Omega3s have established mood enhancing benefits and boost the effectiveness of antidepressants

This is the fifth in a series of posts on non-pharmacologic treatments of depressed mood. Previous posts briefly reviewed research findings on S-adenosylmethionine (SAMe) and folate. This post is offered as a concise review of omega-3 essential fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the treatment of depressed mood.

Multiple mechanisms

Epidemiologic studies have found an inverse relationship between consumption of fish and other foods high in omega-3 fatty acids and the prevalence of depression suggesting that individuals who consume foods richer in omega-3s are at reduced risk of developing depressed mood. Human and animal studies point to several mechanisms of action underlying the antidepressant effects of omega-3 fatty acids, including increased CNS serotonin activity, anti-inflammatory effects, suppression of phosphatidyl-inositol second messenger activity, and possibly increased heart rate variability.

In addition to the above mechanisms, another proposed mechanism of action that may be similar to that of antidepressants, including SSRIs and older so-called ‘tricyclic’ antidepressants, involves the suppression of pro-inflammatory cytokine release by immune cells, resulting in beneficial changes in the brain that manifest as improved mood (Maes 1998). Evidence in support of an anti-inflammatory mechanism of omega-3s is consistent with the observation that increased production of pro-inflammatory cytokines takes place in the initial or “acute phase” of severe depressed mood (Maes 1996). Further, animal studies show that direct administration of pro-inflammatory cytokines into the brain causes dysregulation in serotonin metabolism that mirrors changes observed in depressed individuals. Reports that Omega-3 fatty acids may reduce the incidence of coronary artery disease by influencing the production of pro-inflammatory cytokines in the heart may help to explain the observed correlation between heart disease and major depressive disorder.

Research highlights

Findings of studies on antidepressant effects of omega-3s when used alone or when taken adjunctively with an antidepressant are highly inconsistent, however, over time there has been a trend toward more positive findings of well designed placebo-controlled trials. In some studies patients who had previously been refractory to antidepressants improved significantly when Omega-3s were added to their antidepressant.  Most studies support that EPA has greater antidepressant efficacy than DHA both alone and when used in combination with an antidepressant. There is still no consensus on an effective antidepressant dose of EPA; however, it is probably at least 2gm/day typically taken in divided doses with food for optimal absorption.

Findings on DHA in depressed are highly inconsistent possibly reflecting complex relationships between ratios of Omega-3s and other fatty acids (i.e., Omega-6) in the blood and brain and associated anti-inflammatory effects. In a small double-blind study on the efficacy of DHA alone for severe depressed mood patients treated with DHA 2g/day versus a placebo improved at the same rate (Marangell 2003). However, a subsequent DHA augmentation pilot study found an inverse correlation between dose and antidepressant response, with patients receiving 1gm/day reporting significantly greater improvement in depressive mood symptoms compared to individuals taking DHA at doses of 2gm/day and 4gm/day ( Mischoulon 2008). The authors speculated that an optimal ‘therapeutic window’ may take place when a dose of DHA or EPA results in changes in ratios of omega-3s (which have anti-inflammatory effects) to omega-6 fatty acids (which are pro-inflammatory) in the blood needed to achieve an ‘optimal’ balance between pro- and anti-inflammatory forces.

A meta-analysis of studies on omega-3 supplementation alone found consistent anti-depressant benefits of omega-3 supplementation in individuals diagnosed with major depressive disorder, in depressed individuals who were not diagnosed with MDD, but not in women diagnosed with prenatal depression, or in children and adolescents (Grosso et al 2014). A meta-analysis of 241 placebo-controlled studies on EPA, DHA or combined EPA/DHA augmentation of antidepressants found greater benefits with EPA and combined EPA/DHA; however, the authors reported that their findings were limited by methodological flaws in many studies, heterogeneous study designs, small study sizes, short study duration and (in some cases) evidence of publication bias (Martins 2009).

The above findings support the use of EPA in combination with antidepressants, including bipolar depressed patients and patients who are refractory to antidepressants. It remains unclear whether EPA (or specific ratios of EPA to DHA or other fatty acids) has an independent antidepressant effect or possibly enhances the efficacy of antidepressants via second messenger systems in a manner that is similar to the postulated mechanism for lithium augmentation (Nemets 2002).

Unanswered questions

Many questions about fatty acid composition, optimal dosing strategies and treatment duration have not been answered. Confirmation of the size of an augmentation effect in individuals taking antidepressants and further clarification of the antidepressant mechanism(s) of action of essential fatty acids will require large, long-term placebo-controlled trials designed to answer these questions.

Side effects and safety issues

Gastrointestinal side effects have been reported and Omega-3s may interfere with glucose metabolism in diabetic patients (Glauber 1988). There is one case report of increased bleeding risk when Omega-3 fatty acids are used together with coumadin (Buckley 2004).

Bottom line

Supplementation with EPA may enhance response to available antidepressants. EPA may be safely used in combination with antidepressants and other psychotropic medications. Omega-3s have established cardiovascular benefits and are well tolerated. The majority of people who take EPA at dosages recommended for depressed mood report mild or no adverse effects. On the basis of available data, depressed patients should be encouraged to take EPA (1 to 2g/day) as an augmentation strategy in conjunction with their current antidepressant regimen. Diabetics and individuals taking Coumadin or other anticoagulant medications should consult with their physician before considering taking omega-3s. 

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