According to a recent Harvard Health Blog, the pursuit for omega-3s as a depression solution has been fueled by the fact that the disease appears less common in nations where people eat large amounts of fish. “This suggests that these nutrients could possibly then be deficient in those showing signs of depression,” the author wrote.
But according to new research from the University of East Anglia (UAE), omega-3 fats, especially EPA and DHA in the form of pills, have little or no effect on anxiety and depression. The systematic review, published in the October 24th edition of the British Journal of Psychiatry, was funded by the World Health Organization.
For this meta-analysis, the research team looked at 31 trials of adults with and without depression or anxiety. More than 41,000 participants were randomized to consume more long-chain omega-3s EPA and/or DHA (fish oils), or maintain their usual intake, for at least six months.
They found that omega-3 supplements had little or no effect in preventing depression or anxiety symptoms, which they say is in line with previous studies.
Lead author Dr. Lee Hooper, from UEA’s Norwich Medical School, said: “Our previous research has shown that long-chain omega-3 supplements, including fish oils, do not protect against conditions such as heart disease, stroke, diabetes, or death.
In this most recent study review, which included information from many thousands of people over long periods, Dr. Hooper and his team didn’t see any protective effects for mood health either. “The most trustworthy studies consistently showed little or no effect of long-chain omega-3 fats on depression or anxiety, and they should not be encouraged as a treatment,” he said.
Dr. Katherine Deane, from UEA’s School of Health Sciences, echoed these thoughts: “Oily fish can be a very nutritious food as part of a balanced diet. But we found that there is no demonstrable value in people taking omega-3 supplements for the prevention or treatment of depression and anxiety. Considering the environmental concerns about industrial fishing and the impact it is having on fish stocks and plastic pollution in the oceans, it seems unhelpful to continue to swallow fish oil tablets that give no benefit.”
The median dose in the studies these researchers looked at was 950 mg/day. (We’ll discuss the relevance of dose later in this blog.)
But what about using omega-3s as adjuncts to depression and anxiety medicines?
Some studies of depressed psychiatric patients have suggested that antidepressant efficacy can be increased by adding EPA, so one study looked at whether the addition of EPA could improve the response to sertraline in depressed patients with or at high risk for coronary heart disease (CHD).
Between May 2014 and June 2018, 144 patients with DSM-5 major depressive disorder seen at the Washington University School of Medicine with or at high risk for CHD were randomized to receive either 50 mg per day of sertraline and 2 grams per day of EPA or 50 mg per day of sertraline and corn oil placebo capsules for 10 weeks. The Beck Depression Inventory II (BDI-II) was the primary outcome measure.
After 10 weeks, there were no differences between the groups, leading researchers to conclude: “Augmentation of sertraline with 2 grams per day of EPA for 10 weeks did not result in greater improvement in depressive symptoms compared to sertraline and corn oil placebo in patients with major depressive disorder and CHD or CHD risk factors. Identifying the characteristics of cardiac patients whose depression may benefit from omega-3 and clarifying the pathways linking omega-3 to improvement in depression symptoms are important directions for future research.”
Most in the clinical community agree treating depression anxiety and depression is incredibly complex.
A Harvard Health Blog published in June highlighted the multifaceted nature of depression. “It’s often said that depression results from a chemical imbalance, but that figure of speech doesn’t capture how complex the disease is. Research suggests that depression doesn’t spring from simply having too much or too little of certain brain chemicals,” the author wrote.
“Rather, there are many possible causes of depression, including faulty mood regulation by the brain, genetic vulnerability, stressful life events, medications, and medical problems. It’s believed that several of these forces interact to bring on depression.”
So if treating depression and anxiety is basically an exercise in trial and error, the same seems to be true of clinical studies investigating these issues, especially when it comes to dose. Some studies are giving people 500 mg omega-3s per day while others have administered more than 6 grams per day.
Looking on the Bright Side
On September 9th, World Psychiatry published a meta-analysis of randomized controls trials using nutrient supplements as treatment for mental disorders in which they singled out omega-3s as being in the best position to support proper mental health.
To that end, a team led by Sydney’s NICM Health Research Institute conducted the world’s largest review (a meta-synthesis) of top-tier evidence, examining 33 meta-analyses of randomized control trials (RCTs) and data from nearly 11,000 people with mental health disorders, including depression, stress and anxiety disorders, bipolar disorder, personality disorders, schizophrenia and attention-deficit/hyperactivity disorder (ADHD).
Although the majority of nutritional supplements assessed did not significantly improve mental health, the researchers found strong evidence that certain supplements are an effective additional treatment for some mental disorders, supportive of conventional treatment.
All nutrient supplements were found to be safe when recommended dosages and prescriptive instructions were adhered to and there was no evidence of serious adverse effects or contraindications with psychiatric medications.
The strongest evidence was found for omega-3 supplements as an add-on treatment for major depression — reducing symptoms of depression beyond the effects of antidepressants alone.
