Cognitive impairment is frequently observed in patients with major depressive disorder (MDD) and is associated with significant functional impairment. There is a growing body of evidence indicating that inflammation plays a causal role in the etiology of some forms of depression and may be associated with specific symptoms of depression, including anhedonia, fatigue, and psychomotor slowing. Recent studies have observed that higher doses of omega-3 fatty acids may be particularly effective for the treatment of depression in individuals with markers of high inflammation and that the antidepressant effects of omega-3 fatty acids appear to be related to their potent anti-inflammatory effects.
In a recent study, Naoise Mac Giollabhui, PhD, David Mischoulon, MD PhD and colleagues from the Depression Clinical Research Program have examined the effects of omega-3 fatty acids (omega-3 FA) on cognitive functioning in individuals with high levels of inflammation. The team analyzed data from a multicenter trial funded by the National Center for Complementary and Integrative Health (NCCIH) investigating the efficacy of three different doses of omega-3 fatty acids versus placebo in a population with inflammatory depression. The participants were unmedicated and had a body mass index (BMI) > 25 and confirmed markers of inflammation, including elevated levels of high-sensitivity C-reactive protein (hs-CRP ≥ 3 mg/L). Omega-3 fatty acids used in this trial contained of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a ratio of 3.9:1.
The study examined the relationship between dysregulated inflammatory physiology and baseline cognitive impairment and assessed improvements in motivation-related symptoms and higher-order cognitive functioning following treatment with omega-3 fatty acids. Motivational symptoms (e.g., alertness, energy, enthusiasm) and higher-order cognitive functions (e.g., word-finding, memory) were assessed using validated self-report measures.
Dysregulated immune function was associated with higher levels of cognitive impairment. The researchers assessed participants’ immune functioning by measuring the release of IL-6 and TNFα by peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS). Typically in response to stimulation with LPS, high levels of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα) are produced. In this study, greater dysregulation of immune function (i.e., lower levels of LPS-stimulated cytokine release) at baseline was associated with greater impairment of higher-order cognitive function.
Motivational symptoms improved in depressed individuals receiving higher doses (4 g/day) of omega-3 FA. Over the 12 weeks of the clinical trial, it was motivation-related symptoms that improved in individuals randomized to receive 4 g/day of omega-3 FA when compared to placebo.
Motivational symptoms improved the most in individuals with higher levels of immune dysfunction (lower LPS-induced PBMC response). Notably, within the 4 g/day group, it was individuals with greater levels of immune dysfunction at baseline who exhibited the greatest improvement in motivation-related symptoms of cognitive dysfunction. Specifically, it was subjects expressing lower levels of TNFα in LPS-stimulated PBMCs who experienced significantly greater change in motivational symptoms.
This exploratory clinical trial builds on previous research from the Depression Clinical Research Program indicating that certain individuals with depression, those with elevated levels of inflammation, may benefit the most from supplementation with higher doses of omega-3 fatty acids. The current study indicates that, not only does daily supplementation with 4 g of omega-3-FA improve depressive symptoms, but it also can improve critical aspects of cognition related to motivation (i.e., energy, alertness) in depressed individuals exhibiting an inflammatory phenotype.
As data emerged in the 1990s suggesting the beneficial effects of omega-3 fatty acids in patients with neurodegenerative and psychiatric disorders, researchers speculated that these benefits were related to the effects of omega-3 fatty acids on membrane fluidity and brain development; however, more recent research has suggested a broader range of mechanisms of action and have further noted that the anti-inflammatory effects of omega-3 fatty acids may play an important role.
This study helps to put a finer point on our understanding of the antidepressant effects of omega-3 fatty acids in certain individuals. The omega-3 fatty acids may have many benefits for the brain; however, these studies have shown a correlation between reductions in inflammation and improvements in measures of depression, motivation, and cognitive functioning. Importantly, the beneficial antidepressant and anti-inflammatory effects of omega-3 fatty acids are seen at much higher doses (4g per day) than used in previous studies , which may help to explain, at least in part, some of the discrepant findings in the literature.
The omega-3 fatty acid preparation used in the study contained about 4 g of EPA and 1 g of DHA. While we often recommend that our depressed patients take omega-3 fatty acids to supplement their treatment, it should be noted that most preparations sold over the counter are mixtures of DHA and EPA and tend to have low levels of EPA (typically around 600 to 800 mg of EPA). Even preparations that are labeled “Super EPA” or “Extra EPA” provide less than 1g of EPA per day. (Information on the content of EPA and DHA can be found on the label.)
We also must be cognizant of the fact that the omega-3 fatty acids may not have as robust antidepressant effects in depressed patients without inflammation. Nor do we fully understand how omega-3 fatty acids may benefit patients already taking antidepressants. While this study focused on a specific population of unmedicated, depressed patients with low-grade inflammation (individuals with an elevated BMI), future research will help to better characterize other populations who may receive benefit from treatment with omega-3 fatty acids.
Other researchers involved in this study include Boadie W. Dunlop, Becky Kinkead, Pamela J. Schettler, Richard T. Liu, Olivia I. Okereke, Stefania Lamon-Fava, Maurizio Fava, and Mark Hyman Rapaport.
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Mac Giollabhui N, Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, Liu RT, Okereke OI, Lamon-Fava S, Fava M, Rapaport MH. Individuals with depression exhibiting a pro-inflammatory phenotype receiving omega-3 polyunsaturated fatty acids experience improved motivation-related cognitive function: Preliminary results from a randomized controlled trial. Brain Behav Immun Health. 2023 Jul 7;32:100666.
Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, et al. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. J Clin Psychiatry. 2022 Aug 22;83(5):21m14074.
Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. J Clin Psychiatry. 2022 Aug 22; 83(5):21m14074.
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.
Lamon-Fava S, So J, Mischoulon D, Ziegler TR, Dunlop BW, Kinkead B, Schettler PJ, Nierenberg AA, Felger JC, Maddipati KR, Fava M, Rapaport MH. 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 Jan; 164:102219.
