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      Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder

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          Abstract

          Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114–0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity ( I 2=73.36, P<0.001), meta-regression showed that higher EPA dose ( β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users ( β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year ( β=−0.0735 (−0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

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          Most cited references48

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          Polyunsaturated fatty acids and their metabolites in brain function and disease.

          The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
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            A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression.

            On the basis of evidence from studies showing the antidepressant effects of omega-3 polyunsaturated fatty acids and the inverse relation between fish consumption and the prevalence of depression, the phospholipid hypothesis seems promising in ascertaining the etiology and treatment of depression. Although several studies have shown lower levels of omega-3 (n-3) polyunsaturated fatty acids in depressive patients, the results of individual polyunsaturated fatty acids, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and the omega-6 (n-6) polyunsaturated fatty acid arachidonic acid (AA), were inconsistent. We conducted the meta-analyses of 14 studies comparing the levels of polyunsaturated fatty acids between depressive patients and control subjects. The effect size of each study was synthesized by using a random effects model. Compared with control subjects, the levels of EPA, DHA, and total n-3 polyunsaturated fatty acids were significantly lower in depressive patients. There was no significant change in AA or total n-6 polyunsaturated fatty acids. The results showed lower levels of EPA, DHA, and total n-3 polyunsaturated fatty acids in patients with depression, thus implying that n-3 polyunsaturated fatty acids play a role in the pathogenesis of depression. Our findings provide further support to the phospholipid hypothesis of depression and a rationale for using n-3 polyunsaturated fatty acids as an alternative treatment for depression. With these results, future studies examining specific roles of DHA and EPA in different clusters of depressive symptoms are warranted. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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              Role of Omega-3 Fatty Acids in the Treatment of Depressive Disorders: A Comprehensive Meta-Analysis of Randomized Clinical Trials

              Background Despite omega-3 polyunsaturated fatty acids (PUFA) supplementation in depressed patients have been suggested to improve depressive symptomatology, previous findings are not univocal. Objectives To conduct an updated meta-analysis of randomized controlled trials (RCTs) of omega-3 PUFA treatment of depressive disorders, taking into account the clinical differences among patients included in the studies. Methods A search on MEDLINE, EMBASE, PsycInfo, and the Cochrane Database of RCTs using omega-3 PUFA on patients with depressive symptoms published up to August 2013 was performed. Standardized mean difference in clinical measure of depression severity was primary outcome. Type of omega-3 used (particularly eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and omega-3 as mono- or adjuvant therapy was also examined. Meta-regression analyses assessed the effects of study size, baseline depression severity, trial duration, dose of omega-3, and age of patients. Results Meta-analysis of 11 and 8 trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo (standardized difference in random-effects model 0.56 SD [95% CI: 0.20, 0.92] and 0.22 SD [95% CI: 0.01, 0.43], respectively; pooled analysis was 0.38 SD [95% CI: 0.18, 0.59]). Use of mainly EPA within the preparation, rather than DHA, influenced final clinical efficacy. Significant clinical efficacy had the use of omega-3 PUFA as adjuvant rather than mono-therapy. No relation between efficacy and study size, baseline depression severity, trial duration, age of patients, and study quality was found. Omega-3 PUFA resulted effective in RCTs on patients with bipolar disorder, whereas no evidence was found for those exploring their efficacy on depressive symptoms in young populations, perinatal depression, primary disease other than depression and healthy subjects. Conclusions The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                March 2016
                15 March 2016
                1 March 2016
                : 6
                : 3
                : e756
                Affiliations
                [1 ]Program for Mood Disorders, Department of Psychiatry, Academic Medical Center, University of Amsterdam , The Netherlands
                [2 ]Department of Psychiatry, Mood and Anxiety Disorders, University Medical Center Groningen, University of Groningen , Groningen, The Netherlands
                [3 ]Department of Psychiatry, Radboud University Medical Center , Nijmegen, The Netherlands
                [4 ]Donders Institute for Brain, Cognition and Behavior, Radboud University , Nijmegen, The Netherlands
                Author notes
                [* ]Department of Psychiatry, Academic Medical Centre , Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands. E-mail: R.J.Mocking@ 123456amc.uva.nl
                [5]

                These authors share senior authorship.

                Article
                tp201629
                10.1038/tp.2016.29
                4872453
                26978738
                f53b08f8-b37d-44ae-a120-7887f76daaf9
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 05 November 2015
                : 17 December 2015
                : 03 February 2016
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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