Fish oil for health and happiness?

The Trifecta of Mental Health Supplements: Vitamin D, Probiotics & Fish Oil

This post is the last in a series of three in which we thoroughly explore the darlings of supplementation for mental health: vitamin D, probiotics and fish oil.  Read on to learn it all – the good, the bad and the ugly.

What’s all the fuss about fish?

I can’t argue that you are made up of fish the same way I could argue that you are made up of bacteria. But fish does contain special fatty acids that your brain needs to function at its best and it contains them in a form that you can’t get from just any fish oil supplement. It’s time to get snobby about what you feed your brain…and this article will tell you why!

Your brain is made up of fatty acids in the forms of docosahexaenoic acid (DHA) and arachidonic acid (AA). Eicosapentaenoic acid (EPA) is another fatty acid that exists in the brain but is not present in large amounts [1]. Food sources of the omega-3 fatty acids DHA and EPA include fatty cold-water fish like salmon and tuna. Sources of arachidonic acid include eggs, beef and chicken. Food or supplements containing preformed fatty acids are important because your own ability to synthesize some of these is not that efficient [2].

Unfortunately, modern diets provide an unbalanced ratio of omega-6 (more pro-inflammatory or immune stimulatory) to omega-3 (more anti-inflammatory) fatty acids of over 10:1, whereas the optimal ratio has been suggested to be as low as 2:1 or 1:1 [3]. The high omega-6 content comes from a combination of factors, including the popularity of corn, sunflower, soybean, safflower, and cottonseed oils and the consumption of beef from cows fed corn [2,3]. While we do need some omega-6 fatty acids, balance is key.

DHA, an omega-3 fatty acid, sticks around in our brain for about two and a half years [1]. Due to its role in neuronal membranes in the brain, it has been suggested that changes in dietary DHA could affect the structure of new neurons as they are being formed [1].

In addition, omega-3 fatty acids like DHA and EPA act on dopamine and serotonin systems, as well as regulating pathways of inflammation [4]. Conventional thought is that increasing the amount of omega-3 fatty acids in membranes affects AA-dependent signalling [4]. This is relevant because some drugs that activate dopamine receptors, for example, trigger AA-dependent signalling [4]. It is thought that SSRIs (a type of antidepressant drug) may use AA and its metabolites to effect their actions in the brain as well [4].

One lab-based study actually demonstrated that long-term EPA (but not DHA) supplementation increased the release of AA from membranes, possibly by preventing re-uptake of AA into the membrane [4]. This suggests an inhibitory activity of EPA on enzymes such as lysophospholipid acyltransferase (LPAT) or fatty acid CoA ligase (FACL) which would allow for that re-uptake [4]. Less AA in the membranes means more AA is available for the signalling reactions including those affecting dopamine and serotonin systems [4].

There is also a newer set of compounds that can be made from EPA and DHA and these are called resolvins. We don’t know a lot about the E- and D-series resolvins yet, but we do know that they are involved in decreasing inflammation in the brain [4]. This may be another mechanism by which EPA and DHA supplementation could exert an effect on mental health.

Seafood Consumption

Countries with higher rates of fish or seafood consumption have lower rates of major depressive disorders, postpartum depression, and bipolar disorders in addition to better outcomes for patients with schizophrenia [2]. This idea does not go undisputed, as other researchers suggest it is the amount of sugar we eat that is at fault, and that fish consumption has no significant effect on the mental health disorders [5]. Truly both are important. You can’t feed yourself an epic fish dinner, polish it off with a bag full of leftover Hallowe’en candy and expect them to somehow balance out to a neutral effect.

Fatty Acid Status Screening

It seems most likely that fatty acid status does have something to do with mental health. Interestingly, suicidal ideation is correlated with low fatty acid intake and fatty acid status can provide an indicator for future suicidal attempts in patients with depression [2].

A study performed at a psychiatric inpatient facility in Cincinnati actually screened patients on admission to determine their fatty acid status. Most of these patients (75% of them!) had a whole blood fatty acid composition of less than or equal to 4% EPA and DHA [2]. For the sake of comparison, only 25% of a healthy population would have levels of EPA and DHA that low [2]. While the study shows rates of deficiencies, it is not clear if supplementation was helpful in this population or not. In all the case vignettes provided, changes were made to the patient’s medications aside from fish oil supplementation, and so the patient’s improvements cannot be attributed solely to the fish oil.

You may be familiar with a link between medications that lower cholesterol and risk for suicide. What else does this affect? Lowering cholesterol levels also affects concentrations of polyunsaturated fatty acids. When studied, blood levels of polyunsaturated fatty acid levels are the strongest predictors of 5-HIIA levels in the cerebrospinal fluid (CSF) [6]. 5-HIIA is a metabolite of serotonin and low CSF levels are associated with both suicide and violence [6].

Seasonal Variation in Omega-3 Fatty Acids

Did you know that there is seasonal variation in omega-3 fatty acid levels in your blood? Part of this could be from seasonal variation in diet. EPA, DHA and AA all vary with the seasons, being significantly lower in the winter (December to March) [7]. When extrapolating this data to previous data on suicide rates, it was discovered that there was no significant correlation between EPA, DHA or AA and violent or nonviolent suicide [7].

