PUFAs for Anxiety: The Evidence to Date

Pauline Anderson

September 21, 2018

Treatment with omega-3 polyunsaturated fatty acids (PUFAs) may decrease symptoms of anxiety in patients with a range of conditions, including borderline personality disorder and obsessive compulsive disorder (OCD), new research suggests.

Dr Kuan-Pin Su

In a systematic review and meta-analysis, both placebo-controlled and non-placebo-controlled trials showed that omega-3 had at least some effect on patients with anxiety.

This treatment may provide a safer option than "highly addictive" anxiolytics in some patients, lead author Kuan-Pin Su, MD, PhD, vice dean and professor, College of Medicine, China Medical University, Taichung, Taiwan, told Medscape Medical News.

"For patients who are not responsive to traditional anxiety treatment, such as antidepressants or psychotherapies, omega-3 PUFAs might be a promising alternative and adjunctive treatment with a great safety profile," Su said.

But because the effect size uncovered by the new analysis is small to moderate, it's too early to recommend omega-3 PUFAs as the first-line treatment for anxiety, he added. "We need more well-conducted clinical trials to reach that kind of consensus."

The findings were published online September 14 in JAMA Network Open.

Systematic Literature Search

Anxiety presents in a wide range of psychological and physical illnesses. Anxiolytics are used to treat a number of such illnesses, but since they're the "most abused" of psychotropic drugs and are very addictive, omega-3 might provide a safe alternative, said Su.

PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential nutrients. Research has shown that they may have preventive and therapeutic effects in patients with psychiatric disorders such as anxiety and depression and can help relieve comorbid depression and anxiety in patients with physical illnesses.

The investigators carried out a systematic literature search for randomized or nonrandomized studies that assessed the effect of omega-3 PUFAs on anxiety symptoms in humans. The inclusion criteria were "as broad as possible to avoid missing any potentially eligible studies," the authors write.

The analysis included 19 studies carried out in 11 countries; 16 of the studies had a placebo comparator. In the 19 studies, 1203 participants were treated with omega-3 PUFAs (mean age, 43.7 years; mean omega-3 PUFA dose, 1605.7 mg/day), and 1037 did not take omega-3 PUFA (mean age, 40.6 years).

In all studies, about 55% of the participants were women.

The studies used a number of different scales to evaluate anxiety symptoms, including the Hamilton Anxiety Rating Scale and the anxiety subscale of the Hospital Anxiety and Depression Scale.

The psychiatric and physical health conditions of study participants varied widely. For example, in addition to a study that included patients with OCD and another that included those with personality disorders, other studies included only children with attention deficit/hyperactivity disorder or patients with Alzheimer's disease or Tourette's syndrome.

The primary outcome in the current analysis was change in anxiety symptoms in patients who received omega-3 PUFA supplements compared with those who did not receive such treatment. Dietary omega-3 was not considered.

Owing to the expected heterogeneity, researchers chose to conduct a random-effects rather than a fixed-effects meta-analysis. They point out that random-effects modeling is more stringent and incorporates an among-study variance in the calculations. They used Hedges g and 95% confidence intervals (CIs) to combine the effect sizes of the studies.

Significantly Reduced Anxiety

The meta-analysis showed that anxiety was significantly reduced in patients who received omega-3 PUFAs compared with those who did not receive this treatment (Hedges g, 0.374; 95% CI, 0.081 - 0.666; P = .01).

The results remained significant after removal of any of the included studies, indicating that the significance was not based on any single study.

However, the researchers note the potential influence of two studies they considered outliers. One included women with premenstrual syndrome, and the other included college students with test anxiety. In these studies, anxiety symptoms were evaluated with a visual analogue scale and a test for anxiety severity.

Such tools "are seldom used in psychiatric research," and proof that their sensitivity and specificity equals that of more frequently used scales is lacking, the authors write.

Su stressed that clinicians "should pay attention" to this observation when applying the results to clinical practice, particularly when considering the subgroups in these two studies.

There was no significant association between the Hedges g and mean age, proportion of women, mean omega-3 PUFA dose, EPA to DHA ratio, dropout rate in the omega-3 PUFA groups, or duration of omega-3 PUFA treatment.

The duration of such treatment in the studies ranged from 3 to 26 weeks. Although the analysis did not find significant effects regarding treatment duration, Su said he would recommend using omega-3 PUFAs "for at least 4 weeks when targeting anxiety."

