Share on Pinterest
New research sheds light on key molecular mechanisms that could help turn omega-3 fatty acids into new treatments for depression. Bernine/Getty Images
  • The World Health Organization (WHO) reports that depression affects over 264 million people worldwide and is a leading cause of disability.
  • Researchers from the National Institute of Health Research (NIHR) Maudsley Biomedical Research Centre in the United Kingdom have discovered that high doses of omega-3 fatty acids may provide some relief.
  • The research sheds light on how experts could use the anti-inflammatory effects of omega-3 fatty acids to develop new treatments.
  • The study, a collaboration between scientists from King’s College London and The University of Manchester in the UK and China Medical University, Taiwan, appears in Molecular Psychiatry.

Although experts do not consider depression an inflammatory disease, there is evidence of a relationship between inflammation and depression.

As researchers from the University of Sienna School of Medicine, Italy, point out:

  • people with inflammatory diseases are more likely to exhibit major depressive disorder (MDD)
  • one-third of those with MDD exhibit high inflammatory biomarkers
  • people receiving treatment with inflammatory substances (cytokines) are more likely to develop depression

While inflammation can affect depression and the body in various ways, the hippocampus is particularly vulnerable. While experts believe it to be the site of learning and memory, the hippocampus is also an important part of the limbic system, involved with emotion, memory, and other psychologic functions.

The hippocampus is responsible for the hypothalamus-pituitary-adrenal axis, involved in our fight-or-flight response, which heightens during stress and inflammation. It is also a critical region for new brain cell growth.

Stress and inflammation increase neuronal cell death (apoptosis) and prevent new brain cell generation (neurogenesis) in the hippocampus.

Polyunsaturated fatty acids (PUFAs) are essential for normal functioning, but the body cannot produce them — instead, individuals must ingest them through diet. PUFAs include omega-6 and omega-3 fatty acids, the latter of which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), mostly found in oily fish.

Several studies found an association between eating large amounts of fish and reduced depression risk, prompting scientists to study omega-3 fatty acids as a potential treatment for depression.

Meta-analyses of these studies suggest that omega-3s may be effective in treating depression, but variability in study designs and findings belie a firm conclusion. It has been unclear what dosage may be effective, what ratio of DHA to EPA may be effective, and exactly by what mechanisms omega-3s affect inflammation and depression.

The new NIHR study has established how omega-3s generate anti-inflammatory effects in hippocampus cells and at what dosage.

As lead author Dr. Alessandra Borsini notes: “Using a combination of laboratory and patient research, our study has provided exciting new insight into how omega-3 fatty acids bring about anti-inflammatory effects that improve depression.”

“For some time, we have known that omega-3 PUFAs can induce antidepressant and anti-inflammatory effects, but, without further understanding of how this happens in the human brain, it has been difficult to develop treatments. Our study has helped shine a light on the molecular mechanisms involved in this relationship, which can inform the development of potential new treatments for depression using omega-3 PUFA.”

The in vitro portion of the study used human hippocampal cell lines to study the effects of omega-3s in the presence of cytokines — chemical messengers of inflammation. Cytokines increase apoptosis and decrease neurogenesis.

Treatment of the hippocampal cells with EPA or DHA decreased cell death and prevented a reduction in cell generation. Specifically, the metabolites of lipid mediators of EPA and DHA were responsible for the protective effects.

These key lipid mediators were found for the first time in the human hippocampal cells and included hydroxyeicosapentaenoic acid (HEPE), hydroxydocosahexaenoic acid (HDHA), epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA).

The researchers then discovered that by treating the metabolites with an enzyme inhibitor, they could prevent the breakdown of EpETE and EpDPA, prolonging and enhancing their neurogenic and anti-apoptotic effects.

Study contributor Professor Anna Nicolaou notes: “The lipid mediators that our research identified are broken down in the body relatively quickly, which means they may only be available for a relatively short time.”

“By testing the effect of inhibitors of the enzymes involved in the metabolism of omega-3 PUFA, we showed that we can greatly improve how long they can have an effect in the body and ultimately, increase their efficacy.”

“This is very important for the development of new treatments and means that patients could be given higher doses of EPA and DHA together with these enzyme inhibitors to increase the amount of these important compounds in their blood over time.”

The second leg of the study involved 22 patients with MDD. They were given either 3 grams (g) of EPA or 1.4 g of DHA every day for 2 weeks. The levels of the key lipid mediators were measured in their blood before and after the treatment, along with scores of their depressive symptoms.

There was a correlation between higher levels of metabolites and lower depression scores. The average reduction in depressive symptoms in the patients was 54.5% for EPA and 45.5% for DHA.

The study authors recognize that the human sample size they used was relatively small and that the research was not a randomized placebo-controlled trial — future research may address these limitations. It is also important to note that the doses of omega-3s administered in the study likely cannot be achieved just by dietary consumption of oily fish.

Senior author Professor Carmine Pariante points out:

“It is important to highlight that our research has not shown that by simply increasing omega-3 fatty acids in our diets or through taking nutritional supplements, we can reduce inflammation or depression. The mechanisms behind the associations between depression and omega-3 PUFAs are complicated and require further research and clinical trials to understand how they work fully and inform future therapeutic approaches.”

He adds: “There is an ever-growing interest in the links between the immune system, inflammation, and depression, but in order to develop new treatments in this area, we need to understand better the mechanisms behind these relationships. Our study has provided important insight into how known anti-inflammatory compounds — the omega-3 PUFAs — help reduce depression.”

“By identifying and measuring the exact lipid mediators that are involved, identifying the enzyme that prolongs their effects and finding the same lipid mediators in depressed patients treated with omega-3 PUFAs and demonstrating improvements in symptoms, we have provided vital information to help shape clinical trials for future therapeutic approaches with omega-3 fatty acids.”