ArticlePDF AvailableLiterature Review

Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms: A Systematic Review and Meta-analysis

Authors:
  • College of Medicine, China Medical University, TAIWAN
  • Tsyr-Huey Mental Hospital, Kaohsiung Jen-Ai’s Home, Taiwan

Abstract and Figures

Importance No systematic review or meta-analysis has assessed the efficacy of omega-3 polyunsaturated fatty acids (PUFAs) for anxiety. Objective To evaluate the association of anxiety symptoms with omega-3 PUFA treatment compared with controls in varied populations. Data Sources PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and ClinicalTrials.gov databases were searched up to March 4, 2018. Study Selection A search was performed of clinical trials assessing the anxiolytic effect of omega-3 PUFAs in humans, in either placebo-controlled or non–placebo-controlled designs. Of 104 selected articles, 19 entered the final data extraction stage. Data Extraction and Measures Two authors independently extracted the data according to a predetermined list of interests. A random-effects model meta-analysis was performed and this study was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Main Outcomes and Measures Changes in the severity of anxiety symptoms after omega-3 PUFA treatment. Results In total, 1203 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%) showed an association between clinical anxiety symptoms among participants with omega-3 PUFA treatment compared with control arms (Hedges g, 0.374; 95% CI, 0.081-0.666; P = .01). Subgroup analysis showed that the association of treatment with reduced anxiety symptoms was significantly greater in subgroups with specific clinical diagnoses than in subgroups without clinical conditions. The anxiolytic effect of omega-3 PUFAs was significantly better than that of controls only in subgroups with a higher dosage (at least 2000 mg/d) and not in subgroups with a lower dosage (<2000 mg/d). Conclusions and Relevance This review indicates that omega-3 PUFAs might help to reduce the symptoms of clinical anxiety. Further well-designed studies are needed in populations in whom anxiety is the main symptom.
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Original Investigation | Psychiatry
Association of Use of Omega-3 Polyunsaturated Fatty Acids
With Changes in Severity of Anxiety Symptoms
A Systematic Review and Meta-analysis
Kuan-Pin Su, MD, PhD; Ping-Tao Tseng, MD; Pao-Yen Lin, MD, PhD; Ryo Okubo, MD, PhD; Tien-Yu Chen, MD; Yen-Wen Chen, MD; Yutaka J. Matsuoka, MD, PhD
Abstract
IMPORTANCE No systematic review or meta-analysis has assessed the efficacy of omega-3
polyunsaturated fatty acids (PUFAs) for anxiety.
OBJECTIVE To evaluate the association of anxiety symptoms with omega-3 PUFA treatment
compared with controls in varied populations.
DATA SOURCES PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of
Science, and ClinicalTrials.gov databases were searched up to March 4, 2018.
STUDY SELECTION A search was performed of clinical trials assessing the anxiolytic effect of
omega-3 PUFAs in humans, in either placebo-controlled or non–placebo-controlled designs. Of 104
selected articles, 19 entered the final data extraction stage.
DATA EXTRACTION AND MEASURES Two authors independently extracted the data according to
a predetermined list of interests. A random-effects model meta-analysis was performed and this
study was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-analyses
guidelines.
MAIN OUTCOMES AND MEASURES Changes in the severity of anxiety symptoms after omega-3
PUFA treatment.
RESULTS In total, 1203 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%) showed an
association between clinical anxiety symptoms among participants with omega-3 PUFA treatment
compared with control arms (Hedges g, 0.374; 95% CI, 0.081-0.666; P= .01). Subgroup analysis
showed that the association of treatment with reduced anxiety symptoms was significantly greater
in subgroups with specific clinical diagnoses than in subgroups without clinical conditions. The
anxiolytic effect of omega-3 PUFAs was significantly better than that of controls only in subgroups
with a higher dosage (at least 2000 mg/d) and not in subgroups with a lower dosage (<2000 mg/d).
CONCLUSIONS AND RELEVANCE This review indicates that omega-3 PUFAs might help to reduce
the symptoms of clinical anxiety. Further well-designed studies are needed in populations in whom
anxiety is the main symptom.
