"Omega-3 polyunsaturated fatty acid treatment for anxiety might be effective in clinical settings"

Today I present the findings of yet another systematic review and meta-analysis as per the publication from Kuan-Pin Su and colleagues [1] that concluded: "omega-3 PUFAs [polyunsaturated fatty acids] might help to reduce the symptoms of clinical anxiety." A finding that may have some quite profound implications for lots and lots of different diagnoses/conditions/labels where anxiety seems to be particularly over-represented and life-draining (see here and see here for examples).

So, the starting hypothesis was that "omega-3 PUFAs might have anxiolytic effects in patients with significant anxiety- and fear-related symptoms." Various studies, both in animals and humans, have implicated fatty acids in 'emotional states', particularly the so-called 'good fatty acids' including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The authors reported that "there have been no systematic reviews of this topic to date" so decided to remedy the situation.

Trawling through various repositories and databases of peer-reviewed science, they searched for relevant science on the topic of fatty acid supplementation and anxiety measurement. From little over a hundred possible science articles, they whittled the numbers down to 19 studies including over 1200 participants "with omega-3 PUFA treatment (mean age, 43.7 years; mean female proportion, 55.0%; mean omega-3 PUFA dosage, 1605.7 mg/d)" and "1037 participants without omega-3 PUFA treatment (mean age, 40.6 years; mean female proportion, 55.0%)." Taking into account that some studies (most) included a placebo element to their design, different dosages and formulations of PUFAs were used and that various different tools and schedules were used to 'measure anxiety', there were some boiled-down messages to emerge.

First: "The overall findings revealed modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major physical illnesses." That's not to say that every study was 'positive' in terms of PUFA effects on anxiety, but generally speaking the evidence tended to side more with an effect rather than no effect. Second, dose and formulation seemed to matter: "Participants treated with a daily dose of 2000 mg or more of omega-3 PUFAs showed a significantly greater association of treatment with reduced anxiety symptoms." Third: "the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger in subgroups with specific clinical diagnoses than in subgroups without specific clinical conditions." So the effect of PUFA supplementation was stronger in those with a clinical diagnosis of something like anxiety than those who didn't have one.

Downsides? Well, there are of course limitations to the data included in the Su study; for example, "the significant heterogeneity among the included studies... with potential influence by some outlier studies" and these should not be underestimated. I'm also minded to bring in the [still emerging] issue that meta-analyses are only as good as the data that they are based on (see here and see here for examples). And I'd also mention that side-effects are something not discussed too heavily in the Su study but one shouldn't assume that just because we're talking about a fish oil so this is somehow side-effect free for everyone...

Given the low cost of fatty acid supplements and their wide, very wide, availability, the Su results provide some pretty good support to suggest that 'giving it a go' could be an option for at least some people diagnosed with an anxiety disorder. Please don't however take that as me giving anyone medical or clinical advice; I'm merely following what the results say and the media coverage that has followed (see here).

And since we're on the topic of food and mood, I note the recent meta-analysis from Camille Lassale and colleagues [2] suggesting that "adhering to a healthy diet, in particular a traditional Mediterranean diet, or avoiding a pro-inflammatory diet appears to confer some protection against depression in observational studies" has been garnering news headlines (see here). These studies combined suggest that diet might have an important effect of mood and well being. Now, where have I heard that before (see here)...?

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[1] Su K-P. et al. Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms. JAMA Network Open. 2018;1(5):e182327.

[2] Lassale C. et al. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Molecular Psychiatry. 2018. Sept 26.

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Fatty acids and autism meta-analysed again (yet again)

"Our preliminary meta-analysis suggests that supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in ASD [autism spectrum disorder] patients."

So said the results of the meta-analysis of randomized controlled trials undertaken by Yu-Shian Cheng and colleagues [1] adding further to this interesting area of nutrition with autism in mind. Before venturing through the results, I'll draw your attention to two other occasions this year when fatty acids use and autism have been given the meta-analysis treatment (see here and see here) albeit coming to slightly different conclusions.

This time around six studies made the grade for inclusion in the meta-analysis covering nearly 200 participants. All pitted an omega-3 fatty supplement against placebo and discussed study periods ranging from 6 weeks to 24 weeks. Various schedules were used to measure the impact (if any) of supplementation and/or placebo but the Autism Behavior Checklist (ABC) seemed to be one of the more frequently used assessment scales.

Results: bearing in mind "the average Jadad score was 4.67 with a standard deviation of 0.52" denoting that the methodological quality of the collected literature was pretty good, authors reported a general skewing trend towards 'better response by omega 3' over that of response to the placebos used by the various studies. This covered various areas of both core autistic behaviour(s) such as stereotypy and other, quality of life affecting parameters such as hyperactivity.

