Depression is a complex mental health condition that affects people of all ages worldwide. While medication is often prescribed to manage depression symptoms, currently available pharmacological treatments have only modest effect sizes and various adverse effects.

Therefore, to optimize patient outcomes for depression, clinicians and researchers have begun to explore efficacious and tolerable alternative or adjunct therapies. Omega-3 fatty acids, especially EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), have drawn clinical attention after several lines of evidence have suggested their ability to prevent and treat depressive symptoms.

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This article will explore the potential benefits of the combination of omega-3s + medication in the treatment of depression symptoms.

 

What is Depression?

According to the American Psychiatric Association, depression and major depressive disorder (MDD) are common and serious medical illnesses that negatively affect how a person feels, the way they think, and how they act.

Several factors can play a role in depression, such as individual genetics, biochemistry, personality, nutrition, immunologic, endocrine, and environmental factors.

Depression symptoms can vary from mild to severe and often include:

  • Feeling sad or having a depressed mood
  • Loss of interest in activities once enjoyed
  • Changes in appetite in either direction
  • Changes in sleeping patterns in either direction
  • Loss of energy and motivation
  • Feeling worthless or discomfort without a clear cause
  • Difficulty thinking, concentrating, or making decisions

Fortunately, depression is one of the most treatable mental health disorders, and nearly all patients can gain some relief from their symptoms. Depending on the evaluation and identification of symptoms and possible causes of depression, different courses of action are possible. Some of the most common treatments for depression include medication, nutraceuticals, and psychotherapy.

 

Antidepressant effects of Omega-3 Polyunsaturated Fatty Acids – an Overview

Dietary long-chain polyunsaturated fatty acids, specifically the omega-3s EPA and DHA, have been correlated with mood and mental health conditions. Data suggest that deficiency of omega-3s is associated with and may contribute to the development of mood disorders, and concentrations of EPA and DHA in red blood cell membranes (Omega-3 Index) significantly correlate with depressive symptoms.

Omega-3s are believed to influence depression through several mechanisms that impact both brain structure and activity. For example, DHA is a vital component of neural membrane phospholipids and increases blood flow to the brain. Omega-3s can also increase the expression of dopamine and have been found to balance brain-derived neurotrophic factor (BDNF) among depressed patients and can suppress neuroinflammation, which is involved in the pathogenesis of depression.

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Research has also uncovered possible treatment effects of omega-3s on depression. Several lines of evidence have reported the beneficial effects of omega-3s on depression symptoms, including epidemiological studies, randomized-controlled trials, and meta-analyses.

Current evidence suggests that EPA may play a more powerful role in depression and mood than DHA, as studies find that omega-3 treatment with EPA ≥60% at dosages of at least 1g/d has beneficial effects on depression. Furthermore, studies report that omega-3s have therapeutic potential in patients resistant to common antidepressant medications.

 

Antidepressant Effects of Medication – an Overview

Treatment with antidepressants aims to relieve symptoms of depression, such as restlessness, anxiety, and sleep problems, as well as to prevent suicidal ideation. Some of the most used antidepressants include selective serotonin reuptake inhibitors (SSRIs) and selective serotonin noradrenaline reuptake inhibitors (SNRIs).

It’s believed that antidepressants work by increasing the availability of certain chemicals, like serotonin, which may be imbalanced in people with depression. Antidepressants are usually taken daily and are often taken for six to nine months after symptom resolution. A qualified healthcare provider should manage the duration and dosage of any antidepressant treatment.

Since there are so many different medications and types of depression, it is challenging to report antidepressant treatment effectiveness. Overall, the commonly used SSRIs and SNRIs are equally effective, and studies involving moderate to severe depression have observed the most significant benefits from antidepressant treatment.

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However, antidepressants may not be effective for those with mild depression. Several studies have found that drug-placebo differences in antidepressant efficacy are relatively small and that treatment effects often decline over time.

It appears that, like many other treatments, antidepressants may help in some situations and not in others. Baseline depression severity, treatment duration, dosing regimen, and patient population may all be factors in antidepressant efficacy outcomes. However, cases of non-responsiveness to pharmaceutical treatments altogether suggest other mechanisms may be involved, and complementary depression treatment might be beneficial.

 

Can Omega-3s + Medication Enhance Depression Treatment?