JAMA Network Open. 2018;1(5):e182327. doi:10.1001/jamanetworkopen.2018.2327
Key Points
Question Is omega-3 polyunsaturated
fatty acid treatment associated with an
improvement in anxiety symptoms?
Findings In this systematic review and
meta-analysis of 19 clinical trials
including 2240 participants from 11
countries, improvement in anxiety
symptoms was associated with omega-3
polyunsaturated fatty acid treatment
compared with controls in both placebo-
controlled and non–placebo-controlled
trials. The anxiolytic effects of omega-3
polyunsaturated fatty acids were also
stronger in participants with clinical
conditions than in subclinical
populations.
Meaning Omega-3 polyunsaturated
fatty acid treatment for anxiety might be
effective in clinical settings.
+Supplemental content
Author affiliations and article information are
listed at the end of this article.
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2018;1(5):e182327. doi:10.1001/jamanetworkopen.2018.2327 September 14, 2018 1/16
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Introduction
Anxiety, the most commonly experienced psychiatric symptom, is a psychological state derived from
inappropriate or exaggerated fear leading to distress or impairment. The lifetime prevalence of any
anxiety disorder is reported to be approximately 1 in 3.
1
Anxiety is often comorbid with depressive
disorders
2
and is associated with lower health-related quality of life
3
and increased risk of all-cause
mortality.
4
Treatment options include psychological treatments, such as cognitive-behavioral
therapy and pharmacological treatments, mainly with selective serotonin reuptake inhibitors.
5
Individuals with anxiety and related disorders tend to be more concerned about the potential
adverse effects of pharmacological treatments (eg, sedation or drug dependence) and may be
reluctant to engage in psychological treatments that can be time-consuming and costly, as well as
sometimes limited in availability.
6
Thus, evidence-based and safer treatments are required, especially
for anxious patients with comorbid medical conditions.
Omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), are essential nutrients that have potential preventive and therapeutic
effects on psychiatric disorders, such as anxiety and depression,
7-15
as well as comorbid depression
and anxiety in physically ill patients,
16-19
patients with coronary heart disease,
20,21
and pregnant
women.
22,23
Preclinical data support the effectiveness of omega-3 PUFAs as treatment for anxiety
disorders. Song et al
24,25
found that an EPA-rich diet could reduce the development of anxiety-like
behaviors in rats as well as normalize dopamine levels in the ventral striatum. In addition, Yamada
et al
26
showed that a high dietary omega-3 to omega-6 PUFA ratio reduced contextual fear behaviors
in mice and that these effects were abolished by a cannabinoid CB1 receptor antagonist.
A number of trials have found that omega-3 PUFAs might reduce anxiety under serious stressful
situations. Case-controlled studies have shown low peripheral omega-3 PUFA levels in patients with
anxiety disorders.
27-31
A cohort study found that high serum EPA levels were associated with
protection against posttraumatic stress disorder.
32
In studies of therapeutic interventions, while a
randomized clinical trial of adjunctive EPA treatment in patients with obsessive-compulsive disorder
revealed that EPA augmentation had no beneficial effect on symptoms of anxiety, depression, or
obsessive-compulsiveness,
33
a randomized clinical trial involving participants with substance abuse
showed that EPA and DHA administration was accompanied by significant decreases in anger and
anxiety scores compared with placebo.
34
In addition, a randomized clinical trial found that omega-3
PUFAs had additional effects on decreasing depressive and anxiety symptoms in patients with acute
myocardial infarction,
35
and a randomized clinical trial demonstrated that omega-3 PUFAs could
reduce inflammation and anxiety among healthy young adults facing a stressful major examination.
36
Despite the largely positive findings of these trials, the clinical application of the findings is
unfortunately limited by their small sample sizes.
We hypothesized that omega-3 PUFAs might have anxiolytic effects in patients with significant
anxiety- and fear-related symptoms. However, there have been no systematic reviews of this topic
to date. Thus, we examined the anxiolytic effects of omega-3 PUFAs in participants with elevated
anxiety symptoms in the results of clinical trials to determine the overall efficacy of omega-3 PUFAs
for anxiety symptoms irrespective of diagnosis.