However, there was a significant correlation between a change in these parameters, especially the change in EPA, and violent suicide [7]. In simpler terms, as EPA levels drop the suicide risk increases. It is the drop itself, rather than the actual level that was correlated with suicide risk. This is an important point to consider because studies looking at a static point in time with regards to omega-3 fatty acids levels (as most do) may miss this correlation with suicide risk. Indeed, a review of the literature reveals conflicting results on the association between levels of various omega-3 fatty acids and suicide risk [8].

Considerations in Research on Omega-3 Supplementation

When examining this research, there are several other important factors to consider along with the studies’ results:

• Which fatty acids and fatty acid ratios were studied? Some studies use just EPA, others use just DHA, some use different ratios of EPA and DHA, while yet others combine these with some of the key omega-6 fatty acids as well. This makes studies difficult to compare.

• What type of omega-3 fatty acid supplement (fish oil, cod liver oil, krill oil and salmon oil, etc) was used?

• Fish oil supplement or actual fish intake? Fish oil supplements contain DHA in free form, whereas actual fish contains DHA in a phospholipid form which may be more beneficial for people whose ability to uptake the free DHA into the brain is impaired.9

• Do patients included in the studies actually have a clinical diagnosis of the studied condition, and how severe are their symptoms?

• Are omega-3 deficiencies found in these populations because of the disease process, or because of behavioural changes that result from the disease process?

• Do omega-3 fatty acid deficiencies create problems during development that cannot be corrected with supplementation later on in life, even if that supplementation corrected the fatty acid status [2]?

• How long was the study? Based on animal studies of omega-3 deficiency, at least 8 weeks are needed to change brain composition [10]. It is expected that omega-3 supplementation in human clinical trials would also take several weeks or months to see an effect [10]. In the meantime, the slow onset of effect could cause participants to believe they are in a placebo group, and these beliefs may trigger thoughts and behaviours that affect outcomes [10].

• How do you disguise fish oil? Last but not least, it is challenging to create a placebo for fish oil, because fish oil can be pretty gross and smelly [10]

Despite these drawbacks, omega-3 intake in the form of fish oil supplementation or fish in the diet has been a huge topic in the mental health research and is commonly used clinically.

The following discussion will cover the efficacy of fish oil in:

• Traumatic brain injuries and chronic neurodegenerative diseases

• Memory and cognition

• PTSD

• Depression

• Postpartum Depression

• Manic-Depressive Disorder

• Attention Deficit Hyperactivity Disorder

• Autism

• Anxiety

• Schizophrenia

Feel free to skip to the sections that most interest you!

Traumatic Brain Injuries and Chronic Neurodegenerative Diseases

In the right form, dose and duration, a little bit of stress like exercise can be beneficial. This is a concept known as “hormesis”, or in this case “neurohormesis”. It is how some dietary phytochemicals acting as pro-oxidants actually have a neuroprotective effect by stimulating an antioxidant response in the brain [11].

But in chronic neurodegenerative diseases oxidative stress gets out of control and we end up with excess oxidative stress and programmed cell death [11]. Lipid metabolism is important in traumatic brain injuries, Alzheimer’s disease, Parkinson’s disease, stroke and many other brain disorders. Our brains are pretty delicate when it comes to oxidative stress. Our neuron membranes and our neurotransmitters are easily oxidized and the incredible output of mitochondria in our brain means lots of reactive waste products [11].

Now what protects the fatty acids in fish oil from being oxidized? These are delicate structures just like our neurons’ membranes. One form of omega-3 supplementation being studied in more detail is krill oil. Krill oil is special because it contains the antioxidant astaxanthin within it and this can protect those fatty acids.

The first time I heard about astaxanthin was in an undergraduate biology class. It was intriguing to think that this was what was responsible for the pink colouring of flamingos, salmon and lobster. It would be curious if our hair or skin also turned pink if we ate a lot of salmon!

The therapeutic components of krill oil have good bioavailability because the fatty acids are part of phospholipids and can cross the blood-brain barrier [11]. Animal studies demonstrate that salmon oil and krill oil supplementation result in higher brain DHA than fish oil supplementation [11].

DHA in phospholipid form (such as acquired when you eat and metabolize actual fish) might be particularly helpful for those with Alzheimer’s disease because it can get into the brain through different mechanisms than free DHA [9]. The way free DHA accesses the brain is impaired in people with the APOE4 gene that is linked to Alzheimer’s disease [9]. Getting that DHA into the brain helps prevent the tau tangles and amyloid-beta plaque characteristic of the disease [9].

This sounds pretty good in theory. But where are the clinical trials for effectiveness of omega 3 supplementation in traumatic brain injury or neurodegenerative disease? Definitely scarce in the last few years.