Several researchers and clinicians have begun to explore using omega-3 supplements as adjunct therapy with antidepressant medication to enhance patient outcomes.

A 2002 study investigated the effects of adding EPA as an adjunct to treatment for depressive episodes in patients who were receiving maintenance antidepressant therapy. Researchers found highly significant benefits of adding omega-3s compared with placebo by week 3 of treatment.

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A 2003 double-blind, placebo-controlled trial found similar findings after eight weeks comparing omega-3s with placebo on top of usual treatment in patients with MDD.

Several other studies have described similar results, reporting that EPA, or EPA + DHA, in combination with antidepressant treatment, was superior to either of them alone in decreasing depressive symptoms (1, 2, 3) and may be helpful for those with treatment-resistant depression.

Yet, despite mounting evidence from meta-analyses and clinical trials showing that omega-3s are more effective than placebo in relieving depression symptoms and are safe for use, other meta-analyses (1,2) have failed to detect the antidepressant effects of omega-3 s. So, is combination treatment really more effective?

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New Research on the Use of Omega-3s and Medication for Depression Treatment

A new systematic review and meta-analysis published in October 2023 aimed to provide a more accurate picture of the efficacy of omega-3s in alleviating depression symptoms. For this review a comprehensive search was performed, and articles evaluating the effects of omega-3s on depression symptoms published up to June 2021 were included.

After assessing 22 meta-analyses, including 83 randomized controlled trials, the current systematic review concluded that EPA, DHA, and EPA + DHA supplementation had a significant improvement effect on depression indices in most studies. The study noted that 16 meta-analyses reported significant reductions in depressive symptoms with omega-3 supplementation, with more pronounced effects on depression symptoms when EPA + DHA was used with an average dose of >3 grams per day for an intervention period of >15 weeks.

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The authors of the study were also the first to collect and evaluate various and inconsistent results and offer some explanation for contradictory results, an important one being the degree of depression for the participants.

Omega-3 supplementation seems to have non-significant or minor effects on depression in people with mild symptoms while having a significant positive effect on those with MDD. The next factor to consider is the supplementary dose. Most studies have pointed out a direct relationship between dose and effect size on depressive symptoms. Furthermore, the type of omega-3 fatty acid is essential, and some studies indicate EPA has a superior effect on depression compared to DHA (1, 2, 3, 4, 5).

 

Clinical Practice Guidelines

In line with the study conclusions, the International Society for Nutritional Psychiatry (ISNPR) published Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder. The authors confirm that cumulative evidence favors the efficacy of omega-3s as an adjunct therapy on top of antidepressant medication. The article is the first international research society consensus-based practice guideline for the clinical use of omega-3s in MDDs. The paper includes 12 clinical recommendations on the items that reached the consensus level.

The authors of the ISNPR paper also stress the importance of the concentration (purity) and quality (product preparation) of omega-3 products when using them for adjunct treatment of depressive disorders. The quality and concentration of the product can lead to differences in bioavailability, pharmacodynamics, and, therefore, efficacy. Before choosing an omega-3 supplement, speak to your doctor and read this article to understand better how to find the right supplement.

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Summary

According to a recent umbrella systematic review and meta-analysis, omega-3 — EPA, DHA, and EPA + DHA — supplementation significantly improved depression indices in most studies, with the most significant results in MDD patients. There is a direct relationship between the dose of omega-3s and the effect size on depression, and EPA appears to have more anti-depressive effects than DHA.

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The ISNPR recommends pure EPA or a combination of EPA and DHA (with net EPA starting from at least 1 and up to 2g/day) for at least eight weeks to optimize results. Although omega-3s may have pronounced effects on depressive symptoms, they are not superior to antidepressant drugs and, therefore, should not be used as treatment alone. Thus, omega-3s could be considered an effective therapeutic adjunct to antidepressant treatment in relieving depressive symptoms.

 

These statements have not been evaluated by the Food and Drug Administration. This test is not intended to diagnose, treat, cure, prevent or mitigate any disease. This site does not offer medical advice, and nothing contained herein is intended to establish a doctor/patient relationship. OmegaQuant, LLC is regulated under the Clinical Laboratory improvement Amendments of 1988 (CLIA) and is qualified to perform high complexity clinical testing. The performance characteristics of this test were determined by OmegaQuant, LLC. It has not been cleared or approved by the U.S. Food and Drug Administration.

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