Methods
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) reporting guidelines.
37
The study protocol adhered to the requirements of the
institutional review board of Tri-Service General Hospital.
Literature Search and Screening
Two psychiatrists (P.-T.T. and T.-Y.C .) separately performed a systematic literature search of the
PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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ClinicalTrials.gov databases to March 4, 2018. Because we presumed some clinical trials would use
investigating scales for some other mood symptoms but also contain symptoms of anxiety, we tried
to use some nonspecific medical subject heading terms to include those clinical trials. Therefore, we
used the following keywords: omega-3, eicosapentaenoic acid, EPA, DHA, or docosahexaenoic acid;
and anxiety, anxiety disorder, generalized anxiety disorder, agoraphobia, panic disorder, or
posttraumatic stress disorder. After removing duplicate studies, the same 2 authors screened the
search results according to the title and abstract to evaluate eligibility. List of potentially relevant
studies were generated for a full-text review. Any inconsistencies were discussed with a third author
to achieve final consensus. To expand the list of potentially eligible articles, we performed a manual
search of the reference lists of review articles in this area.
12,38,39
Because of the preliminary state of knowledge on the effects of omega-3 PUFA treatment on
anxiety, we decided to include as many studies as possible and not to set further limitations on
specific characteristics, such as length of study, diagnosis, omega-3 PUFA dosage, omega-3 PUFA
preparation (EPA to DHA ratio), rated anxiety coding scale, or type of control. Therefore, we chose to
make the inclusion criteria as broad as possible to avoid missing any potentially eligible studies. The
inclusion criteria included clinical trials in humans (randomized or nonrandomized), studies
investigating the effects of omega-3 PUFA treatment on anxiety symptoms, and formal published
articles in peer-reviewed journals. The clinical trials could be placebo controlled or non–placebo
controlled. The target participants could include healthy volunteers, patients with psychiatric illness,
and patients with physical illnesses other than psychiatric illnesses. The exclusion criteria included
case reports or series, animal studies or review articles, and studies not investigating the effects of
omega-3 PUFA treatment on anxiety symptoms. We did not set any language limitation to increase
the number of eligible articles. Figure 1 shows the literature search and screening protocol.
Meta-analysis and Data Extraction and Input
Due to the anticipated heterogeneity, a random-effects meta-analysis was chosen rather than a
fixed-effects meta-analysis because random-effects modeling is more stringent and incorporates an
among-study variance in the calculations. The entire meta-analysis procedure was performed on the
platform of Comprehensive Meta-analysis statistical software, version 3 (Biostat). Under the
preliminary assumption that the scales for anxiety symptoms are heterogeneous among the
recruited studies, we chose Hedges gand 95% confidence intervals to combine the effect sizes, in
accordance with the manual of the Comprehensive Meta-analysis statistical software, version 3.
Regarding the interpretation of effect sizes, we defined Hedges gvalues 0 or higher as a better
association of treatment with reduced anxiety symptoms of omega-3 PUFAs than in controls. For
each analysis, a 2-tailed Pvalue less than .05 was considered to indicate statistical significance. When
more than 1 anxiety scale was used in a study, we chose the one with the most informative data (ie,
mean and standard deviation [SD] before and after treatment). We entered the primary outcome
provided in the included articles or obtained from the original authors. As for the variance
imputation, we mainly chose the mean and SD before and after treatment. Later, we entered the
mean and SD and calculated the effect sizes based on the software option, standardized by post
score SD. In the case of studies with 2 active treatment arms, we merged the 2 active treatment arms
into 1 group. If these 2 active treatment arms belonged to different subgroups (ie, different PUFA
dosage subgroups), we kept them separate. Regarding the numbers of participants counted, we
chose intention-to-treat as our priority. If there were insufficient data in the intention to treat group
(ie, some studies only provided the changes in anxiety severity in those participants completing
trials), we chose instead the per-protocol numbers of participants.
The quality of the included clinical trials were assessed using the Jadad score,
40
which was
designed to evaluate the risk of bias in interventional trials in 3 specific domains: randomization,
blindness, and cohort follow-up.
