Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial

David Mischoulon, MD, PhD^a,‡,* ; Boadie W. Dunlop, MD^b,‡ ; Becky Kinkead, PhD^b ; Pamela J. Schettler, PhD^b ; Stefania Lamon-Fava, MD, PhD^c ; Jeffrey J. Rakofsky, MD^b ; Andrew A. Nierenberg, MD^a ; Alisabet J. Clain, MS^a ; Tanja Mletzko Crowe, BA^b ; Andrea Wong, BA^b ; Jennifer C. Felger, MD^b ; Lisa Sangermano, BA^a ; Thomas R. Ziegler, MD^d ; Cristina Cusin, MD^a ; Lauren B. Fisher, MD^a ; Maurizio Fava, MD^a,§ ; Mark Hyman Rapaport, MD^b,e,§

J Clin Psychiatry 2022;83(5):21m14074

ABSTRACT

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.

Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m², and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.

Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).

Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.

Trial Registration: ClinicalTrials.gov identifier: NCT02553915

References (35)

Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2018;7:CD003177. PubMed CrossRef
Arca M, Borghi C, Pontremoli R, et al. Hypertriglyceridemia and omega-3 fatty acids: their often overlooked role in cardiovascular disease prevention. Nutr Metab Cardiovasc Dis. 2018;28(3):197–205. PubMed CrossRef
Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146–154. PubMed CrossRef
Chang JP-C, Su K-P, Mondelli V, et al. Omega-3 polyunsaturated fatty acids in youths with attention deficit hyperactivity disorder: a systematic review and meta-analysis of clinical trials and biological studies. Neuropsychopharmacology. 2018;43(3):534–545. PubMed CrossRef
Saunders EFH, Ramsden CE, Sherazy MS, et al. Omega-3 and omega-6 polyunsaturated fatty acids in bipolar disorder: a review of biomarker and treatment studies. J Clin Psychiatry. 2016;77(10):e1301–e1308. PubMed CrossRef
Liao Y, Xie B, Zhang H, et al. Efficacy of omega-3 PUFAs in depression: a meta-analysis. Transl Psychiatry. 2019;9(1):190. PubMed CrossRef
Ellulu MS, Khaza’ai H, Abed Y, et al. Role of fish oil in human health and possible mechanism to reduce the inflammation. Inflammopharmacology. 2015;23(2-3):79–89. PubMed CrossRef
Itariu BK, Zeyda M, Hochbrugger EE, et al. Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: a randomized controlled trial. Am J Clin Nutr. 2012;96(5):1137–1149. PubMed CrossRef
Abbate R, Gori AM, Martini F, et al. n-3 PUFA supplementation, monocyte PCA expression and interleukin-6 production. Prostaglandins Leukot Essent Fatty Acids. 1996;54(6):439–444. PubMed CrossRef
Baumann KH, Hessel F, Larass I, et al. Dietary omega-3, omega-6, and omega-9 unsaturated fatty acids and growth factor and cytokine gene expression in unstimulated and stimulated monocytes: a randomized volunteer study. Arterioscler Thromb Vasc Biol. 1999;19(1):59–66. PubMed CrossRef
Caughey GE, Mantzioris E, Gibson RA, et al. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr. 1996;63(1):116–122. PubMed CrossRef
Meydani SN, Endres S, Woods MM, et al. Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr. 1991;121(4):547–555. PubMed CrossRef
Trebble T, Arden NK, Stroud MA, et al. Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br J Nutr. 2003;90(2):405–412. PubMed CrossRef
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22–33, quiz 34–57. PubMed
de Waard F. Body Mass Index. J Chronic Dis. 1978;31(2):129. PubMed CrossRef
Osimo EF, Baxter LJ, Lewis G, et al. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019;49(12):1958–1970. PubMed CrossRef
Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26(3):477–486. PubMed CrossRef
Lichtenstein AH, Matthan NR, Jalbert SM, et al. Novel soybean oils with different fatty acid profiles alter cardiovascular disease risk factors in moderately hyperlipidemic subjects. Am J Clin Nutr. 2006;84(3):497–504. PubMed CrossRef
Chandler GM, Iosifescu DV, Pollack MH, et al. RESEARCH: validation of the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS Neurosci Ther. 2010;16(5):322–325. PubMed CrossRef
Block G, Wakimoto P, Jensen C, et al. Validation of a food frequency questionnaire for Hispanics. Prev Chronic Dis. 2006;3(3):A77. PubMed
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. PubMed CrossRef
Guy W, ed. ECDEU Assessment Manual for Psychopharmacology, Revised. DHEW Pub. No. (ADM) 76-338. National Institute of Mental Health; 1976.
Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21(10):1358–1365. PubMed CrossRef
Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31–41. PubMed CrossRef
Lenhard W, Lenhard A. Calculation of Effect Sizes. Dettelbach, Germany. Psychometrica website. https://www.psychometrica.de/effect_size.html. Published 2016. Accessed May 9, 2020.
Innes JK, Calder PC. The differential effects of eicosapentaenoic acid and docosahexaenoic acid on cardiometabolic risk factors: a systematic review. Int J Mol Sci. 2018;19(2):532. PubMed CrossRef
Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial. Eur Heart J. 2020;41(40):3925–3932. PubMed CrossRef
Lamon-Fava S, So J, Mischoulon D, et al. Dose- and time-dependent increase in circulating anti-inflammatory and pro-resolving lipid mediators following eicosapentaenoic acid supplementation in patients with major depressive disorder and chronic inflammation. Prostaglandins Leukot Essent Fatty Acids. 2021;164:102219. PubMed CrossRef
Furuyashiki T, Akiyama S, Kitaoka S. Roles of multiple lipid mediators in stress and depression. Int Immunol. 2019;31(9):579–587. PubMed CrossRef
Papakostas GI, Fava M. Does the probability of receiving placebo influence clinical trial outcome? a meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol. 2009;19(1):34–40. PubMed CrossRef
Rapaport MH, Nierenberg AA, Schettler PJ, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry. 2016;21(1):71–79. PubMed CrossRef
Bruggeman C, O’Day CS. Selective Serotonin Reuptake Inhibitor (SSRI) Toxicity. In: StatPearls. StatPearls Publishing. 2019. Accessed September 1, 2019. NIH website. https://www.ncbi.nlm.nih.gov/books/NBK534815/
Garcia E, Santos C. Monoamine Oxidase Inhibitor Toxicity. In: StatPearls. StatPearls Publishing; NIH website. https://www.ncbi.nlm.nih.gov/books/NBK459386/. 2019. Accessed September 1, 2019.
Khalid MM, Waseem M. Tricyclic Antidepressant Toxicity. In: StatPearls. StatPearls Publishing;. NIH website. https://www.ncbi.nlm.nih.gov/books/NBK430931/. 2019. Accessed September 1, 2019
Chang JP-C, Su K-P, Mondelli V, et al. High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels. Transl Psychiatry. 2019;9(1):303. PubMed CrossRef