But... the clinical picture was not so clear-cut when it came to other autism-related measures such as the SRS - Social Responsiveness Scale - where "there was only borderline improved response by placebo in SRS total scores than those by omega 3." Taking into account the collected results, I do wonder whether use of something like an omega-3 supplement with autism in mind might actually be more relevant to the presence of co-occurring attention-deficit hyperactivity disorder (ADHD) given that (a) ADHD is very much over-represented in relation to autism (see here) and (b) the evidence base on the use of fatty acid supplements for ADHD seems to show a much more 'clear' positive relationship (see here).

There is another point raised in the Cheng paper that is worth noting: "Meta-analysis demonstrated no significant difference in the rate of discontinuation due to side effects between children receiving omega 3 and those treated by placebo." Although this does not mean that fatty acid supplements are universally 'side-effect' free, it does provide some good evidence that such supplementation was generally well-tolerated by the cohorts included for study. I say this bearing in mind that: "Gastrointestinal discomfort and irritability were most commonly reported side effects in the omega 3 groups" understanding that gastrointestinal (GI) issues are already over-represented when it comes to autism (see here).

Minus sweeping generalisations and keeping in mind the prime directive of this blog - no medical or clinical advice is given or intended - I have to say that the peer-reviewed science base for using omega-3 fatty acid supplements in the context of autism (or autism+ADHD?) is looking rather favourable. I say that in connection to the behavioural data that has so far been produced following supplementation but also more generally, with population evidence that omega-3 supplement seems to be good for aspects of physical health and wellbeing too. Certainly, the risk-benefit profile of fatty acid supplementation seems to favour benefit over risk...

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[1] Cheng Y-S. et al. Supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in children with autism spectrum disorders: a meta-analysis of randomized controlled trials. Neuropsychiatric Disease and Treatment 2017: 13  2531–2543.

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Eicosapentaenoic acid (EPA)-predominant fatty acid supplements and the treatment of depression

"Further RCTs [randomised-controlled trials] should be conducted on study populations with diagnosed or clinically significant depression of adequate duration using EPA [eicosapentaenoic acid] -predominant omega-3 HUFA [highly unsaturated fatty acids] formulations."

So went the conclusions of the review article published by Brian Hallahan and colleagues [1] who searched the peer-reviewed science literature for clinical trials "evaluating efficacy of omega-3 highly unsaturated fatty acids (HUFAs) in major depressive disorder." They found over 30 trials of omega-3 supplementation vs. placebo published between 1980 and 2014 that together included participant numbers in the thousands.

They reported that among those diagnosed with depression, the type of fatty acid supplement used might matter: "eicosapentaenoic acid (EPA)-predominant formulations (>50% EPA) demonstrated clinical benefits compared with placebo." When it came to that other commonly discussed omega-3 fatty acid - docosahexaenoic acid (DHA) - the results were not so great for those diagnosed with depression in terms of changes to symptom presentation(s). Importantly too, the authors noted that: "EPA failed to prevent depressive symptoms among populations not diagnosed for depression."

Interesting. More so when read alongside another recent review paper by Husted & Bouzinova [2] who similarly suggest that more targeted research is needed to "clarify an optimal dosage of EPA and DHA in [the] prevention of depression." They also described the idea that various processes particularly pertinent to the concept of inflammation (yes, depression and inflammation do seem to have some commonalities) might be a target for certain omega-3 fatty acids and onwards the presentation of depression. There may even be 'critical windows' where such supplementation might be more useful (see here) than others.

What's the critical difference between EPA and DHA that could account for the Hallahan findings? Well, there are a few good articles on how not all omega-3 fatty acids are the same, but I found one that is pretty informative (see here). Chemically-speaking, there are differences in structure which might account for where and when these compounds might fit when it comes to various chemical reactions in the body. Going back to the whole inflammation thing, I understand that EPA might also have some important effects on an enzyme called delta-5-desaturase (D5D) but I'd guess this is not the only difference that might be important.

I'll be keeping a watch out for developments in this area of study but for now, yet more evidence that food and nutrition might have some important influences on behaviour and psychiatry. Nutritional psychiatry is starting to come out from the clinical shadows perhaps...

Music: The Fall and Eat Y'Self Fitter ('Up the stairs mister').

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[1] Hallahan B. et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British Journal of Psychiatry. 2016; 209: 192-201.

[2] Husted KS. & Bouzinova EV. The importance of n-6/n-3 fatty acids ratio in the major depressive disorder. Medicina (Kaunas). 2016;52(3):139-47.

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Hallahan B, Ryan T, Hibbeln JR, Murray IT, Glynn S, Ramsden CE, SanGiovanni JP, & Davis JM (2016). Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British journal of psychiatry : the journal of mental science PMID: 27103682

Omega-3 fatty acids, gut bacteria and mouse behaviour

I read with great interest the paper by Ruairi Robertson and colleagues [1] (open-access available here) recently, talking about how "neurobehavioural changes induced by altering n-3 PUFA [omega-3 polyunsaturated fatty acids] status are closely associated with comprehensive alterations in gut microbiota composition, HPA-axis activity and inflammation" in mice.

