June 16, 2021

expert reaction to study looking at omega-3 fatty acids, inflammation and depression

A study published in Molecular Psychiatry looks at the anti-inflammatory effects of omega-3 polyunsaturated fatty acids and relevance to depression.

Dr Eric Ruhé, Psychiatrist-epidemiologist, Department of Psychiatry, Radboud University Medical Center, Netherlands, said:

“I think this is a very nice fundamental paper which also attempts to look at whether the in vitro lab findings may be relevant to humans.

Does the press release accurately reflect the science?

“Yes, however I would not name it ‘oily fish’ but ‘fish oil’.

Is this good quality research?  Are the conclusions backed up by solid data?

“Yes these experiments are well thought of and beautifully set up, answering hypotheses about how omega-3 PUFAs might interfere with inflammation, causing apoptosis in neurons.

How does this work fit with the existing evidence?

“There has been a longstanding interest in the association of Major Depressive disorder with inflammation.  Previous meta-analyses of clinical trials with PUFA-supplementation showed beneficial antidepressant effects, especially when added to antidepressants and when high doses (>2gram/day) of EPA in particular are prescribed (See e.g. Mocking et al. Translational Psychiatry 2016;6:e756).

“This study shows how the effects of omega 3 PUFAs and EPA in particular might have their anti-inflammatory effect and also provide a way to increase the effects of EPA-supplementation in vivo.  This opens up the way to, as a next step, perform well designed clinical trials to show whether there are indeed additional benefits of interfering with enzyme function to further increase the levels of LOX (5-HEPE, 4-HDHA), CYP450 hydroxylase (18-HEPE, 20-HDHA) and epoxygenase (17(18)-EpETE and 19(20)-EpDPA) lipid mediators.

Have the authors accounted for confounders?  Are there important limitations to be aware of?

“Yes, they have done so.  The most important limitation is that this paper provides fundamental knowledge and we would still need to transform this via future clinical trials to applicable treatments in people.  However, that is not a limitation of the present research but a necessary next step to provide evidence-based care to our patients.  Moreover it would be nice to find a way to identify which patients specifically might benefit from such a treatment.  We’d need to identify an efficacy biomarker that shows that in a particular patient this inflammation-issue is present, so we could stratify treatment to these patients instead of applying this to all patients and have diluted effect-sizes.

What are the implications in the real world?  Is there any overspeculation?

“If next steps are taken and turn out positive, this finding could be an important contribution to pre-stratify depressed patients to receive targeted mechanistically based treatments instead of the current trial-and-change approach.”

Dr Michael Bloomfield, Excellence Fellow, Head of Translational Psychiatry Research Group and Consultant Psychiatrist, UCL, said:

“This is fascinating research conducted by an internationally respected team of scientists.  There has been quite a lot of interest in omega oils across a range of mental health problems.  However, some of the findings from trials have been disappointing.  This new study sheds light on some of the potential mechanisms that may underlie response to omega oils.  This is important because understanding these mechanisms could lead to new treatment targets and because it might explain why some people seem to get better with omega oils and others do not.  That said, more research is needed into omega oils and their potential mechanisms of action.  As with any treatment, patients who need to take antidepressants should discuss any potential changes to the treatment with their psychiatrist.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“It’s important to be clear on what this study was investigating, what it actually found, and why the senior author says (as quoted in the press release) 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 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.  That’s an important part of understanding whether changing people’s consumption of these fatty acids might affect disease, which in turn might influence how they are used with patients – and, as a statistician, I can’t comment on the details of those findings.  The lead researcher does make it clear that more research is needed to establish how and when omega-3 fatty acids might work clinically, although this study does seem to have made progress.

“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 twelve weeks.  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.  Those reductions were statistically significant – that is, they were too large to be explained away by random variability alone.  In the light of that finding, why does the senior author make it so explicit that their research has not shown that taking such supplements can reduce depression?  The reason is that there was no control group of patients who did not take any supplements (and instead, probably, took a placebo – an identical-looking supplement but not containing any active ingredient).  Depression symptoms change over time anyway, for many reasons.  The study did find that, on average, the depression was less severe, on the measurement scale that was used, at the end of the twelve weeks.  But perhaps the score would have improved in that way, over that timescale, even if the patients have not been given the omega-3 acids.  We just can’t tell, since every patient got omega-3 fatty acids.  So these result 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.  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.”

‘Omega-3 polyunsaturated fatty acids protect against inflammation through production of LOX and CYP450 lipid mediators: relevance for major depression and for human hippocampal neurogenesis’ by Alessandra Borsini et al. was published in Molecular Psychiatry at 01:00 UK time on Wednesday 16 June 2021.

DOI: 10.1038/s41380-021-01160-8

Declared interests

Dr Michael Bloomfield: “I’m a Director of Bloomfield Health.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  However, my quote above is in my capacity as an independent professional statistician.”

None others received.