There has been one clinical trial of omega-3 (from flaxseed oil, which is not quite the same as fish oil in omega-3 content) combined with vitamin E supplementation in Parkinson’s disease. This trial saw a decrease in disease rating over 12 weeks along with improvements in insulin sensitivity and inflammation [12].

The lack of studies is frustrating because despite theoretical benefits, quite promising animal studies and potential effects based on research in other disease states we just don’t have human clinical trials to support this approach. There are two case studies on this topic. One provides a word of caution on fish oil supplementation and the other provides a glimmer of hope.

First, the word of caution. Fish oil can dramatically increase the INR in people taking anticoagulant medications like warfarin. INR is a measure that is used to determine correct dosing of warfarin and if it gets too high you’ll have an increased bleeding risk. Why mention this as part of the trauma and neurodegenerative disease section? Because elderly populations are going to have a greater likelihood both of experiencing those conditions and of being on an anticoagulant.

The published case was an 83-year old male who was admitted to the ER with head trauma as the result of a motor vehicle accident [13]. He was on several medications, including warfarin. He was also taking fish oil supplements, possibly because he also had a diagnosis of dementia. The initial CT scan showed a left-sided subdural hematoma (brain bleed) and the patient was given therapies to reduce the effects of warfarin and help stop the bleeding [13]. Despite this, the INR kept creeping up [13]. The brain bleed got bigger and bigger and the patient ended up passing away later that day [13].

This patient was in an accident but given the age you might also consider the risk of traumatic brain injury from falls, especially in the elderly. If a patient is at risk for falling and hitting his head, should we supplement with fish oil? This is where each individual case needs to be considered in terms of dosing and risks and benefits.

The other case is much more optimistic. This was the case of a teenager involved in a motor vehicle accident who had such a severe TBI that it was supposed to be lethal [14]. Omega-3 fatty acids were added to his enteral feedings on day 3 [14]. On day ten, the patient started receiving 15 ml twice per day of Nordic Naturals Ultimate Omega consisting of over 9g EPA and over 6g DHA per day [14]. The patient went from being in what the physicians thought would be a permanent vegetative state to a specialized rehabilitation institute on day 24 [14]. Four months after the injury he was able to go home [14]. Two years later he has difficulties with speech, balance and use of the left side of his body but is otherwise doing well [14]. That’s an incredible improvement. This highlights the importance of timing and dosage as well as the potential of omega-3 supplementation as a therapy.

Memory and Cognition

What about memory and cognition?

We have some observational data demonstrating a correlation between fish oil supplementation and maintaining good cognitive function with age [15]. However, there are a lot of drawbacks to this type of study. The people who took fish oil supplements also took other supplements and quite likely put more effort into health promoting behaviours in other areas of their life. Taking a fish oil supplement cannot be isolated as the cause of their good cognitive function.

Clinical trials on supplementation with omega-3 fatty acids seems to help some people with dementia but not others [1]. This may be related to the type of dementia experienced or it may be the result of the doses or form used [1,16]. Those with intracellular A-beta oligomer-associated AD responded better to DHA supplementation and Rhonda Patrick suggests a phospholipid form specifically (krill oil or actual fish consumption) will have superior benefits for those with the APOE4 gene [1,9]. Overall, a Cochrane review found that there isn’t currently enough evidence to support the effectiveness of omega-3 supplements in mild to moderate Alzheimer’s disease [17].

What about supplementation earlier in life? There is one study that was completed last year on the effects of krill oil supplementation in adolescents on learning and cognition [18]. The results haven’t been published yet, but it will be interesting to see if it makes a difference.

It’s important to remember that no matter how well you supplement, diet still matters. A particularly relevant point in the context of omega-3 supplementation is that omega-3 intake in the presence of dietary fructose appears to have a negative effect on learning and memory [19]. You can’t expect your supplements to do all the work in keeping you healthy!

PTSD

For Post-Traumatic Stress Disorder (PTSD), there is a focus in the research on how to prevent fear memories from forming related to whatever event triggered the onset of PTSD. It takes a period of time before our fleeting thoughts and experiences become more long-term memories and it is during this time that we want to intervene. Theoretically, during a traumatic event, a large amount of stress hormones are released which causes fear memories to be remembered more than they should [20].

The areas of the brain involved processing these fear memories include the hippocampus, amygdala and medial prefrontal cortex [20]. We can potentially get fear memories to move out of the hippocampus if we stimulate hippocampal neurogenesis early after the traumatic event has occurred [20].

Increasing hippocampal neurogenesis can be useful aside from PTSD, in that it is also linked to improvements in cognition and mood [20].

How do we increase hippocampal neurogenesis? It has been proposed that omega-3 supplementation could be beneficial for those with newly acquired PTSD by upregulating brain-derived neurotrophic factor (BDNF) and stimulating new neurons to grow in the hippocampus, an area of the brain involved in fear responses and fear memory [1,20].

Indeed, in one small pilot trial, patients given omega-3 supplementation in the form of 1470 mg DHA and 147 mg EPA every day for two weeks had a much lower Clinician-Administered PTSD Scale score [20]. Of the patients given the omega-3 supplementation, only one went on to develop PTSD. In the responders there was an increase in serum BDNF, which was not seen in the one patient who did not respond [20].