Coming out of the 'bacterial research powerhouse' that is University College Cork, such research potentially unites some important concepts that are of some interest to this blog.

Based on questions still requiring answers about how maternal and early years consumption of everyone's favourite kind of essential fatty acids (the omega-3 variety) might impact on things like gut bacteria and "behavioural outcomes", researchers set about looking at possible connections in mice. Said mother mice with child and their male offspring were provided with one of a number of combinations of diet including "omega-3 deficient (O3-) or omega-3 supplemented (O3+) diet" and various measurements of mouse behaviours were undertaken as well as studies pertinent to what was going in their poo(p) from a bacterial perspective.

As per that opening paragraph, there were some 'subtle' changes to offspring behaviours at various developmental stages according to their omega-3 dietary status. So: "O3- animals displayed impaired communication, social and depression-related behaviours and O3+ animals displayed enhanced cognition." Alongside, researchers also observed some potentially important bacterial differences according to omega-3 diet or not that could be related to the reaction to stress (as per the examination of the HPA-axis). All-in-all, a diet rich (or not) in omega-3 fatty acids might have some quite far-reaching effects, at least in mice.

I'm interested in this kind of research for several reasons. First, is the idea that ensuring that human diets - all diets - are adequately supplemented with omega-3 fatty acids is a win-win situation. Outside of the somatic health benefits associated with appropriate omega-3 fatty acid ratios are the various 'psychological' benefits that might also be linked. Examples include the link between fatty acids and [some] cases of attention-deficit hyperactivity disorder (ADHD) or ADHD-type symptoms (see here). This is followed by some peer-reviewed evidence of possible effect on things like reading ability (see here) and even potentially off-setting the risk of psychosis for some (see here). Lots to potentially see from the humble fish oil minus any sweeping generalisations [2].

Second, this is not the first time that fatty acid status has been 'associated' with the various goings-on of the trillions of wee beasties that call our gastrointestinal (GI) tract home: the gut microbiota. I'll refer you to a previous post I wrote about some recent research on how omega-3 fatty acids might impact on [mouse] 'antibiotic exposure-induced gut microbiota dysbiosis' and obesity (see here) as another example where "dietary lipids affect specific populations of gut microbes and their metabolic end products" [3]. You and your gut bacteria are very much a product of what you do or do not eat. The value-added bit to the Robertson findings is the inclusion of a behavioural aspect to proceedings.

Obviously I have to point out that this is yet more mouse-based research and so one always needs to be a little cautious about over-generalising to humankind. But this work does provide an important insight into how fatty acids might link into gut bacteria and aspects of behaviour ripe for further scientific research. Indeed plucking one interpretation of their findings from their paper: "the adolescent period may be a critical timeframe in which omega-3 PUFA exert their effects on cognitive processes" I'd be minded to suggest quite a bit more science might be useful in this area including the idea that "the neuroprotective effects of omega-3 PUFA are not solely attributed to their direct incorporation into neural tissues but indirectly through their beneficial effects on gut microbiota composition and subsequent inflammatory status." Food for thought eh?

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[1] Robertson RC. et al. Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood. Brain Behav Immun. 2016 Jul 13. pii: S0889-1591(16)30339-7.

[2] Bozzatello P. et al. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. J Clin Med. 2016 Jul 27;5(8). pii: E67.

[3] Shen W. et al. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem. 2014 Mar;25(3):270-80.

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Robertson RC, Oriach CS, Murphy K, Moloney GM, Cryan JF, Dinan TG, Paul Ross R, & Stanton C (2016). Omega-3 polyunsaturated fatty acids critically regulate behaviour and gut microbiota development in adolescence and adulthood. Brain, behavior, and immunity PMID: 27423492

On fatty acid metabolism and autism and ADHD (again)

"Children with ADHD [attention-deficit hyperactivity disorder] and ASD [autism spectrum disorder] had low levels of EPA [eicosapentaenoic acid], DHA [docosahexaenoic acid] and AA [arachidonic acid] and high ratio of n-6/n-3 PUFAs [polyunsaturated fatty acid] and these correlated significantly with symptoms. Future research should further investigate abnormal fatty acid metabolism in these disorders."

So said the research publication by Natalie Parletta and colleagues [1] (open-access available here) who completed assessments on erythrocytes in blood samples from "565 children aged 3-17 years with ADHD (n = 401), ASD (n = 85) or controls (n = 79)." Alongside fatty acid analyses (undertaken at "a commercial Pathology Laboratory") researchers also included various behavioural measures with their participant group looking at aspects such as attention and impulsivity and also autistic symptoms (via the CARS). Importantly we are told that: "Participants who had taken any nutritional supplement during the previous year were excluded" from the study.

