Key Driver of Fish Oil's Antidepressant Effects Revealed

Megan Brooks

June 23, 2021

A key molecular mechanism underpinning the anti-inflammatory, antidepressant, and neuroprotective effects of omega-3 fatty acids has been identified.  

In findings that could lead to the development of new treatments for depression, the research provides the "first evidence" that hippocampal neurons are able to produce two key lipid metabolites of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) — lipoxygenase and cytochrome P450, lead investigator Alessandra Borsini, PhD, told Medscape Medical News.

This is how EPA and DHA exert their anti-inflammatory and neurogenic properties in vitro, as well as antidepressant properties in patients with depression, said Borsini, from King's College London, United Kingdom.

"Indeed, we found evidence for a correlation between increased levels of these metabolites and a decrease in severity of depressive symptoms in patients with major depressive disorder," Borsini said.

The study was published online June 16 in Molecular Psychiatry.

"Depression in a Dish"

Despite the known role of inflammation in depression, there remains a lack of data showing anti-inflammatory strategies that are effective, safe for everyday use, and with a clear mechanism of action, the researchers note.  

Borsini and colleagues tested the theory that when EPA and DHA are metabolized, some of their metabolites, or lipid mediators, can protect the brain from the harmful effects of inflammation. They used a validated "depression in a dish" in vitro human hippocampal cell model to test their theory.

They found that treating human hippocampal cells with EPA or DHA before exposing them to cytokines prevented increased cell death and decreased neurogenesis. Both these impacts had been previously observed in cells exposed to cytokines alone.

They confirmed that these effects were mediated by the formation of several key lipid mediators produced by EPA and DHA — namely hydroxyeicosapentaenoic acid, hydroxydocosahexaenoic acid, epoxyeicosatetraenoic acid (EpETE), and epoxydocosapentaenoic acid (EpDPA).

It's the first time these lipid mediators were detected in human hippocampal neurons, the researchers say.

They also found that treating the neurons with an enzyme inhibitor increased the availability of two of these metabolites (EpETE and EpDPA), suggesting a possible way by which future treatments could be optimized.

The findings were replicated in 22 patients with major depression given either EPA (3 g/day) or DHA (1.4 g/day) for 12 weeks. In both groups, EPA or DHA treatment was associated with an increase in their respective metabolites and significant improvement in depressive symptoms.

The average reduction in symptom scores was 64% and 71% in the EPA and DHA groups, respectively, and there was some evidence that higher levels of the same metabolites correlated with less severe depressive symptoms.

"For some time we have known that omega-3 [polyunsaturated fatty acid (PUFA)] 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," Borsini said in a news release.

"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," Borsini added.

"We need to be cautious when interpreting data generated from the correlation between levels of metabolites and depressive symptoms as findings require further validation in a bigger sample of patients," Borsini said.

"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," study author Carmine Pariante, MD, PhD, from King's College London, said in the news release.

"The mechanisms behind the associations between depression and omega-3 PUFA are complicated and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches," Pariante said.

No Clinical Implications

Weighing in on this research in a Science Media Centre statement, Kevin McConway, emeritus professor of applied statistics, The Open University, Milton Keynes, United Kingdom, said, "The point of the study was to throw some light on the mechanisms in the body by which omega-3 fatty acids might work to reduce inflammation or depression."

"The research mostly involved cells in laboratory dishes, but it also involved treating a small sample of patients with major depression by giving them supplements of one or other of the two omega-3 acids under investigation for 12 weeks," he noted.

"The researchers found that the patients' average scores on a standard set of questions, used to diagnose and measure depression, improved over that 12-week period, for each of the two fatty acids.

While depression symptoms improved over 12 weeks with omega-3 fatty acid treatment, "depression symptoms change over time anyway, for many reasons" and depressive symptoms might have improved over 12 weeks even if the patients had not been given the omega-3 acids, McConway said.

"We just can't tell since every patient got omega-3 fatty acids. So these results can hint that omega-3 fatty acids might help in depression, but it comes nowhere near showing that this is the case with a reasonable degree of certainty," he cautioned.

"Indeed the researchers did not carry out this part of their study to see whether the omega-3 supplements help with depression — they did it to see whether the biochemical changes that they had seen in cell cultures in the lab might also occur in human bodies," he noted.

Mol Psychiatry. Published online Jun 16, 2021. Full text

This research was funded in part by grants to the investigators from the UK Medical Research Council, the European Commission Horizon 2020, and the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London. Borsini has received research funding from Johnson & Johnson for research on depression and inflammation. McConway is a trustee of the Science Media Centre and a member of its advisory committee.

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