Follow-up studies with larger groups of participants did not find a difference in Clinician-Administered PTSD Scale scores compared to placebo [21,22]. However one study did find that the omega-3 supplementation group experienced decreased heart rates [21]. The authors suggested this might be a result of increased activity of the vagus nerve [21].

You may be familiar with the effects of exercise on neurogenesis and cognition in general. Combining both exercise and DHA supplementation seems to have greater effects on the brain than exercise alone [20]. Therapies combining supplementation with lifestyle interventions are harder to study but might be more clinically useful in the real-world.

Depression

As with many diseases that have increased in prevalence and incidence in modern society, changes in diet quality also impact depression. Resulting imbalances in omega-6 to omega-3 content in the foods we eat have led to the investigation of omega-3 supplementation as a therapeutic strategy for mood disorders [4]. 


Of earlier studies, lower doses (1 gram per day) of EPA resulted in better improvement of depressive symptoms than higher doses (such as 2 grams or 4 grams per day) [4]. This effect was seen as early as four weeks [4]. Although significant compared to the placebo, the results were not dramatic [4]. Other studies have found beneficial effects from supplementing with 2 grams of EPA per day [4]. The recommended dosage is typically 1–2 g of an EPA/DHA combination, preferably at a ratio of 3:2 or higher [23].

A high EPA content appears more helpful than a high DHA content for depressive symptoms and this is suspected to be due to EPA working better as an anti-inflammatory [1,4]. However, the authors of one review paper suggest caution in discounting DHA altogether, because trials comparing DHA and EPA are lacking and EPA alone is not effective as a single therapy [4].

A randomized, double-blind, placebo-controlled trial of omega-3 supplementation in an elderly population specifically found no effect on mental well-being at 26 weeks for high (1800 mg) or low (400 mg) dose supplementation [24]. Although, 1800 mg might still be considered a low dose by some physicians, this study is valuable because of its design. The follow-up at 26 weeks should be long enough to take into account long-term changes in, for example, membrane structure. The randomized, double-blind, placebo-controlled aspect of it helps us to determine that whatever effects were present were not due to patient expectations upon receiving a supplement.

A thorough review of studies up to 2015 also comes to the conclusion that supplementation with omega-3 fatty acids has a small effect at best on depressive symptoms, and that based on the evidence so far this effect is not clinically significant compared to placebo [25].

In a newer study on treatment-resistant depression, omega-3 supplementation was quite helpful after four weeks but the number of patients in the study was small, so the finding needs repeating [23].

Clearly, there is a lot of discrepancy over the effectiveness of omega-3 supplementation. So why are we so drawn to using it still? These negative studies could indicate that it really isn’t effective, but they could also indicate that we aren’t studying the right things. For example, severity of depression or different underlying causes for depression.

Are we studying the right variables?

One group of researchers decided to address this. Considering the multiple pathophysiological processes behind depressive symptoms, they not only studied a group of participants who met criteria for depression, they also obtained information on inflammation markers in these participants.

They found no significant difference between the treatment group and the placebo group overall [26]. However, something very interesting emerged when looking at those markers of inflammation. In participants with at least one marker for high inflammation, there was a significant difference for EPA-rich supplementation (about 1 g EPA per day) over both placebo or DHA-rich supplementation [26]. After eight weeks, these participants had improved by eleven points on the HAM-D-17, a scale commonly used to assess depressive symptoms [26]. The total number you can score on this scale is 52 (9 items scored from 0-4 and 8 items scored from 0-2). A drop by eleven points is a considerable improvement.

Participants without high markers for inflammation had a better response to placebo or to the DHA-rich supplementation than to the EPA-rich supplementation [26].

Remission rates in this study looked like the following: [26]

The researchers also found that looking at a combination of inflammatory markers was more helpful than looking at any single marker [26]. The markers they used included plasma hs-CRP, IL-1ra, IL-6, adiponectin (low levels indicating inflammation), and leptin. Obese participants, especially obese women, were the most likely to have high levels of inflammation in this group [26].

This study gives us a new perspective on omega-3 fatty acid supplementation in patients with depression. We can look at inflammatory markers in patients to help us assess whether or not they might be a good candidate for omega-3 supplementation.

There are several reasons that individualizing treatment like this is important. The one that comes to mind most readily is simply that quality (and trust me, quality is very important!) omega-3 supplements can get expensive, so you want to make sure that it is actually giving you benefit. Information like this helps identify which patients will benefit most from omega-3 supplementation. You might speculate from this that using lifestyle interventions to reduce inflammation might remove the need for supplementation down the road.

On the flip side, it also helps identify which patients are not likely to benefit from supplementation. Importantly, if you take a closer look at the numbers above or the paper itself, you will see that patients with low levels of inflammation actually got worse on EPA-rich supplementation than they did on placebo [26]. Not only was the supplementation not helpful, it appeared to be harmful!

In addition, without looking closer at the causes behind an individual’s depressive symptoms we could miss other important contributing factors whether that’s inflammation, infection, anemia, social factors, etc.