Results:  well as I've mentioned, compared to the asymptomatic (not autism nor ADHD) controls, group values for those with autism or ADHD were lower in terms of EPA and DHA among other things. In fact we are told that: "Children with ASD had lower DHA, EPA and AA and higher n-3/n-6 ratio than children with ADHD" suggesting that fatty acid metabolism might be even more irregular in this group compared to the others. EPA and DHA specifically fall under the banner of omega-3 fatty acids and are generally thought to be the 'good guys' when it comes to all-manner of health effects. I might particularly mention the word 'inflammation' when it comes to this class of fatty acids [2] which could be relevant to quite a bit of the autism spectrum as well (see here). When it however came to the overall ratio between omega 3 and omega 6 fatty acids (sometimes thought of the not-so-good guys), it was ADHD that beat autism that beat controls. The authors make a case for some interesting correlations between fatty acids levels and the various behavioural scores obtained but to be honest, I'm not all that impressed with the figures as they stand.

I've used the word 'again' in the title of this post to denote how this is not the first time that unusual fatty acid metabolism has been described with both autism and ADHD in mind (see here and see here respectively). Minus any sweeping generalisations, the body of peer-reviewed evidence looking at fatty acids and autism or ADHD is pretty consistent in the the findings being reported that one for reason or another, there seems to be 'issues' with fatty acids and screening services should perhaps be preferentially offered as and when a diagnosis (or both) is received."This cross-sectional study is the largest of its kind, supporting previous work that showed low n-3 PUFA levels, particularly DHA, in children with neurodevelopmental disorders." Indeed.

Then comes the question of whether supplementation as and when an atypical fatty acid profile is detected might be useful or not. The jury is still out on this side of things particularly when it comes to autism and the possible effects of supplementation (see here). For ADHD the evidence is a little stronger (see here) and continues to garner research attention [3] as a potentially cost-effective intervention option for some. I was also intrigued to read the authors' reasoning on a possible role for the trillions of wee beasties that call us home (the gut microbiota) and how: "Another explanation could involve the influence of gut microbiota on PUFA uptake and metabolism." In an unrelated post, I've talked about research suggesting a possible role for fatty acids in terms of gut bacteria and something like obesity (see here). One therefore wonders how deep the rabbit hole might go?

For now however, we have more scientific evidence for a potential role for fatty acid metabolism and at least some autism and ADHD...

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[1] Parletta N. et al. Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PLoS One. 2016 May 27;11(5):e0156432.

[2] Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505.

[3] Gow RV. et al. Current evidence and future directions for research with omega-3 fatty acids and attention deficit hyperactivity disorder. Curr Opin Clin Nutr Metab Care. 2015 Mar;18(2):133-8.

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Parletta N, Niyonsenga T, & Duff J (2016). Omega-3 and Omega-6 Polyunsaturated Fatty Acid Levels and Correlations with Symptoms in Children with Attention Deficit Hyperactivity Disorder, Autistic Spectrum Disorder and Typically Developing Controls. PloS one, 11 (5) PMID: 27232999

Add-on nutraceuticals for depression?

It came as no surprise to me that the systematic review and meta-analysis article by Jerome Sarris and colleagues [1] found what it did in relation to the use of [certain] adjunctive (add-on) nutraceuticals alongside antidepressants to reduce depressive symptoms: some of them might actually be clinically useful.

With no medical or clinical advice given or intended, the authors report that "adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants" might be something to consider "for improving inadequate response to antidepressants." Dr Sarris was one among many authors who contributed to the 'personal view' paper titled: 'Nutritional medicine as mainstream in psychiatry' [2] which was also covered a while back on this blog (see here). This latest addition to that and other opinions [3] which covered the peer-reviewed literature on a variety of nutrients also found something of a mixed bag of results for various other compounds including the aromatic amino acid tryptophan, zinc, folic acid and vitamin C.

Quite a bit more science needs to be done in this area, not least around the hows and whys that the various preparations might exert some effect. Vitamin D has of course been covered quite a bit on this blog in relation to something like depression (see here for example) so that particular nutraceutical might already have a research head start compared to others. I'm also minded to suggest that the involvement of something like SAMe (S-adenosylmethionine) as an add-on treatment might also imply a role for epigenetic variables in relation to at least some depression [4]. And then there is the question of who might be best responders to such nutraceutical use which implies heterogeneity and possible plural depressions...

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[1] Sarris J. et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. American Journal of Psychiatry. 2016. April 26.

[2] Sarris J. et al. Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry. 2015 Mar;2(3):271-4.

[3] Sarris J. et al. International Society for Nutritional Psychiatry Research consensus position statement: nutritional medicine in modern psychiatry. World Psychiatry. 2015 Oct;14(3):370-1.

[4] McGowan PO. & Kato T. Epigenetics in mood disorders. Environ Health Prev Med. 2008 Jan;13(1):16-24.

