation on plasma lipids and susceptibility of low-density lipoprotein to oxidative alteration in free-living spanish male patients with peripheral vascular disease. Clin Nutr 1999;18:167-74
143. Yavin E, Glozman S, Green P. Docosahexaenoic acid accumulation in the prenatal brain: Prooxidant and antioxidant features. J Mol Neurosci 2001;16:229-35
144. Kinrys G. Hypomania associated with omega3 fatty acids. Arch Gen Psychiatry 2000;57:715-16
145. Philip NS, Carpenter LL, Tyrka AR, et al. Augmentation of antidepressants with atypical antipsychotics: A review of the current literature. J Psychiatr Pract 2008;14:34-44
146. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry 2010;68:140-7
147. Papakostas GI. Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. J Clin Psychiatry 2009;70(Suppl 5):18-22
148. Freeman MP. Complementary and Alternative Medicine (CAM): Considerations for the treatment of major depressive disorder. J Clin Psychiatry 2009;70(Suppl 5):4-6
149. Lyoo IK, Yoon S, Kim TS, et al. A randomized, double-blind placebocontrolled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder. Am J Psychiatry 2012;169:937-45
150. Pae CU, Sohi MS, Seo HJ, et al. Quetiapine XR: Current status for the treatment of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1165-73
151. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA 1996;276:293-9
152. Anderson GJ, Connor WE, Corliss JD. Docosahexaenoic acid is the preferred dietary n-3 fatty acid for the development of the brain and retina. Pediatr Res 1990;27:89-97
153. Makrides M, Crowther CA, Gibson RA, et al. Docosahexaenoic acid and post-partum depression-is there a link Asia Pac J Clin Nutr 2003;12(Suppl):S37
154. Verlengia R, Gorjao R, Kanunfre CC, et al. Comparative effects of eicosapentaenoic acid and docosahexaenoic acid on proliferation, cytokine production, and pleiotropic gene expression in Jurkat cells. J Nutr Biochem 2004;15:657-65
155. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: Evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutr 2009;28:525-42
156. Ross BM, Seguin J, Sieswerda LE. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid Lipids Health Dis 2007;6:21
157. Bares M, Novak T, Kopecek M, et al. The early improvement of depressive symptoms as a potential predictor of response to antidepressants in depressive patients who failed to respond to previous antidepressant treatments. Analysis of naturalistic data. Eur Psychiatry 2012;27:522-7
158. Henkel V, Seemuller F, Obermeier M, et al. Does early improvement triggered by antidepressants predict response/remission Analysis of data from a naturalistic study on a large sample of inpatients with major depression. J Affect Disord 2009;115:439-49
159. Papakostas GI, Perlis RH, Scalia MJ, et al. A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder. J Clin Psychopharmacol 2006;26:56-60
160. Tadic A, Helmreich I, Mergl R, et al. Early improvement is a predictor of treatment outcome in patients with mild major, minor or subsyndromal depression. J Affect Disord 2010;120:86-93
161. Szegedi A, Muller MJ, Anghelescu I, et al. Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. J Clin Psychiatry 2003;64:413-20
162. Nierenberg AA, McLean NE, Alpert JE, et al. Early nonresponse to fluoxetine as a predictor of poor 8-week outcome. Am J Psychiatry 1995;152:1500-3
163. Shen H, He MM, Liu H, et al. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 2007;35:1292-300
164. Chong SA, Tan CH, Khoo YM, et al. Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizophrenia. Ther Drug Monit 1997;19:219-23
165. Iso H, Sato S, Folsom AR, et al. Serum fatty acids and fish intake in rural Japanese, urban Japanese, Japanese American and Caucasian American men. Int J Epidemiol 1989;18:374-81
166. Kris-Etherton PM, Harris WS, Appel LJ, et al. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151-2
167. Chiu CC, Huang SY, Shen WW, et al. Omega-3 fatty acids for depression in pregnancy. Am J Psychiatry 2003;160:385
168. Freeman MP, Sinha P. Tolerability of omega-3 fatty acid supplements in perinatal women. Prostaglandins Leukot Essent Fatty Acids 2007;77:203-8
169. Kendall-Tackett K. Long-chain omega-3 fatty acids and womens mental health in the perinatal period and beyond. J Midwifery Womens Health 2010;55:561-7
170. Hallahan B, Hibbeln JR, Davis JM, et al. Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br J Psychiatry 2007;190:118-22
171. Mischoulon D. The impact of omega-3 fatty acids on depressive disorders and suicidality: Can we reconcile 2 studies with seemingly contradictory results J Clin Psychiatry 2011;72:1574-6
172. 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;160:167-9
173. Gabbay V, Babb JS, Klein RG, et al. A double-blind, placebo-controlled trial of omega-3 fatty acids in Tourettes disorder. Pediatrics 2012;129:e1493-500
174. Matsuoka Y, Nishi D, Yonemoto N, et al. Tachikawa project for prevention of posttraumatic stress disorder with polyunsaturated fatty acid (TPOP): study protocol for a randomized controlled trial. BMC Psychiatry 2013;13:8
175. Silvers KM, Woolley CC, Hamilton FC, et al. Randomised double-blind placebocontrolled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids 2005;72:211-18