The primary outcome was analyzed by changes in anxiety symptoms in patients receiving
omega-3 PUFA treatment compared with those not receiving omega-3 PUFA treatment.
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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Heterogeneity, Publication Bias, and Sensitivity Testing
Heterogeneity was examined using the Q statistic and the corresponding Pvalues,
41
and the I
2
statistic was used to evaluate the proportion of variation resulting from among-study differences.
Any possible publication bias was detected with both funnel plots and Egger regression in the main
part of the meta-analysis.
42
By using Duval and Tweedie’s trim-and-fill test, we adjusted the effect
sizes for potential publication bias if there was evidence of publication bias detected by this test in
the Comprehensive Meta-analysis statistical software, version 3.
43
To investigate the potential
confounding effects of any outliers within the recruited studies, sensitivity testing was conducted
with the 1-study removal method to detect the potential outliers.
44
Metaregression and Subgroup Meta-analysis
To exclude the possible confounding effects of clinical variables on the Hedges g, metaregression
analysis was conducted with an unrestricted maximum likelihood random-effects model of single
variables when there were more than 10 data sets available. Specifically, the clinical variables of
interest included mean age, female proportion, sample size, mean body mass index, daily omega-3
PUFA dosage, EPA to DHA ratio, treatment duration, dropout rate, and others. In addition, a
subgroup meta-analysis was conducted to investigate potential sources of heterogeneity,
specifically, a further subgroup meta-analysis focused on those trials that were placebo controlled or
non–placebo controlled. To more clearly uncover the differences in the meta-analysis results among
the recruited studies, a further subgroup meta-analysis was performed according to the presence of
a specific clinical diagnosis or no specific clinical condition, mean omega-3 PUFA daily dosage, and
Figure 1. Flowchart of the Selection Strategy and Inclusion and Exclusion Criteria for This Meta-analysis
3584 Records identified through
database searching
4Additional records identified through
other sources
3588 Records identified
2141 Records after duplicates removed
1447 Excluded duplicated records
2037 Excluded by title and abstract
104 Full-text articles assessed for
eligibility
19 Studies included in current
meta-analysis
16 Compared with placebo
3Do not use placebo
85 Excluded articles
6Not human clinical trials
2Case report
7Review article
2Meta-analysis
15 Lack of adequate control
3Duplicated database from
other studies
38 Not related to treatment
effect of omega-3 on anxiety
2Protocol but not result of
study
3Did not simply treat with PUFAs
1Database study but not
clinical trial
6No detailed information after
request of raw data
PUFAs indicates polyunsaturated fatty acids.
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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mean age. In addition, in a previous study, the EPA percentage (ie, 60%) in the PUFA regimens had
different effects on depression treatment.
9
Therefore, we also arranged the subgroup meta-
analysis based on the EPA percentage. Furthermore, we arranged subgroup meta-analysis
procedures only when there were at least 3 data sets included.
45
To investigate the potentially
different estimated effect sizes between subgroups, we performed an interaction test and calculated
the corresponding Pvalues.
46
Results
Characteristics of the Included Studies
After the initial screening process, a total of 104 articles were considered for full-text review (Figure 1;
eFigure 1 in the Supplement); 85 were excluded according to the exclusion criteria (eAppendix in the
Supplement), leaving 19 articles for analysis in this study (Table).
33-36,47-61
In the 19 recruited studies,
33-36,47-61
there were a total of 1203 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%).