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Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, & Ng CH (2016). Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. The American journal of psychiatry PMID: 27113121

Fish oils for schizophrenia?

Hot on the heels of the peer-reviewed research-based suggestion that fish oil supplementation (high in omega-3 PUFAs) might have some rather important effects pertinent to the transition to full-threshold psychotic disorder for 'young people with an at-risk mental state' (see here), are the results from Tomasz Pawełczyk and colleagues [1].

This time around it was a randomised, placebo-controlled trial "of either 2.2 g/day of n-3 PUFA, or olive oil placebo, with regard to symptom severity in first-episode schizophrenia patients." I might add that we have been expecting these results given the publication of the trial protocol not so long ago [2]. n-3 by the way, refers to omega-3 or rather the Greek lower case character ω or ωμέγα.

Seventy-one participants were randomly assigned to olive oil (placebo) or "1320 mg/day of EPA and 880 mg/day of DHA" and monitored over the course of the 26-week study period. "The primary outcome measure of the clinical evaluation was schizophrenia symptom severity change measured by the Positive and Negative Syndrome Scale (PANSS)."

Results: quite a few changes were noted as a consequence of the fish oil supplementation including that: "A fifty-percent improvement in symptom severity was achieved significantly more frequently in the n-3 PUFA group than in the placebo group." Also: "N-3 PUFA intervention was also associated with an improvement in general psychopathology, measured by means of PANSS... depressive symptoms..., the level of functioning... and clinical global impression." All-in-all, there was quite a bit to see from the use of a humble fish oil supplement in this cohort and hence quite a bit more research is indicated.

A quick survey of the other research literature in this area suggests that the Pawełczyk findings were probably not unexpected. A Cochrane Review ('Cochrane does...') a few years back [3] pointed out that whilst the available literature at that time was not all one-way when it comes to the use of polyunsaturated fatty acids (PUFAs) for people with schizophrenia, there were pockets of evidence suggesting some positive effects might be had from this quite simple intervention. Some but not all subsequent trials have hinted as possible positive effects for some on the schizophrenia spectrum.

If I had to quibble with the Pawełczyk study in any way I might suggest that one has to be slightly cautious about the use of olive oil as a placebo condition. Bearing in mind my not confusing a high fat diet with a ketogenic diet (high fat / low carbohydrate), one has to pause a little to take in the potentially interesting mouse results published by Ann Katrin Kraeuter and colleagues [4] that some media have headlined with "High fat/low carb diet could combat schizophrenia." I personally would like to see the fish oils pitted against a non-fat alternative in clinical study just to be sure.

Music: and what else but goodbye to a legend...

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[1] Pawełczyk T. et al. A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. J Psychiatr Res. 2015 Nov 25;73:34-44.

[2] Pawełczyk T. et al. Omega-3 fatty acids in first-episode schizophrenia - a randomized controlled study of efficacy and relapse prevention (OFFER): rationale, design, and methods. BMC Psychiatry. 2015 May 2;15:97.

[3] Joy CB. et al. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev. 2003;(2):CD001257.

[4] Kraeuter AK. et al. Ketogenic diet reverses behavioral abnormalities in an acute NMDA receptor hypofunction model of schizophrenia. Schizophr Res. 2015 Dec;169(1-3):491-3.

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Pawełczyk, T., Grancow-Grabka, M., Kotlicka-Antczak, M., Trafalska, E., & Pawełczyk, A. (2016). A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia Journal of Psychiatric Research, 73, 34-44 DOI: 10.1016/j.jpsychires.2015.11.013

Fatty acid chemistry and autism

"Fatty acids in both serum and red blood cells were abnormal among this small group of Canadian children with autism compared to controls, underlining a need for larger age- and gender-matched investigations in this community."

Based on the analysis of fatty acid status in a small group of children with autism spectrum disorder (ASD) (n=11) compared with a small group of 'not-autism' control participants (n=15), the paper by Joan Jory [1] reports that there may be more to see in this important area. Specifically, the author reports on how lower levels of various important fatty acids (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA)) were detected in both analysis of red blood cells and serum for the group of children diagnosed with autism compared to controls.

This is not the first time that such findings have been talked about with autism in mind (see here). That also Jory reported that the ratio between the omega-3 fatty acids and the omega-6 fatty acids was lower in the autism group is not also new news in light of some quite speculative discussions on how "disturbances in n-6/n-3 ratios may contribute to the emergence of ASDs" [2]. I might add that such speculative opinions require quite a lot more science before anyone makes any sweeping generalisations.

Appreciating that science has been a bit hit-and-miss when it comes to attempts to correct fatty acid issues with autism and behaviour in mind (see here), I'm of the opinion that if we take autism out of the equation, fatty acid deficiency/insufficiency when diagnosed should be managed. I say this on the same basis that important issues with other nutrients such as vitamin D when diagnosed should be acted upon irrespective of a diagnostic label of autism or anything else (see here).

