Meta-Analysis of the Effects of Eicosapentaenoic Acid (EPA) in Clinical Trials in Depression

New York State Psychiatric Institute, New York, NY 10032, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 09/2011; 72(12):1577-84. DOI: 10.4088/JCP.10m06634
Source: PubMed


Randomized trials of omega-3 polyunsaturated fatty acid (PUFA) treatment for depression have differed in outcome. Recent meta-analyses ascribe discrepancies to differential effects of eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) and to diagnostic heterogeneity. This meta-analysis tests the hypothesis that EPA is the effective component in PUFA treatment of major depressive episodes.
PubMed/MeSH was searched for studies published in English from 1960 through June 2010 using the terms fish oils (MeSH) AND (depressive disorder [MeSH] OR bipolar depression) AND randomized controlled trial (publication type). The search was supplemented by manual bibliography review and examination of relevant review articles.
The search yielded 15 trials involving 916 participants. Studies were included if they had a prospective, randomized, double-blinded, placebo-controlled study design; if depressive episode was the primary complaint (with or without comorbid medical conditions); if omega-3 PUFA supplements were administered; and if appropriate outcome measures were used to assess depressed mood.
Extracted data included study design, sample sizes, doses and percentages of EPA and DHA, mean ages, baseline and endpoint depression ratings and standard deviations for PUFA and placebo groups, and P values. The clinical outcome of interest was the standardized mean difference in the change from baseline to endpoint scores on a depression rating scale in subjects taking PUFA supplements versus subjects taking placebo.
In a mixed-effect model, percentage of EPA in the supplements was the fixed-effect predictor, dichotomized into 2 groups: EPA < 60% or EPA ≥ 60% of the total EPA + DHA. Secondary analyses explored the relevance of treatment duration, age, and EPA dose.
Supplements with EPA ≥ 60% showed benefit on standardized mean depression scores (effect size = 0.532; 95% CI, 0.277-0.733; t = 4.195; P < .001) versus supplements with EPA < 60% (effect size = -0.026; 95% CI, -0.200 to 0.148; t = -0.316; P = .756), with negligible contribution of random effects or heteroscedasticity and with no effects of treatment duration or age. Supplements with EPA < 60% were ineffective. Exploratory analyses supported a nonlinear model, with improvement determined by the dose of EPA in excess of DHA, within the range of 200 to 2,200 mg/d of EPA.
Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression. Translational studies are needed to determine the mechanisms of EPA's therapeutic benefit.

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Available from: J. John Mann, Aug 11, 2014
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    • "However, the effect of these PUFA treatments later in childhood is not clear [33] [34]. Lower post-mortem brain DHA is present in major depressive disorder relative to controls [35] [36] [37], however, supplemental EPA, but not DHA, appears to be effective in the management of depressive symptoms [38] [39]. Table 1 Summary of published studies that have used stable-isotope labeled ALA to measure DHA synthesis. "

    • "We found that low plasma EPA, but not low DHA, was linked to higher aggression scores in MDD patients with a history of SUD, although both EPA and DHA were significantly lower in MDD than in HV. In the context of depression, several meta-analyses suggest a therapeutic benefit of EPA over DHA in clinical trials in depression (Lin et al., 2012; Martins, 2009; Martins et al., 2012; Sublette et al., 2011a), despite the greater importance of DHA for brain functioning suggested by much higher brain concentrations of DHA than EPA, and the finding of selective deficits of DHA in postmortem depressed brains (McNamara et al., 2007). Similarly, a direct comparison study showed that EPA, but not DHA, as adjuvant to antidepressant medication lowered HDRS-17 scores after 12 weeks (Mozaffari-Khosravi et al., 2012). "
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    ABSTRACT: Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n=48) and healthy volunteers (HV, n=35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n=39; HV, n=33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76=12.493, p=0.001), and impulsivity (F1,65=5.598, p=0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76=7.941, p=0.001) and impulsivity (F1,65=3.485, p=0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission.
    Journal of Psychiatric Research 10/2014; 57(1). DOI:10.1016/j.jpsychires.2014.06.012 · 3.96 Impact Factor
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    • "Thus, altogether, the choice in previous meta-analyses to pool together studies with such different baseline conditions, in which depression occurred, may have affected the quality of the studies as well as utilizability of the results [27], [28]. Moreover, the last meta-analysis included studies up to 2010 [29]. Thus, the aim of this study was to update the current knowledge about the overall clinical efficacy of omega-3 fatty acids (particularly EPA and DHA) in previous and more recent RCTs published in the last years, minimizing, from a clinical point of view, the differences among the populations of patients included in the studies, finally focusing on patients with a DSM-defined diagnosis of MDD. "
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    ABSTRACT: Despite omega-3 polyunsaturated fatty acids (PUFA) supplementation in depressed patients have been suggested to improve depressive symptomatology, previous findings are not univocal. 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. 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. 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. The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD.
    PLoS ONE 05/2014; 9(5):e96905. DOI:10.1371/journal.pone.0096905 · 3.23 Impact Factor
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