This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day−1, docosahexaenoic acid (DHA)-enriched n-3 900 mg day−1 or placebo. Outcomes were determined using mixed model repeated measures analysis for ‘high’ and ‘low’ inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=−0.13 to +0.04), subjects with any ‘high’ inflammation improved more on EPA than placebo (ES=−0.39) or DHA (ES=−0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with ‘high’ IL-1ra or hs-CRP or low adiponectin (‘high’ inflammation) had medium ES decreases in HAM-D-17 scores vs subjects ‘low’ on these biomarkers. Subjects with ‘high’ hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.
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The study was funded by grant 5R01MH74085 from the National Institutes of Health to DM and MHR. EPA-enriched and DHA-enriched preparations and matching placebos were provided by Nordic Naturals (Watsonville, CA).
DM has received research support from the Bowman Family Foundation, Fisher Wallace, Nordic Naturals, Methylation Sciences (MSI) and PharmoRx. He has received honoraria for speaking from Pamlab, and the Massachusetts General Hospital Psychiatry Academy. He has received royalties from Lippincott Williams & Wilkins for the book 'Natural Medications for Psychiatric Disorders: Considering the Alternatives'. AAN has served as a consultant to: Appliance Computing (Mindsite), Brain Cells, Brandeis University, Bristol-Myers Squibb, Clintara, Dainippon Sumitomo (now Sunovion), Eli Lilly and Company, EpiQ, Forest, Novartis, PamLabs, PGx Health, Shire, Schering-Plough, Sunovion, Takeda Pharmaceuticals, Teva and Targacept. He has consulted through the MGH Clinical Trials Network and Institute (CTNI): Astra Zeneca, Brain Cells, Dainippon Sumitomo/Sepracor, Johnson and Johnson, Labopharm, Merck, Methylation Sciences, Novartis, PGx Health, Shire, Schering-Plough, Targacept and Takeda/Lundbeck Pharmaceuticals. AAN received honoraria or travel expenses including CME activities from: APSARD, Belvoir Publishing, Boston Center for the Arts, University of Texas Southwestern Dallas, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Bayamon Region Psychiatric Society, San Juan, PR, Baystate Medical Center, Canadian Psychiatric Association, Columbia University, Douglas Hospital/McGill University, IMEDEX, International Society for Bipolar Disorders, Israel Society for Biological Psychiatry, John Hopkins University, MJ Consulting, New York State, Massachusetts Association of College Counselors, Medscape, MBL Publishing, Physicians Postgraduate Press, Ryan Licht Sang Foundation, Slack Publishing, SUNY Buffalo, University of Florida, University of Miami, University of Wisconsin, University of Pisa and SciMed. AAN is a presenter for the Massachusetts General Hospital Psychiatry Academy (MGHPA). The education programs conducted by the MGHPA were supported through Independent Medical Education (IME) grants from the following pharmaceutical companies in 2008: Astra Zeneca, Eli Lilly and Janssen Pharmaceuticals; in 2009 Astra Zeneca, Eli Lilly and Bristol-Myers Squibb. No speaker bureaus or boards since 2003. AAN owns stock options in Appliance Computing and Brain Cells. Additional income is possible from Infomedic.com depending on overall revenues of the company, but no revenue has been received to date. Through MGH, AAN is named for copyrights to: the Clinical Positive Affect Scale and the MGH Structured Clinical Interview for the Montgomery-Asberg Depression Scale exclusively licensed to the MGH Clinical Trials Network and Institute (CTNI). AAN has received grant/research support through MGH from AHRQ, Cephalon, Forest, Mylan, NIMH, PamLabs, Pfizer Pharmaceuticals, Takeda, Elan and Shire. PJS works part-time both as Senior Research Associate in the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine, Atlanta, Georgia; as well as Principal Statistician in the Department of Psychiatry of the School of Medicine at the University of California, San Diego. She has no other direct or indirect affiliations or financial interests in connection with the contents of this paper. MHR has provided consulting services to PAX (unpaid) and has been funded by the NIH. The remaining authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Rapaport, M., Nierenberg, A., Schettler, P. 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 21, 71–79 (2016). https://doi.org/10.1038/mp.2015.22
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