That also there may be specific comorbidities and skills potentially affected by fatty acid issues (see here and see here respectively) with autism in mind is worth noting. Allied to the idea that specific parts of the autism spectrum may be more 'sensitive' to fatty acid intervention (see here) and we have recipe for quite a bit more investigation. Insofar as the notion from Jory that fatty acids might be part of a complex story involving "propionic acid production" and autism, well, I'm not adverse to this message in light of other preliminary research in this area (see here). I say that mindful of the fact that there may be many 'links' between fatty acids and autism [3] and one shouldn't necessarily get bogged down with just one potential association...

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[1] Jory J. Abnormal fatty acids in Canadian children with autism. Nutrition. 2015. Dec 2.

[2] van Elst K. et al. Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev. 2014 Sep;45:369-78.

[3] Weiser MJ. et al. Dietary Docosahexaenoic Acid Alleviates Autistic-Like Behaviors Resulting from Maternal Immune Activation in Mice. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA). 2015. Dec 2.

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Jory, J. (2015). Abnormal fatty acids in Canadian children with autism Nutrition DOI: 10.1016/j.nut.2015.10.019

Fish oils preventing psychosis: long-term effects?

"This is the first study to show, to the best of our knowledge, that a 12-week intervention with omega-3 PUFAs [polyunsaturated fatty acids] prevented transition to full-threshold psychotic disorder and led to sustained symptomatic and functional improvements in young people with an at-risk mental state for 7 years (median)."

So said the quite remarkable findings reported by Paul Amminger and colleagues [1] (open-access available here) who followed up their previous research study [2] looking at the effects of a 12-week supplementation program consisting of either 1.2 grams per day of fish oil or placebo. On that previous occasion, said omega-3 PUFA supplement ("700 mg of eicosapentaenoic acid (20:5n3), 480 mg of docosahexaenoic acid (22:6n3), and 7.6 mg of mixed tocopherol (vitamin E)") reduced the risk of progression to psychotic disorder in individuals at ultra-high risk of psychosis for up to a year post-intervention baseline.

The latest results represent quite an impressive post-intervention follow-up to the original Amminger study. Looking at some of the original cohort of participants and drawing on several types of information including screening / questionnaire data and "rate of prescription of antipsychotic medication", the authors were able to quite confidently conclude that "omega-3 PUFAs may offer a viable longer-term prevention strategy with minimal associated risk in young people at ultrahigh risk of psychosis."

Insofar as the precise hows and whys of omega-3 PUFAs potentially affecting psychosis risk, well, we are left in quite a typical position of speculating. "Omega-3 PUFAs provide a range of neurochemical activities via modulation of neurotransmitter (noradrenaline, dopamine and serotonin) reuptake, degradation, synthesis and receptor binding, as well as anti-inflammatory and anti-apoptotic effects, and the enhancement of cell membrane fluidity and neurogenesis." Take yer pick, bearing in mind there may also be additive and interacting effects within this menu of potential modes of action.

If one assumes however that the possible connection between omega-3 PUFAs and various behavioural and psychiatric labels might have some commonalities (see here and see here for example), one might see a few additional ways and means that 'mode of action' might become a little clearer in the future. One factor, cognitive decline linked to cases of psychosis onset, might not however be the prime factor extrapolating from other recent results [3]...

Music: Felix Jaehn - Ain’t Nobody (Loves Me Better).

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[1] Amminger GP. et al. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat Commun. 2015 Aug 11;6:7934.

[2] Amminger GP. et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54.

[3] Chew EY. et al. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function. JAMA. 2015; 314: 791-801.

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Amminger GP, Schäfer MR, Schlögelhofer M, Klier CM, & McGorry PD (2015). Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nature communications, 6 PMID: 26263244

Autism and altered levels of essential fatty acids

Brigandi et al. 2015. Int. J. Mol. Sci. 16: 10061-10076.

A quote to begin this post is taken from the paper by Sarah Brigandi and colleagues [1] (open-access available here): "Our study demonstrates an alteration in the PUFA [polyunsaturated fatty acids] profile and increased production of a PUFA-derived metabolite in autistic patients, supporting the hypothesis that abnormal lipid metabolism is implicated in autism."

The Brigandi results were based on the analysis of blood samples for fatty acid content for "121 autistic patients and 110 non-autistic, non-developmentally delayed controls, aged 3-17." Participants with autism met DSM-IV criteria and CARS scores for autism although did not include those "on the broader autism spectrum" diagnosed with Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) for example.

Using various analytical techniques including gas chromatography and liquid chromatography-mass spectrometry (LC-MS), authors assayed for various fatty acids (saturates, monosaturates and polyunstaurates) and also levels of that "PUFA-derived metabolite" prostaglandin E2 (PGE2) a "pro-inflammatory AA [arachidonic acid] metabolite" that "increases the risk of neuroinflammation which can lead to excessive production of reactive oxygen species (ROS)." For some further background you might wish to have a look at a previous occasion that PGE2 has been discussed on this blog (see here) and another occasion covering ROS (see here).