There was also some evidence to suggest that omega-3 supplements may also have small benefits for ADHD.
Also in September, the International Society for Nutritional Psychiatry Research (ISNPR) released practice guidelines for omega-3s as adjunctive therapy for major depressive disorder. The panel focused their efforts on five important areas, including general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. From there, they devised several strategies to assist doctors in administering omega-3s to their patients.
The group believes that personalizing the clinical application of omega-3s in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.
Depression is one of the most complex illnesses to treat, so there is great interest in trying to figure out what types of solutions will have long-lasting benefits. Omega-3s are of particular interest in this area because they are found in the brain and studies have shown they interact with certain mood-regulating neurotransmitters like serotonin. Their anti-inflammatory benefits are also likely to play a role.
Another depression study published last year in the Journal of the American College of Cardiology’s Heart Failure found significant correlations between blood levels of EPA plus DHA omega-3s (i.e., Omega-3 Index) in “cognitive” (as opposed to “somatic”) depression among heart failure subjects. (Cognitive depression would include symptoms like sadness and pessimism, whereas somatic would include manifestations such as fatigue and sleep disturbances.)
This randomized controlled pilot study was designed to investigate the effects of supplemental omega-3s (EPA and DHA) on depressive and psychomotor symptoms in people with chronic heart failure and depression.
The study included 108 subjects who were assigned to one of three groups each taking 2 grams per day of either 1) a 2:1 mg EPA/DHA supplement; 2) a high EPA product; or 3) a placebo. The study lasted 12 weeks with blood testing (i.e., Omega-3 Index, RBC levels of EPA and DHA) completed pre- and post-supplementation.
The Omega-3 Index reached 6.79% in the 2:1 EPA/DHA group, 6.32% in the EPA only group, and 4.61% in the placebo group. In those who were determined to have taken at least 70% of their capsules and finish all testing (n=80), these values were 7.32%, 7.11%, and 4.42%, respectively. This indicates that the dose (and compliance) were both adequate to significantly improve the Omega-3 Index in only three months.
The social functioning sub-score of the SF-36, a short general health survey, was significantly improved on the 2:1 EPA/DHA supplement and tended to improve with the high EPA supplement.
Significant correlations between the Omega-3 Index and measures of cognitive depression were also found. More specifically, a higher Omega-3 Index was related to lower cognitive depression scores on the Beck Depression Inventory-II (BDI-II), which is the most widely used instrument for detecting depression.
Offering some context on this study, Dr. Bill Harris, one of the study’s authors and the co-inventor of the Omega-3 Index test, said, “This was a study in already depressed individuals, which meant the researchers are looking to high-dose (although it could have been higher) omega-3 supplements to improve depressive symptoms, like a drug,” he said.
“Generally, we think of the function of omega-3s as preventative rather than as treatment. If used as treatment, the dose must be fairly high (4 grams is a typical ‘drug’ dose) and blood levels must be measured,” Dr. Harris continued. “In their larger follow-up study, I would recommend they choose just one of the supplements (probably the pure EPA product) and increase the dose and duration of the study.”
In terms of anxiety, one of the first studies to show that omega-3s EPA and DHA might help was published in 2011.
In this study, researchers evaluated anxiety levels in 68 medical students, who provided serial blood samples during lower-stress periods as well as on days before an exam. The students also received either 2.5 grams per day of omega-3s (2085 mg EPA and 348 mg DHA) or placebo capsules that mirrored the proportions of fatty acids in the typical American diet.
Compared to controls, those students who received omega-3 supplementation showed a 20% reduction in anxiety symptoms. For these researchers, the data suggest that omega-3s can reduce inflammation and anxiety even among healthy young adults.
And then just last year, a meta-analysis published in JAMA added another layer of support to the role of omega-3s in reducing anxiety.
This report tapped data from 19 clinical trials, which included 2240 participants (1203 treated with omega-3s and 1037 without) from 11 countries. Participants had a wide range of psychiatric and physical conditions, including borderline personality disorder, depression, obsessive-compulsive disorder, Alzheimer’s disease, test anxiety, acute myocardial infarction, and premenstrual syndrome. Others were from the general population and had no specific clinical conditions.
“Although participants and diagnoses were heterogeneous, the main finding of this meta-analysis was that omega-3s were associated with significant reduction in anxiety symptoms compared with controls,” researchers wrote. “This effect persisted vs placebo controls.”
But most important, researchers discovered daily dosages higher than 2000 mg of EPA and DHA combined were linked with a significantly higher anxiolytic effect, compared with lower dosages. In addition, supplements with less than 60% eicosapentaenoic acid (EPA) were significantly associated with reduced anxiety symptoms, but supplements with 60% or more EPA were not.
One of the other major limitations in this study was the small sample size, however, researchers are confident they are onto something here. The next round of studies, they said, should focus on finding the most appropriate dose.