n-3 Fatty acids and mood: the devil is in the detail

Abstract:

The full text of this short paper is reproduced here for FAB Research under author copyright.

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Increasing evidence suggests that a low dietary intake of the omega-3 long-chain polyunsaturated fatty acids EPA and DHA may contribute not only to the risks for various physical illnesses (particularly cardiovascular and immune system disorders) but also to many disorders of mental health and performance. (1)(2)  From their recent comprehensive review of the evidence for these omega-3 in the prevention and treatment of psychiatric disorders,(3) the American Psychiatric Association (APA) made the following recommendations:

• all adults should eat fish at least 2 x week
• patients with mood, impulse control or psychotic disorders should consume 1g/day of EPA+DHA - the omega-3 found in fish oils
• a supplement may be useful in patients with mood disorders (1-9g/day). Use of > 3g/day should be monitored by a physician.

It was strongly emphasised that these recommendations are not intended as a substitute for standard treatments for psychiatric disorders, as most trials to date have used omega-3 adjunctively.

The APA’s recommendations of 1-9g/day EPA+DHA (combined) for mood disorders followed from their meta-analysis of 8 trials involving adults with clinical depression or bipolar disorder, showing overall benefits from supplementation with these omega-3 (p<0.03). This showed considerable heterogeneity, however, so the need to examine carefully the differences between study populations, as well as specific formulations and doses used, was emphasised.  It was also pointed out that treatment primarily or exclusively with EPA appeared to be most effective.

In view of this, it seems unfortunate that a high-DHA formulation was chosen for the trial now reported by Rogers and colleagues,(4) which showed no effects on mood or cognition in generally healthy adults from 12 weeks of supplementation with omega-3.  Clearly this population differs from those considered by the APA, both in having no formal psychiatric diagnoses and in receiving no other treatment for their mood symptoms, but the rationale for the study was sensible. The prevalence of mild to moderate depression in primary care settings (where most participants were recruited) is high; and concerns about antidepressant medications, along with mounting evidence linking low omega-3 intake to mood disorders, have raised the very important question of whether simple dietary interventions to improve that intake might improve depressive symptoms in this population.  The issues involved are not simple, however – and definitive answers must still await further research.

The evidence supporting the use of EPA+DHA in the management of psychiatric disorders appears strongest for conditions involving disturbances of mood/anxiety and/or impulse control.  Thus in addition to the benefits for major depression and bipolar disorder highlighted by the APA’s meta-analysis of studies of these patients, 1g/day of EPA reduced both depression and hostility in patients with borderline personality disorder.(5)  In two newer studies, 1.2g EPA + 0.9g DHA improved depression, suicidality and daily stresses (but not impulsivity, aggression and hostility) in patients with recurrent self-harm,(6) and 2.3g EPA + 0.5g DHA reduced anxiety in a pilot study of substance abusers.(7) 

By contrast, a separate meta-analysis by the APA’s reviewers of 4 trials involving schizophrenia patients showed no overall benefits for psychotic symptoms, although it was noted that an increased intake of omega-3 might help to combat the increased risks of cardiovascular disease, diabetes and other physical health problems associated with this illness, which are exacerbated by some antipsychotic medications. Some benefits for mood, impulsivity, stress-aggression and other aspects of behaviour or cognition have also been reported in psychiatrically normal populations,(8),(9) children with attention-deficit hyperactivity disorder (ADHD) and related conditions,(10) and patients with mild dementia,(11) although findings in these areas remain preliminary or mixed, and most studies have been small.

The new study by Rogers and colleagues, supported by the UK Food Standards Agency (FSA), set out to investigate whether omega-3 supplementation could improve mental health in a sample more representative of the general population.  As they noted, existing evidence does suggest that adults with sub-clinical depressive symptoms might be likely candidates to benefit from an increased omega-3 intake. So their choice of a new population to study makes good sense.  But pooling their results with those of other studies involving very different populations does not. 