It would be great to see a replication of this study, or to see more studies that seek to examine underlying mechanisms for the depressive symptoms in relation to the experimental supplementation.

Can we disregard DHA in the context of depression completely? Likely not, although most studies suggest effects with EPA-rich supplementation. White matter in the brain has been seen to change with 6 weeks of omega-3 supplementation in association with increasing percent DHA levels [27]. This was only seen in those with a diagnosis of major depressive disorder (compared to healthy controls) and only in those that improved with the supplementation [27].

How do we make sense of this information if we just went through a study that suggested EPA-rich supplementation was the way to go? Well the authors of the white matter changes study suggest that EPA helps DHA to get into the brain more easily which would explain why EPA-rich supplementation is more helpful than DHA-rich supplementation but white matter changes in the brain correlate with increases in DHA levels [27].

Now say you have a patient with depression who has elevated markers of inflammation and you want to try omega-3 supplementation with a high EPA to DHA ratio. How much supplementation is needed?

While most studies use 1-2 g EPA per day, a fairly recent study in children suggests bodyweight makes a considerable difference in how supplementation affects blood levels of these fatty acids [28]. Not only that, but heavier children/adolescents in which levels increased to a smaller degree saw better improvement in mood [28]. The authors propose more research on dosing and metabolism should be conducted, and the possibility of a U-shaped curve explored [28].

A U-shaped curve is like what we’ve seen for vitamin D supplementation where too little is associated with poor health outcomes but too much is also associated with poor health outcomes. More studies need to be done to elucidate the “Goldilocks” range for omega-3 fatty acids.

However, what is another possible reason the overweight group saw greater improvements? Inflammation. As the other study we discussed found out, there was greater inflammation in obese participants and participants with inflammation were the ones who benefited most from omega-3 supplementation.

Clearly, there are still many questions to answer in this area but this is exciting progress.

Postpartum Depression

Postpartum depression is another area for which omega-3 supplementation is attractive. Supplementing with fish oil during and after pregnancy may be a safer option than some of the pharmaceuticals that could be used for depression [4]. Unfortunately, studies in this area either have not been promising and/or are very small [4,29–31].

For example, a study in 2013 randomly assigned 118 women (determined to be at risk for depression) in early pregnancy to receive either a EPA dominant fish oil, a DHA dominant fish oil or a soy oil placebo [29]. A depression inventory was taken at enrollment, 26-28 weeks, 34-36 weeks and then 6-8 weeks postpartum. Serum (blood) levels of EPA or DHA increased with supplementation [29]. However, neither EPA nor DHA supplementation prevented depressive symptoms [29].

In 2014, a slightly smaller study of 80 pregnant (over 20 weeks) women with mild depression found supplementation with 1 gram of omega-3 fatty acids (composition unspecified) for 6 weeks to be significantly more effective than placebo in reducing scores on a Beck Depression Inventory [32]. It’s hard to reconcile these conflicting results without knowing more about the makeup of the supplementation used.

Another study taking into account long-term effects of diet on pregnancy and child development found that women who consumed no fish during pregnancy were more likely to have depressive and anxiety symptoms [33]. It’s possible that actual fish consumption has benefits over fish oil supplementation for this purpose.

Interestingly, DHA-rich fish oil supplementation has been seen to result in longer gestation lengths, significantly higher birthweight, and significantly higher Apgar scores [29]. In contrast, in another study the association between actual fish consumption and gestation and birth weight disappear when adjusting for factors like child’s sex, maternal smoking, maternal age, maternal education and number of other children [33].

This doesn’t mean supplementation or actual fish consumption is useless in this population, but we are lacking information on subgroups of the population which might benefit. For example, markers of inflammation or other mechanisms behind the depressive symptoms which could indicate the use of omega-3 supplementation as helpful. There are too many causes behind depressive symptoms to expect one supplement to provide a cure-all.

Aside from maternal depression, there may be other reasons for supplementing during pregnancy. One example would be the apparent effect of fish consumption or fish oil during pregnancy and breastfeeding on the child’s visual development [33]. It also appears to have an association with the child’s prosocial behaviour and fine motor skills development [33].

Manic-Depressive Disorder

While omega-3 supplementation does not seem to affect manic symptoms, research suggests there may be some benefit for the depressive symptoms in manic-depressive disorder [4]. One randomized controlled trial in particular found a positive effect for omega-3 supplementation in bipolar I disorder [34]. This is an important finding because treating depressive symptoms without triggering manic episodes can be a tricky balancing act [4].

However, considering these studies overall, the effect on depressive symptoms was quite small and omega-3 supplementation may not be the most useful intervention. A meta-analysis of randomized controlled studies published prior to May 2015 found five studies on omega-3 supplementation in manic-depressive disorder with only two reporting a significant positive result over placebo [35]. This review suggested that although omega-3 supplementation didn’t have a significant effect, anti-inflammatories in general might be helpful in depressive symptoms of manic-depressive disorder, with promise specifically for N-acetylcysteine [35].

