In June, a study published in the Journal of Clinical Psychiatry showed that there was no added benefit when researchers paired omega-3s EPA and DHA with the anti-depressant sertraline (i.e., Zoloft). Experts believe there are many reasons omega-3s didn’t rise to the occasion and this blog will discuss some of them.
Depression: One of the Most Complex Diseases
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.
Unfortunately, depression is the leading cause of disability worldwide, and although there are many treatment options, only about one third of patients treated with conventional antidepressants experience a positive response.
Maybe it’s because there are several forms of depression, so finding treatment is basically an exercise in trial and error. The same seems to be true of clinical studies investigating depression.
To clarify the type of depression you have, the Mayo Clinic says your doctor may add one or more “specifiers.” A specifier means that you have depression with specific features, such as:
- Anxious distress— depression with unusual restlessness or worry about possible events or loss of control
- Mixed features— simultaneous depression and mania, which includes elevated self-esteem, talking too much and increased energy
- Melancholic features— severe depression with lack of response to something that used to bring pleasure and associated with early morning awakening, worsened mood in the morning, major changes in appetite, and feelings of guilt, agitation or sluggishness
- Atypical features— depression that includes the ability to temporarily be cheered by happy events, increased appetite, excessive need for sleep, sensitivity to rejection, and a heavy feeling in the arms or legs
- Psychotic features— depression accompanied by delusions or hallucinations, which may involve personal inadequacy or other negative themes
- Catatonia— depression that includes motor activity that involves either uncontrollable and purposeless movement or fixed and inflexible posture
- Peripartum onset— depression that occurs during pregnancy or in the weeks or months after delivery (postpartum)
- Seasonal pattern— depression related to changes in seasons and reduced exposure to sunlight
The Role of Omega-3s in Depression
According to the Harvard Health Blog, there are more than 30 clinical trials that have tested different omega-3 preparations in people with depression. “Most studies have used omega-3s as add-on therapy for people who are taking prescription antidepressants with limited or no benefit,” the author wrote. “Fewer studies have examined omega-3 therapy alone.
The author went on to say that clinical trials typically use EPA alone or a combination of EPA plus DHA, at doses from 0.5 to 1 gram per day to 6 to 10 grams per day. To give some perspective, he said, 1 gram per day would correspond to eating three salmon meals per week.
The pursuit for omega-3s as a depression solution is 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.
Recent Positive Studies
Research published last August 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.”
The authors were also exploring a few different supplement options, focusing on recent evidence that EPA might be more effective for treating depression while DHA may be better for general cognition. “From this study, it’s not clear to me that one supplement type was better than the other,” Dr. Harris said, adding, “However, linking higher blood levels of omega-3s to improved depression symptoms in people with both depression and heart failure is encouraging and hopefully leads to better treatment for their conditions.”
In late 2018 meta-analysis published in JAMA adds another layer of support to the role of omega-3s in reducing anxiety, a condition that frequently accompanies depression.
This report tapped data from 19 clinical trials, which included 2240 participants (1203 treated with omega-3 PUFAs 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.”
Researchers also discovered daily dosages higher than 2000 mg 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.
“This review indicates that omega-3s might help to reduce the symptoms of clinical anxiety. Further well-designed studies are needed in populations in whom anxiety is the main symptom,” the researchers concluded.
The Latest Failed Depression Study
Studies of depressed psychiatric patients have suggested that antidepressant efficacy can be increased by adding EPA, so researchers were determined to find out if 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/d of sertraline and 2 g/d of EPA or 50 mg/d 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 g/d 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.”