Various scales were used in these studies to evaluate the target outcome of anxiety symptoms:
the Yale-Brown Obsessive-Compulsive Scale, Profile of Mood States, State-Trait Anxiety Inventory,
Hamilton Anxiety Rating Scale, Generalized Anxiety Disorder questionnaire, Depression, Anxiety, and
Stress Scales, Clinician-Administered Posttraumatic Stress Disorder Scale, Beck Anxiety Inventory,
visual analog scale of anxiety, Impact of Event Scale–Revised, Conners score anxiety subscale,
Neuropsychiatric Inventory, test anxiety severity, Hospital Anxiety and Depression Scale anxiety
subscale, and Child Behavior Checklist anxiety subscale. The psychiatric and physical health
conditions of the recruited participants also varied widely: general population without specific clinical
conditions,
36,47,51,55,60
participants with acute myocardial infarction,
35
borderline personality
disorder,
2
mild to severe depression,
59
obsessive-compulsive disorder,
33
severe accidental injury,
49
participants who were traumatized by disaster,
54
participants with substance abuse disorder,
34
women with premenstrual syndrome,
56
children with attention-deficit/hyperactivity disorder,
48,53
Alzheimer disease,
58
generally healthy undergraduate college students but with test anxiety,
61
Parkinson disease,
52
and participants with Tourette syndrome.
57
Sixteen studies compared the effect
of omega-3 PUFA treatment with that of the placebo
33,34,36,47-49,51-53,55-61
; the other 3 studies were
non–placebo controlled trials.
35,50,54
The mean (SD) Jadad score of the recruited studies was 3.8 (1.0)
(eTable in the Supplement).
Meta-analysis of Changes in Anxiety Symptoms in Patients Receiving
and Not Receiving Omega-3 PUFA Treatment
In total, 19 articles with 19 data sets revealed the main results of the meta-analysis, namely that there
was a significantly better association of treatment with reduced anxiety symptoms in patients
receiving omega-3 PUFA treatment than in those not receiving it (k, 19; Hedges g, 0.374; 95% CI,
0.081-0.666; P=.01;Figure 2), with significant heterogeneity (Cochran Q, 178.820; df, 18; I
2
,
89.934%; P< .001) but no significant publication bias via Egger regression (t, 1.736; df,17;P= .10) or
inspection of the funnel plot (eFigure 2 in the Supplement). According to the trim-and-fill test, there
was no need for adjustment for publication bias. The meta-analysis results remained significant after
removal of any one of the included studies, which indicated that the significant results are not owing
to any single study.
There was no significant association between the Hedges gand mean age (k,17;P= .51), female
proportion (k, 18; P= .32), mean omega-3 PUFA dosage (k, 19; P= .307), EPA to DHA ratio (k,17;
P= .86), dropout rate in the omega-3 PUFA group (k, 18; P= .71), duration of omega-3 PUFA
treatment (k, 19; P= .14), Jadad score of randomization (k, 19; P= .10), Jadad score of blindness (k,
19; P= .57), or total Jadad score (k, 19; P= .18).
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Table. Characteristics of RecruitedStudies
Source Diagnosis Comparison Participants, No. Anxiety Scale Age, Mean (SD), y Female, No. (%)
Omega-3
Dosage, mg/d
Dropout Rate,
No./Total No.
Treatment
Duration,
wk Country
Watanabe et al,
47
2018 Junior nurses work in
hospital
Omega-3 PUFA
Placebo
40
40
HADS-A 29.6 (9.1)
30.5 (7.8)
40 (100.0)
40 (100.0)
1800.0 0/40
3/40
13 Japan
Cornu et al,
48
2018 Children with ADHD Omega-3 PUFA
Placebo
80
82
Conners 10.2 (2.8)
9.7 (2.5)
19 (23.7)