When we see a link between omega-3/omega-6 status in a particular patient population but they don’t seem to improve with diet change or supplementation we can also investigate whether there is an actual physiological issue in how that nutrient is absorbed or used. One fatty acid breakdown product is known to be lower in patients with manic-depressive disorder [36]. This product normally stops the production of hydrogen peroxide in thyroid cells. However, the implications or relevance of this finding is unknown [36].

Attention Deficit Hyperactivity Disorder

It is thought that ADHD may partly arise from a diet that isn’t balanced in the types of fatty acids that we need, and elevated omega-6 to omega-3 ratios have been found in this population [4,37]. However, in earlier reviews covering research on essential fatty acid supplementation for ADHD, no trials demonstrated any impressive effect [4,23,38]. These studies used DHA, DHA/EPA mixtures or mixtures of both essential omega-3 and omega-6 fatty acids [4].

More recently, there have been two randomized, controlled trials with positive effect. One compared Ritalin, omega-3 supplementation and placebo in a double-blind trial in children (average age of 8 years old) [39]. The researchers found that omega-3 and Ritalin were both effective in reducing symptom scores in children with hyperactivity-impulsivity or combined type but neither were effective in attention deficit disorder [39].

The omega-3 supplement was dosed at 1 gram once per day and Ritalin was 0.3-1 mg/kg three times per day. Unfortunately, the publication seemed unclear as to how long the intervention lasted. The methods state the omega-3 supplement was given for three days, which seems odd if the Ritalin was used continuously throughout the study.

A similar study in male adolescents found no benefit after 12 weeks of omega-3 and omega-6 supplementation but the amount of omega-3 they used was very low [40].

What if we combine EPA/DHA with something that will allow the omega-3 fatty acids better access to the brain? There is a prescription medical food called Vayarin available specifically for ADHD that does just that. This product combines a small amount of EPA and DHA with phosphatidylserine, which allows the omega-3 fatty acids to get to the brain. The phosphatidylserine also has effects of its own, including improvements in memory and stress.

This combination has been studied in a double-blind placebo-controlled trial, but the results weren’t exactly astounding. Although symptom scores significantly improved in the group of children receiving the phosphatidylserine-omega-3 combination, their scores overall were not all that better than those of the children in the placebo group [41].

The study evaluated results with a teacher rating scale, a parent rating scale and a child health scale. If scrutinized further, there was a significant reduction (seen only in male participants) in the DSM-Inattentive subscale score of a teacher rating for those receiving the experimental treatment compared to those receiving placebo [41]. But this is only one subscale of one of three rating scales used!

It also appeared that a subgroup of the initial set of participants who displayed more severe hyperactive and impulsive behaviour experienced greater improvement compared to the placebo group [41]. This analysis occurred after study completion and needs repeating to determine if there really is a beneficial effect in a particular subgroup of children with certain characteristics.

A different study found that the combination of phosphatidylserine and EPA/DHA actually did have a beneficial effect [42]. Why the difference? This study used a different measure – a computerized test of inattention. It also used a smaller set of participants. Because of the discrepancies in how the symptoms were measured it is hard to compare the two studies’ results.

This study stands out in that it found improvements in inattention, whereas the other studies we’ve discussed that show any positive effect mainly demonstrated a positive effect in impulsivity or hyperactivity. It was also odd to note that this study combined the fish oil or EPA/DHA/phosphatidylserine combination into a chocolate paste that the children were to consume! Hard to imagine what that would taste like!

It also seems that omega-3 fatty acid supplementation could improve inattention in boys without ADHD as well as with ADHD [43]. These researchers combined the omega-3 fatty acids with margarine. What will they think of next? Omega-3-enriched donuts??!

On the topic of food, just last year a study was published on the effect of fish intake on attention in adolescents. This is interesting because whole foods or a good diet can provide benefits beyond that of an isolated supplement. In this case, fish intake had a slight benefit over meat or fish oil supplementation on attention [44]. The effect was small due to compliance issues but gives direction for future research in this area.

Autism Spectrum Disorders (ASD)

Neuroinflammation is a major contributor to autism spectrum disorders. This includes imbalances of omega-3 fatty acids, which contribute to the regulation of neuroinflammation, synaptic plasticity, the activity of the microglia that provide an immune system in the brain and even affect the gut microbiome [45]. The effects of omega-3 fatty acid deficiency on the gut microbiome are especially fascinating in the context of ASD because omega-3 deficiency is associated with dysbiosis, whereas omega-3 supplementation is associated with decreased LPS (a toxin produced by bacteria) and decreased gut permeability [45]. Maybe it’s not the brain we need to be looking at in these studies, but the gut!

This imbalance in omega-3 fatty acids in ASD could be attributed to either genetics (such as abnormalities in Fabp7 gene expression) or nutrition [45]. Children with autism spectrum disorders have been found to consume fewer foods containing omega-3 fatty acids like DHA, [45] and this quandary of picky eating and poor nutrient intake is something I also highlighted in the previous post on Vitamin D. Low DHA in these kids is associated with elevations in anti-myelin basic protein antibodies [45]. Studies in patients also display increased phospholipase A2, an enzyme that is very important to fatty acid metabolism. This enzyme’s activity is reduced by supplementing EPA [45,46].