Results: "a number of PUFA, mainly AA and DHA [docosahexaenoic acid], were significantly lower in autistic individuals than controls." DHA, by the way, is known as an omega-3 fatty acid, so called because of the specific positioning of a chemical double bond in its chemical arrangement. Alongside another omega-3 fatty acid called eicosapentaenoic acid (EPA), this is the stuff that is usually listed as the active ingredient in the various fish oil supplements that you find dotted around these days.

When it came to levels of PGE2, Brigandi et al report some really quite interesting results albeit based on the analysis of considerably smaller participant groups (autism n=20 and controls n=20). So: "All control samples were under the detection limit for PGE2 detection of <0.71 ng/mL." The same however could not be said for the autism group where "PGE2 levels were detected in 9 of the 20 plasma samples from autistic individuals, ranging from 1.21 to 3.91 ng/mL." This was translated as a "marked difference" between the groups.

Just before I head into what these results *might* mean, it's worthwhile pointing out a few caveats surrounding the Brigandi study. As the authors report: "we did not conduct an age-matched nor gender-matched analysis between the autistic and control groups." Fair enough, so we can't rule out those factors impacting on the results obtained. Further: "Fasting was not a requirement prior to blood draws" and authors "did not collect dietary information from study participants." This last point in particular combines with a perhaps a too sweeping generalisation from the authors that they "do not expect dietary differences between the groups to be a primary explanation" for some of their results. Diets can and do differ when it comes to autism [2] and sometime in the most serious ways (see here). One needs to be very mindful of that fact more so when it comes to actual fat intake in cases of autism [3].

That all being said, I do think that these results invite much further study of fatty acids and autism (some autism) on top of quite a bit of other research in this area [4]. As per my previous posts in this area, the collected data so far on supplementing fatty acids in cases of autism is not exactly 'concrete' in terms of effectiveness (see here). Whereas an important comorbidity noted in quite a few cases of autism, ADHD (attention-deficit hyperactivity disorder) in whole or in part, is enjoying some rather more positive findings (see here and see here) indeed, even more generally [5], core autism does not seem to be benefiting as much from the supplementation side of things. It could be worthwhile focusing less on syndromes and more on symptoms [6] when it comes to supplementation as per the idea that fatty acids might be [partially] linked to things like reading ability (see here) or even with critical periods of requirement [7] in mind but I'd like to see a lot more science done on this first. That also includes looking at other potential biological correlates too [8]...

Maybe the VIDOMA study will provide a little more insight?

Music: Sheppard - Geronimo.

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[1] Brigandi SA. et al. Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. Int J Mol Sci. 2015 May 4;16(5):10061-10076.

[2] Kuschner ES. et al. A preliminary study of self-reported food selectivity in adolescents and young adults with autism spectrum disorder. Research in Autism Spectrum Disorders. 2015; 15-16: 53-59.

[3] Marí-Bauset S. et al. Fat intake in children with autism spectrum disorder in the Mediterranean region (Valencia, Spain). Nutr Neurosci. 2015 May 28.

[4] Bell JG. et al. Red blood cell fatty acid compositions in a patient with autistic spectrum disorder: a characteristic abnormality in neurodevelopmental disorders? Prostaglandins Leukot Essent Fatty Acids. 2000 Jul-Aug;63(1-2):21-5.

[5] Raine A. et al. Reduction in behavior problems with omega-3 supplementation in children aged 8–16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. Journal of Child Psychology & Psychiatry. 2015; 56: 509-520.

[6] Bent S. et al. Internet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autism. J Am Acad Child Adolesc Psychiatry. 2014 Jun;53(6):658-66.

[7] van Elst K. et al. Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders. Neurosci Biobehav Rev. 2014 Sep;45:369-78.

[8] Mostafa GA. et al. A possible association between elevated serum levels of brain-specific auto-antibodies and reduced plasma levels of docosahexaenoic acid in autistic children. J Neuroimmunol. 2015 Mar 15;280:16-20.

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Brigandi SA, Shao H, Qian SY, Shen Y, Wu BL, & Kang JX (2015). Autistic Children Exhibit Decreased Levels of Essential Fatty Acids in Red Blood Cells. International journal of molecular sciences, 16 (5), 10061-10076 PMID: 25946342

Blood biomarkers and suicide

Science can be a pretty cold thing.

Take for example some of the discussions on the recent paper by Helen Le-Niculescu and colleagues* (open-access) on the potential for a suite of blood biomarkers to predict suicidal behaviour (see here for some more commentary). The very complicated tragedy that is suicide - whether attempted or completed - [potentially] boiled down to genes, and in particular the product expression of one gene, SAT1 described by the authors as "head and shoulders above the rest" in terms of its [potential] predictive capability.