16 (19.5)
600.0 3/80
1/82
12 France
Matsuoka et al,
49
2015 Severe accidental injury Omega-3 PUFA
Placebo
53
57
CAPS 38.1 (13.5)
40.9 (17.3)
9 (17.0)
11 (19.3)
2100.0 8/53
6/57
12 Japan
Bellino et al,
50
2014 Borderline personality
disorders
Omega-3 PUFA + valproate
Control + valproate
18
16
HAM-A 25.2 (6.4) 26 (76.5) 2000.0 5/23
4/20
12 Italy
Cohen et al,
51
2014 Generally healthy
participants
Omega-3 PUFA
Placebo
177
178
GAD-7 54.7 (3.7) 177 (100.0)
178 (100.0)
1800.0 4/177
5/178
12 United States
Pomponi et al,
52
2014 Parkinson disease Omega-3 PUFA
Placebo
12
12
HAM-A 64.0 (4.9)
64.0 (9.8)
5 (41.7)
6 (50.0)
2000.0 0/12
0/12
24 Italy
Widenhorn-Müller
et al,
53
2014
Children with ADHD Omega-3 PUFA
Placebo
46
49
CBCL-A 8.9 (1.5)
8.9 (1.2)
11 (23.9)
10 (20.4)
720.0 7/55
6/55
16 Germany
Haberka et al,
35
2013 AMI Omega-3 PUFA + AMI
treatment
Control + AMI treatment
26
26
STAI 56.4
59.6 (6.0)
3 (11.5)
4 (15.4)
1000.0 0/26
0/26
4 Poland
Nishi et al,
54
2013 Disaster-related trauma Omega-3 PUFA + education
Education
86
86
IES-R 37.9 (7.4)
37.4 (7.4)
24 (27.9)
23 (26.7)
2240.0 0/86
1/86
12.6 Japan
Sauder et al,
55
2013 Healthy, nonsmoking men
and postmenopausal
women with moderate
hypertriglyceridemia
Omega-3 PUFA (3.4 g/d)
Omega-3 PUFA (0.85 g/d)
Placebo
26
26
26
STAI-state 44.0 3 (11.5) 3400.0
850.0
0/26
0/26
0/26
8 United States
Sohrabi et al,
56
2013 Women with premenstrual
syndrome
Omega-3 PUFA
Placebo
63
61
VASA 31.2 (6.5)
31.6 (8.4)
63 (100.0)
61 (100.0)
1000.0 7/70
8/69
12 Iran
Gabbay et al,
57
2012 Tourette syndrome Omega-3 PUFA
Placebo
17
16
C-YBOCS 11.9 (3.6)
10.6 (2.3)
3 (17.6)
3 (18.8)
4074.0 3/17
5/16
20 United States
Kiecolt-Glaser et al,
36
2011
Generally healthy
participants
Omega-3 PUFA
Placebo
34
34
BAI 23.9 (2.0)
23.4 (1.7)
16 (47.1)
14 (41.2)
2496.0 0/34
0/34
12 United States
Buydens-Branchey
et al,
34
2008
Substance abuse Omega-3 PUFA
Placebo
11
11
POMS NA 0
0
3000.0 0/11
0/11
12 United States
Freund-Levi et al,
58
2008
Alzheimer disease Omega-3 PUFA
Placebo
89
85
NPI 72.6 (9.0)
72.9 (8.6)
51 (57.3)
39 (45.9)
2320.0 12/103
14/101
24 Sweden
Rogers et al,
59
2008 Mild to severe depression Omega-3 PUFA
Placebo
109
109
DASS 38.0 (13.5)
38.2 (13.7)
85 (78.0)
83 (76.1)
2369.5 13/109
15/109
12 United
Kingdom
van de Rest et al,
60
2008
Elderly volunteers Omega-3 PUFA (1.8 g/d)
Omega-3 PUFA (0.4 g/d)
Placebo
96
100
106
HADS-A 69.9 (3.4)
69.5 (3.2)
70.1 (3.7)
43 (44.8)
45 (45.0)
47 (44.3)
1800.0
400.0
0/96
0/100
3/106
26 Netherlands
Yehuda et al,
61
2005 Undergraduate college
students with test anxiety
Omega-3 PUFA
Placebo
88
38
TAS NA NA 225.0 0/88
0/38
3 Israel
Fuxetal,
33
2004 Obsessive-compulsive
disorder
Omega-3 PUFA
Placebo
6
5
YBOCS 33.5 (5) 8 (72.7) 2000.0 1/11 6 Israel
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; AMI, acute myocardial infarction; BAI, Beck anxiety
index; CAPS, clinician-administered posttraumatic stress disorder scale; CBCL-A, Child Behavior Checklist anxiety
subscale; C-YBOCS, children’s Yale-Brown obsessive-compulsive scale; DASS, depression, anxiety, and stress
scales; GAD-7, generalized anxiety disorder questionnaire; HADS-A, Hospital Anxiety and Depression Scale anxiety
subscale; HAM-A, Hamilton anxiety rating scale; IES-R, impact of event scale-revised; NA, not available; NPI,
Neuropsychiatric Inventory; POMS, profiles of mood states; PUFA, polyunsaturated fattyacid; STAI, state-trait
anxiety inventory; TAS,test anxiety severity; VASA, visual analog scale of anxiety; YBOCS, Yale-Brown obsessive-
compulsive scale.