Rodent models of autism spectrum disorders demonstrate the detrimental effects of omega-3 depletion on changing neurotransmitter systems in the brain [45]. They also show promising effects of supplementation on social interactions, anxiety, memory repetitive behaviours and other facets of ASD [45].

However, review of human research on essential fatty acid supplementation for ASD reveals a lack of rigorous trials demonstrating an impressive or significant effect over placebo, despite a trend towards benefit [23,47–50].

One of the negative trials was quite small, and participants were between 18 and 40 years old [51]. This is problematic, as supplementation by that age may not be able to reverse the effects of deficiencies during prenatal or childhood development. Another study focused on children aged 2 to 5 years old but again, did not find significant benefit of supplementation [52].

There is controversy over the optimal amount of omega-6 vs omega-3 fatty acids we need at different developmental stages [53]. After all, omega-6 is still an important fatty acid. For example, when we depress arachidonic acid by giving omega-3 supplementation, some research has associated this with poor growth in preterm infants [53]. Yet fish consumption during pregnancy is associated with better developmental scores in infants at 18 months [54].

This doesn’t necessarily mean it doesn’t work at all in ASD, but we don’t have enough data to determine which subsets of patients it would work for, if at all. For example, there is genetic variability in fatty acid metabolism and we don’t know much about this variability in the context of ASD [45].

Anxiety

There are few early studies on omega-3 supplementation for anxiety. One of the more curious findings of early research was that supplementing with a combination of EPA/DHA for a couple of months decreased levels of catecholamines compared to placebo [4]. Catecholamines include adrenaline, noradrenaline and dopamine.

Although fish oil supplementation is not generally associated with adverse events, and there is some support for fish oil being helpful for anxiety, there is one interesting case where high-EPA fish oil supplementation had some unwanted effects. For this patient, the supplementation was very helpful in reducing depressive symptoms, but after several years of use he began to experience severe anxiety and insomnia [55]. These symptoms subsided when he ran out of fish oil, and then returned after he started taking it again [55].

This may be an anomaly, but there does happen to be a larger study on fish consumption and anxiety and depression that could shed some light on this finding. In the larger trial, fish intake was helpful for anxiety and depression…but only up to a certain point [56]. Higher intakes of fish seemed to lean towards increased rates of mental disorders [56]. This finding didn’t quite reach statistical significance; nevertheless it is something worth considering. Again, we have that possibility of a U-shaped curve we discussed previously in the section on “Depression”. The authors proposed mercury content as one potential reason for creating a higher risk with increased consumption [56]. This seems unlikely as the fish we commonly consume is higher in selenium then mercury and this should provide a protective effect against the mercury.

Schizophrenia

A curious finding in patients with schizophrenia is that these patients have been seen to undergo a resolution of symptoms during periods of high fever…only to relapse once the fever subsides. Years ago, Horrobin made a connection between fever and phospholipid metabolism and suggested that if something as simple as a fever can reverse symptoms, it is possible that schizophrenia could result from a minor biochemical problem and be resolved with minor changes. Omega-3 supplementation could be considered as one such minor change.

It’s thought that in a fever, the fever provides a sink for excess arachidonic acid – and by supplementing with EPA, we create a similar effect by adjusting the ratio of AA to EPA without having to use a fever to do so.

There are several other associations between essential fatty acids and schizophrenia. One is the Fabp7 gene. This gene plays a role in our ability to take in and use fatty acids and problems with this family of genes can result in impaired sensorimotor gating function [1]. It’s not only involved in schizophrenia, but increased expression of this gene has been seen in autism spectrum disorders [45]. Another is caspase-3, an enzyme involved in the loss of brain tissue in schizophrenia [23]. This enzyme can be inhibited by the omega-3 fatty acid EPA [23].

What does all this mean for a patient with schizophrenia? Let’s start with an optimistic outlook and then dive in with a more critical perspective.

There is a rather remarkable case report of a 31-year old male diagnosed with schizophrenia at the age of 28 [57,58]. At the time of the study he was not on antipsychotic medication. He showed remarkable improvement on both positive and negative symptom scales two months from the start of treatment with 2 grams of EPA per day [57,58]. At six months from the start of treatment his positive symptom scores had dropped from 46 to 4 and his negative symptoms scores had dropped from 16 to 3 [57,58]. Changes on imaging revealed decreases in ventricular size with treatment [57,58].

This case is very exciting because it shows how such a small change can make a very dramatic change to a patient’s life. However, there are many variables involved in complex conditions such as schizophrenia, and given the multifactorial nature of many such psychiatric conditions, these results may not be seen in all or even very many patients.

Before we jump into clinical trials on omega-3 supplementation for schizophrenia, let’s first consider omega-3 intake across populations from more of a bird’s eye view. Schizophrenia is actually milder in some populations, and it has been found that as the ratio of essential fatty acids to other fats in the diet increase, the severity of schizophrenia decreases [59].