The Good Samaritan @ Wikipedia 

With my science hat on, I was obviously interested in this research, and how despite the relatively small participant group "In each of the suicide completers, the increase in SAT1 was at least three s.d. above the average levels".

But then as I read the words again, the realisation set in that these 'completers' were not just mice or rats in a cage, they were people. People who only 24 hours prior to their inclusion in the study were alive. And then for whatever reasons decided to end their life and with it the hopes and dreams of their parents, siblings, partners, extended family and friends.

Don't get me wrong, I'm not saying that we shouldn't be actively engaging in research looking at how we might eventually predict those at greatest risk from suicide. On the contrary, if this work pans out and survives replication the potential savings both in terms of that most precious commodity (life) and beyond could be enormous. But it is still an 'if' and those were real people.

The Le-Niculescu paper is open-access so I'm not going to go through it with a fine-toothed comb on this occasions. Suffice to say that this study, following previous interest from this authorship group (see here), set out to explore whether it was possible to predict and track suicidal states, particularly in those at high-risk for suicide as per their selection of participants diagnosed with "a major mood disorder (bipolar disorder)".

This involved first looking at blood gene expression in participants focused specifically on those who "switched from having no suicidal thoughts to scoring highly on a suicide-risk scale". The myriad of data this generated was then subject to analysis via an author favourite technique called Convergent Functional Genomics (see here**) used "to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality". It was then a process of checking the top ranking gene biomarkers in those suicide completers (drawn from a different population) and "Niculescu's team was left with six which they was reasonably confident were indicative of suicide risk". More boiling down of the biomarkers was accomplished by looking at a further group of those hospitalised for suicide (attempts) and "SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well".

In all the chatter about this study, one particular question was floating around my mind: if these biomarkers are verified, does this mean we could eventually affect gene or biochemistry and somehow alter the behaviour of those attempting or thinking of attempting suicide?

Actually the authors do mention some potentially important information about this. They report for example, that the drug clozapine might affect expression of some of the biomarkers "in opposite direction to our human suicidality data in previous independent animal model pharmacogenomics studies conducted by us". Clozapine as they note is indicated for suicidality under certain circumstances (see here). Fair enough, an antipsychotic might help, bearing in mind it is an antipsychotic and carries some of the usual side-effects (see here).

But they also mention another possibility that requires some further study, as per this quite long quote:

"Several of the biomarkers from our current study (SAT1, S100A8, IL1B and 16 others) were changed in expression by omega-3 treatment in the blood of the circadian clock gene DBP (D-box binding protein) knock-out mouse model in opposite direction to our human suicidality data".

So, fatty acids, particularly those of the omega-3 variety might [might!] also impact on some of those biomarkers too? This point in particular is of real interest to me and this blog. A quick trawl of the literature looking at measured fatty acids and suicidality turns up some interesting data as per studies like this one*** and this one****. I don't think anyone has convincingly said that fatty acids 'cause' suicide because suicide is a very complicated process reliant on more than just biology, but the association is an interesting one. Some recent coincidental literature on suicides in prison (see here) confirms the multi-faceted nature of suicide.

Indeed, I've talked previously on this blog about how nutrition, in many forms, has been associated with suicide risk as per the vitamin D and independently, the lithium research (see here) reported in the scientific literature. To stress again, these are associations; so one has to be cautious not to say too much at the present time about causation.

I started this post by saying how cold science is when it comes to its operation. I suppose I should end by saying that science is cold, at least in the way it is carried out and reports, because it has to be. It has to be cold and objective. Assuming that the Le-Niculescu findings are successfully replicated however, science then can start to move out of the freezer and into something rather 'warmer' approaching real-life with regards to its translation into potentially saving lives.

To close, just in case you need to talk to someone, remember that these guys are only a phone call or email away (similar organisations are also in the US and other parts of the world).

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* Le-Niculescu H. et al. Discovery and validation of blood biomarkers for suicidality. Molecular Psychiatry. 20 August 2013. doi: 10.1038/mp.2013.95

** Le-Niculescu AB. & Le-Niculescu H. Convergent Functional Genomics: what we have learned and can learn about genes, pathways, and mechanisms. Neuropsychopharmacology. 2010 January; 35(1): 355–356.

*** Lewis MD. et al. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry. 2011 Dec;72(12):1585-90. doi: 10.4088/JCP.11m06879.

**** Vaz JS. et al. Omega-6 fatty acids and greater likelihood of suicide risk and major depression in early pregnancy. J Affect Disord. 2013 May 30. pii: S0165-0327(13)00346-7. doi: 10.1016/j.jad.2013.04.045.

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Le-Niculescu H (2013). Discovery and validation of blood biomarkers for suicidality Molecular Psychiatry DOI: 10.1038/mp.2013.95