Double-Blind, Randomized, Placebo-Controlled Trials of Ethyl-Eicosapentanoate in the Treatment of Bipolar Depression and Rapid Cycling Bipolar Disorder

Psychopharmacology Research Program, Department of Psychiatry, University of Cincinnati College of Medicine and the Mental Health Care Line, Cincinnati, Ohio 45267-0559, USA.
Biological Psychiatry (Impact Factor: 10.26). 12/2006; 60(9):1020-2. DOI: 10.1016/j.biopsych.2006.03.056
Source: PubMed


The results of pilot trials suggest that omega-3 fatty acids may have efficacy in the treatment of mood symptoms in bipolar disorder.
We conducted a 4-month, randomized, placebo-controlled, adjunctive trial of ethyl-eicosapentanoate (EPA) 6 g/day in the treatment of bipolar depression and rapid cycling bipolar disorder. Subjects were receiving mood-stabilizing medications at therapeutic doses or plasma concentrations. The measures of efficacy were early study discontinuation, changes from baseline in depressive symptoms (Inventory for Depressive Symptomology total score) and in manic symptoms (Young Mania Rating Scale total score), and manic exacerbations ("switches"). We also measured side effects and bleeding time, a biomarker of drug action.
Overall, there were no significant differences on any outcome measure between the EPA and placebo groups.
This study did not find overall evidence of efficacy for adjunctive treatment with EPA 6 g/day in outpatients with bipolar depression or rapid cycling bipolar disorder.

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    • "Several randomized controlled trials (RCTs) have been conducted evaluating the effects of adjunctive omega-3s, a natural anti-inflammatory agent. Results have been mixed with several trials showing an antidepressant effect in BD (Stoll et al., 1999;Frangou et al., 2006) and others showing no significant difference compared to conventional therapy alone (Hirashima et al., 2004;Keck et al., 2006;Frangou et al., 2007). In a recent meta-analysis, a moderate and statistically significant anti-depressant effect size of adjunctive omega-3 in BD was found compared to conventional therapy alone (Bloch and Hannestad, 2012). "
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    ABSTRACT: Background: Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology of BD and cognitive impairment. Methods: For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter. Results: Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistically, elevation in inflammatory cytokines alters monoamine levels leading to cognitive and affective dysfunction. Neuro-inflammation, manifesting as microglial activation, leads to increased oxidative stress, pathologic synaptic pruning and impaired neuroplasticity in key brain regions sub-serving mood and cognition. Immune dysfunction also activates the hypothalamic-pituitary-adrenal (HPA) axis leading to hypercortisolemia and metabolic dysfunction, further promoting neuronal dysfunction. Anti-inflammatory agents are therefore currently being investigated in the treatment of BD and appear to exert an antidepressant effect; however, cognitive outcomes have yet to be reported. Conclusion: Several studies suggest that immune dysfunction is associated with cognitive impairment in BD. Several neurobiological pathways have been identified whereby immune dysfunction may promote cognitive impairment in BD. Future investigations of anti-inflammatory agents targeting cognitive function as a treatment outcome are merited.
    No preview · Article · Sep 2015 · Journal of Affective Disorders
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    • "The most of RCTs used the Hamilton Depression Rating Scale [46], [48], [49], [54], [57], [58], [63], [65], [69], [75]–[84], 10 studies [46], [49], [56], [68], [79], [85]–[89] used the Beck Depression Inventory, and 13 studies [47], [50], [54], [62], [64], [67], [77], [84], [90]–[94] the Montgomery-Asberg Depression Scale as the main outcome measure. Among the studies not included in the quantitative analysis,due to lack of data, one was conducted on patients with obsessive-compulsive disorder [57] and one on patients with chronic fatigue syndrome [56], both reporting no relevant effects of omega-3 fatty acids compared with placebo; four studies conducted in bipolar depressed patients [58], [59], [61], [63] reporting that there were no significant differences on any outcome measure between the EPA and placebo groups; one study on diabetes mellitus patients with MDD [62] reporting no effect of omega-3 fatty acids on depression severity; and one on older adults with mild cognitive impairment suggesting that increased intakes of DHA and EPA can reduce depressive symptoms and the risk of progressing to dementia [60]. "
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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.
    Full-text · Article · May 2014 · PLoS ONE
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    • "This is supported by the findings that preformed DHA corrects erythrocyte and cortical DHA deficits in patients with peroxisomal biogenesis disorders (Martinez et al., 2000; Moser et al., 1999). Moreover, this may explain in part why supplementation with DHA in addition to EPA (Stoll et al., 1999), but not EPA alone (Keck et al., 2006), is efficacious in the treatment of mood symptoms in BD patients. Additionally, increasing erythrocyte DHA to levels observed in the Japanese population (6.8%, Itomura et al., 2008), where the lifetime prevalence rates if MDD and BD are among the lowest in the world, may represent an appropriate target for future primary and secondary prevention trials (McNamara, 2009). "
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    ABSTRACT: Epidemiological and controlled intervention trials suggest that omega-3 (n-3) fatty acid deficiency represents a reversible risk factor for recurrent affective disorders. However, there is limited comparative information available regarding the n-3 fatty acid status and associated mood symptoms in medication-free patients with major depressive disorder (MDD) and bipolar disorder (BD). The fatty acid composition of erythrocyte membranes from adult male and female healthy controls (n=20) and medication-free patients with MDD (n=20) and BD (n=20) was determined by gas chromatography. Associations with depression and mania symptom severity scores were investigated. After correction for multiple comparisons, both MDD (-20%) and BD (-32%) patients exhibited significantly lower erythrocyte docosahexaenoic acid (DHA, 22:6n-3) composition relative to healthy controls, and there was a trend for lower DHA in BD patients relative to MDD patients (-15%, p=0.09). There were no gender differences for DHA in any group. Other n-3 fatty acids, including eicosapentaenoic acid (EPA, 20:5n-3) and docosapentanoic acid (22:5n-3), and n-6 fatty acids, including arachidonic acid (AA, 20:4n-6), were not different. Erythrocyte DHA composition was inversely correlated with indices of delta-9 desaturase activity (18:1/18:0), and associated elevations in oleic acid (18:1n-9) composition, and delta-6 desaturase activity (20:3/18:2). DHA composition was not significantly correlated with depression or mania symptom severity scores. Data regarding diet and life style factors (cigarette smoking) were not available to evaluate their contribution to the present findings. Male and female patients with MDD and BD exhibit selective erythrocyte DHA deficits relative to healthy controls, and this deficit was numerically greater in BD patients. Selective DHA deficits are consistent with impaired peroxisome function, which has implications for n-3 fatty acid interventions aimed at preventing or reversing this deficit.
    Full-text · Article · Oct 2010 · Journal of Affective Disorders
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