It has been argued that it is impossible for omega-3 supplementation to prove beneficial to the wide range of mental health conditions discussed in this post because these conditions involve different types of activity in different neurotransmitter systems of the brain [4]. Since omega-3 fatty acids have an effect on these neurotransmitter systems, researchers don’t know how they can be beneficial for both (for example) mood disorders and schizophrenia, which result in different neurotransmitter functioning [4].

Schizophrenia is typically associated with excess in the neurotransmitter dopamine. Deficiencies in omega-3 fatty acids in utero are actually associated with less dopamine, less dopamine receptors, and increased dopamine breakdown [4]. These findings imply that omega-3 supplementation could be helpful for mood and anxiety disorders, but would increase dopamine and make schizophrenia worse [4]!

Conversely, a different animal model found that omega-3 deficiencies were associated with increased dopamine activity [4]. The authors suggest that decreased dopamine may make the dopamine receptors more sensitive to the dopamine that becomes available [4]. These findings are difficult to extrapolate to human patient populations, but clinical trials of supplementation in mood disorders support an effect of increasing both serotonin and dopamine activity [4].

A review of clinical trials up to 2007 concluded that results of EPA and other omega-3 supplementation for schizophrenia were inconsistent and that supplementation likely had no clinical utility [4].

More recent clinical trials on omega 3 supplementation have shown beneficial effects on both positive and negative symptoms, but suggest that supplementation is best used as a preventative measure in high-risk groups or first episode psychosis populations [60–62]. One trial showed rather remarkable results in a young population experiencing subthreshold psychotic states. These participants were given omega-3 supplementation for 12 weeks and this reduced their risk of progressing to psychotic disorders at both 12 months and at seven years later compared to the placebo group [60–62].

Of young people with ultra-high risk for psychosis, more severe baseline negative symptoms and higher erythrocyte (red blood cell) alpha-linolenic acid levels predicted improvement with omega-3 supplementation [61]. Studies like this, although small, allow us to further refine which patients this intervention would be best suited for. A longer trial of omega-3 supplementation in first-episode psychosis also demonstrated a benefit [63].

Not all studies show benefit. One trial demonstrated no benefit over placebo, but participants in this trial were allowed to take additional non-antipsychotic medications (such as antidepressants or benzodiazepines) and cognitive behavioural case management as needed [64].

Supporting this effect specific to first-episode psychosis or high-risk patient populations, a study on lipid profiles between first-episode, chronic unmedicated and healthy participants revealed that low levels of omega-3 fatty acids were present in the first-episode group only [65]. It is thought that this deficiency is characteristic of early schizophrenia, and antipsychotic treatment was seen to correct the fatty acid levels in the first episode patients [65].

In addition, patients taking EPA have been found to need lower doses of antipsychotic medication and to have fewer extrapyramidal side effects than those taking antipsychotics plus a placebo [66]. This was an interesting study that is hard to interpret in a standard fashion because adding in the medications provides confound in the interpretation of the results. On the other hand, it does demonstrate a more practical scenario as in real life patients are likely going to be on a variety of antipsychotic medications and dosages, and it is useful to see how omega-3 supplementation may affect outcomes for this group.

In contrast, omega-3 supplementation may worsen symptoms in chronic schizophrenia or after discontinuation of antipsychotic medication [67]. One possible explanation for this is that the omega-3 supplementation cannot counteract progressive gray matter loss later in the disease process [67]. Other discrepancies in effectiveness on a case by case basis may be the result of different biological subtypes [67].

Other studies have started exploring combinations of omega-3 and antioxidant supplementation [68,59].

Final Thoughts

Overall, the answer to whether fish oil supplementation is helpful in mental health conditions is a rather unhelpful: it depends. We don’t have enough evidence to demonstrate a clear positive effect in the case of traumatic brain injury, dementia, autism spectrum disorders or anxiety. We haven’t fully elucidated when or if it is helpful in PTSD, manic-depressive disorder or ADHD. We are just starting to understand how certain subsets of depressed patients could benefit (namely those with inflammation behind their depressive symptoms) or how it might be a useful preventative for those at increased risk for psychotic disorders.

While we are making progress in this area, more investigation needs to be done to identify subsets of patients that will benefit, that will not benefit or that might experience a detrimental effect. Supplementation can be useful to speed up progress for a patient, but it should not be used as a band-aid and the exact type of supplementation (fish oil vs cod liver oil vs krill oil etc) should be chosen thoughtfully. Lifestyle factors are important to consider, and the root cause of the problem should be sought. And, last but not least, don’t forget fish can also be consumed as a food rather than a supplement!

Further Reading

For any nerds out there I highly recommend this paper for a more thorough look at how vitamin D and omega-3 fatty acids affect serotonin synthesis and the implications for mental health.

Patrick, R. P. & Ames, B. N. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 29, 2207–2222 (2015).

And learn more about other common mental health supplements by checking out these posts on vitamin D and probiotics!

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