This all-encompassing approach to meta-analysis was used in an earlier publication from the same group,(12) and it is repeated in the current paper, with the inclusion of this latest trial.  What have males with angina, chronic patients with schizophrenia, and mothers who choose to breastfeed got in common?  They all show no improvements in ‘mood’ following ‘omega-3 supplementation’ in these meta-analyses.  And what might ‘omega-3 supplementation’ mean here?  Well, these chronic schizophrenia patients received 3g/day of pure ethyl-EPA (other studies of schizophrenia using lower doses were not included), the breastfeeding mothers received only 200mg/day of pure algal-source DHA; and the angina sufferers were apparently just told to ‘eat more fatty fish’ or were given EPA capsules, with no dose reported. 

It seems less than meaningful to combine results from studies using such totally diverse populations and treatments. Furthermore, these 3 particular (negative) trials receive 50% of the total weight in the latest meta-analysis, and the new (negative) trial of generally healthy adults adds a further 17%.  The overall conclusion is therefore that EPA+DHA has no effect on mood (although the positive results in patients with diagnosed mood disorders are acknowledged in the small print of both papers).

Useful meta-analyses require expertise in both methodology and the specific subject area. Combining different populations is one potential confound; but combining totally different treatment formulations and dosages can be equally misleading – and doing both together is likely to multiply any confusion. The actual treatment used is obviously rather a key factor, but in this particular field it is all too often overlooked.  Ideally, separate meta-analyses should be performed by formulation and dosage.  Unfortunately, treatments have differed so widely in trials of ‘omega-3’ for mental health and performance that this approach remains impractical until more studies are forthcoming. As the APA group emphasised, close examination of individual trials is warranted in the meanwhile; and the current pattern shows a clear superiority of EPA over DHA for these purposes.

This is not what most people might have predicted, because DHA is an essential component of neuronal membranes and thus critical to the very structure of the brain and nervous system, while EPA is not. EPA can affect brain function, however, in a huge number of ways. Its eicosanoid derivatives are key regulators of immune, endocrine and cardiovascular functions, and EPA has direct actions on cyclo-oxygenases, lipoxygenases, phospholipases, acylating systems, ion channels, mitochondria and peroxisome proliferator-activated receptors (PPARs), as well as regulatory influences on gene expression. The mechanisms underlying any treatment benefits observed still remain a matter for speculation and future research – but so far, EPA does seem to produce better results than DHA.

Thus studies using either pure DHA, or more DHA than EPA, for adult mental health symptoms have all been negative to date; and Rogers and colleagues’ study has just joined this list.  By contrast, pure EPA has shown benefits in several trials (but only at doses of 1-2g/day), and all positive studies in this area have used more EPA than DHA (ratios 1.8 to infinity; most ordinary fish oils provide around 1.5). The few controlled trials in children with behavioural and learning difficulties also suggest that EPA may be more effective than DHA, although the picture here is less clear, and is complicated by other ingredients such as antioxidants and omega-6 fatty acids.(10) There are just two underpowered dose-ranging trials to date, both in adults with psychiatric disorders, and using 1g, 2g or 4g /day of pure ethyl-EPA. For depression, the 1g dose performed best (2g or 4g were no better than placebo)(13) and for schizophrenia, only the 2g dose showed any benefits.(14)  Any successful trials using higher doses have provided EPA and DHA in combination, and this may be important, as high doses of any one fatty acid could potentially create imbalances in fatty acid profiles.

In keeping with FSA guidelines, Rogers and colleagues wanted an omega-3 dose that was realistically achievable from the diet, and settled on 1.5g of EPA+DHA in total. This is well above the minimum of 450-500mg/day of EPA+DHA now recommended for cardiovascular health,(15) - (which most UK consumers fail to get near); and it could easily have provided the minimum 1g/day of EPA indicated by previous research. For reasons unspecified, however, an unusually low ratio of EPA:DHA of 0.7 was chosen.  For such a large-scale study that otherwise appears extremely well-designed and conducted, this seems a very strange decision. 

The negative results certainly add to the case against DHA-rich formulations for mood. But they also represent a wasted opportunity to find out if the existing evidence that omega-3 can (adjunctively) help patients with mood disorders might extend (as monotherapy) into the general population.  It can only be hoped that neither this study, nor the use of over-inclusive meta-analyses, will deter the further research that is urgently needed to address this issue.