The anxiolytic effect of omega-3 PUFAs was significant in those who received a mean omega-3 PUFA dose of at least 2000 mg/day, but was not significant in those taking less.

Studies comparing omega-3 PUFAs with placebo revealed a significantly greater association with reduced anxiety in those who received the treatment (P = .03). So, too, did non-placebo-controlled trials (P = .001).

According to the authors, this "meant that the anxiolytic effect of omega-3 PUFAs is probably not entirely owing to the placebo effect."

The association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly stronger in subgroups with specific clinical diagnoses than in subgroups without such conditions (P = .03).

Effect on Depression

Six of the included studies also assessed at the effect of omega-3 PUFAs on depressive symptoms. This analysis showed a nearly null effect in healthy participants.

Other research, including that from Su and his team, has shown positive effects of PUFAs on depression. Su's group was the first to publish a study demonstrating antidepressant effects of omega-3 PUFAs in pregnant women with major depression.

But, because of inconsistent findings, the beneficial properties of omega-3 PUFAs have "taken occasional hits," and many people are now skeptical about taking supplements for depression, said Su.

For complex diseases such as psychiatric disorders, the effect sizes of single-drug or nondrug treatments are limited, he noted.

"Indeed, it is very easy to miss the small signals of therapeutic efficacy in placebo-controlled clinical trials and/or meta-analytic reviews without careful considerations on study designs," Su added.

Regarding the possible mechanism of action, the authors note that brain membranes contain a high proportion of omega-3 PUFAs and their derivatives. Most studies suggest that a lack of omega-3 PUFAs in the brain may induce various behavioral and neuropsychiatric disorders, including anxiety-related behaviors, they write.

"Emerging evidence suggests that omega-3 PUFAs interfere with and possibly control several neurobiological processes, such as neurotransmitter systems, neuroplasticity, and inflammation, which is postulated to be the mechanism underlying anxiety and depression," write the investigators.

Because the study has a number of limitations, including the heterogeneity of the study populations, the authors stress that the findings should be considered with caution.

"Encouraging" Findings

Asked to comment by Medscape Medical News, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry, Harvard Medical School, and director of the Depression Clinical and Research Program at Massachusetts General Hospital, Boston, said this new meta-analysis is significant.

"It represents the first attempt to systematically evaluate the known scientific literature examining the potential impact of omega-3 fatty acids on symptoms of anxiety," said Mischoulon, who was not involved with the research.

The findings that appear to support an antianxiety effect of the omega-3 fatty acids are "encouraging," he added.

However, he stressed that the populations enrolled in the included studies did not, for the most part, receive a formal diagnosis of an anxiety disorder, such as generalized anxiety disorder or panic disorder, from the Diagnostic and Statistical Manual of Mental Disorders (DSM).

"We need to be careful not to assume that the benefits observed here on individual symptoms of anxiety would necessarily translate into a high-impact treatment for anxiety disorders," he said.

Mischoulon found it "especially interesting" that doses of at least 2000 mg/day of omega-3 seemed more effective than lower doses — especially because many studies of omega-3 in depression have suggested greater efficacy at doses of 1000 to 2000 mg/day compared with higher doses.

This may imply that the antianxiety effects of omega-3 may involve a different mechanism of action than its antidepressant effects, he noted.

The new meta-analysis "strongly supports" developing clinical trials to test the efficacy of omega-3 in anxiety disorders that are rigorously diagnosed using the DSM, he said.

Mischoulon also agreed with Su that because omega-3 is generally very safe and well tolerated and has general health benefits, "physicians may want to consider omega-3s in some of their patients, particularly those who may be prone to side effects from standard antidepressant or anxiolytic medications and who are not so severely ill that it would be dangerous to try a less proven remedy."

The study was supported by the Japan Society for the Promotion of Science; the National Cancer Center Research and Development Fund and Ministry of Science and Technology, Taiwan; the National Health Research Institutes, Taiwan; and the China Medical University, Taiwan. Dr Su received grants from the Ministry of Science and Technology, the National Health Research Institutes, and the China Medical University during the conduct of the study. Dr Mischoulon has received research support from Nordic Naturals; has provided unpaid consulting for Pharmavite LLC and Gnosis USA, Inc; has received honoraria for speaking from the the Massachusetts General Hospital Psychiatry Academy, Blackmores, and PeerPoint Medical Education Institute, LLC; and has received royalties from Lippincott Williams & Wilkins for the book Natural Medications for Psychiatric Disorders: Considering the Alternatives.

JAMA Network Open. Published online September 14, 2018. Full text

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