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Subgroup Meta-analysis When Focusing on Placebo-Controlled Trials
or Non–Placebo-Controlled Trials
Among the 16 studies comparing the effect of omega-3 PUFA treatment with that of the
placebo,
33,34,36,47-49,51-53,55-61
the main results revealed a significantly greater association of
treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in
those not receiving it (k, 16; Hedges g, 0.372; 95% CI, 0.032-0.712; P= .03; eFigure 3 in the
Supplement). The meta-analysis of the subgroup focusing on non–placebo-controlled trials also
showed a significantly greater association of treatment with reduced anxiety symptoms in patients
receiving omega-3 PUFA treatment than in those not receiving it (k, 3; Hedges g,0.399;95%CI,
0.154-0.643; P= .001).
35,50,54
Subgroup Meta-analysis When Focusing on Trials Recruiting Participants
Without Specific Clinical Conditions or Trials Recruiting Participants
With Specific Clinical Diagnoses
Five studies with 7 data sets recruited participants without specific clinical conditions.
36,47,51,55,60
The
main results revealed that there was no significant difference in the association of treatment with
reduced anxiety symptoms between patients receiving omega-3 PUFA treatment and those not
receiving it (k, 5; Hedges g, –0.008; 95% CI, –0.266 to 0.250; P= .95) (Figure 3A). Fourteen studies
with 14 data sets recruited participants with specific clinical diagnoses.
33-35,48-50,52-54,56-59,61
The
main results revealed a significantly greater association of treatment with reduced anxiety symptoms
in patients receiving omega-3 PUFA treatment than in those not receiving it (k, 14; Hedges g, 0.512;
95% CI, 0.119-0.906; P= .01) (Figure 3A). Furthermore, according to the interaction test, 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
(P= .03).
Figure 2. Meta-Analysis Forest Plot of the Association of Treatment With Reduced Anxiety Symptoms in Patients Receiving and Not Receivingomega-3 PUFA s
–4 2 40
Hedges g (95% CI)
–2
Relative
Weight, %
Worse effect
by omega-3 PUFAs
Better effect
by omega-3 PUFAs
Participants, No.
Source
6.03
5.40Sauder et al,55 2013
5.27
van de Rest et al,60 2008
6.08
Freund-Levi et al,58 2008
5.70
Cohen et al,51 2014
5.87
Omega-3
196
52
36
177
53
79
46
6
18
109
40
17
86
12
34
26
11
88
63
Control
106
26
24
178
57
81
49
5
16
109
40
16
86
12
34
26
11
38
61
P Value
.08
.22
.57
.19
.57
.63
.69
.77
.61
.14
.33
.37
.01
.23
.01
.03
.02
.01
<.001
<.001
Matsuoka et al,49 2015
5.62
3.36
4.76
5.97
5.51
4.72
5.89
4.32
5.36
5.14
4.07
5.53
5.42
100.00
Cornu et al,48 2018
Widenhorn-MÜller et al,53 2014
Fux et al,33 2004
Bellino et al,50 2014
Rogers et al,59 2008
Watanabe et al,47 2018
Gabbay et al,57 2012
Nishi et al,54 2013
Pomponi et al,52 2014
Kiecolt-Glaser et al,36 2011
Haberka et al,35 2013
Buydens-Branchey et al,34 2008
Yehuda et al,61 2005
Sohrabi et al,56 2013
Overall
Hedges g (95% CI)
–0.214 (–0.450 to 0.023)
–0.290 (–0.759 to 0.178)
–0.149 (–0.659 to 0.362)
–0.139 (–0.347 to 0.069)
–0.107 (–0.479 to 0.264)
–0.077 (–0.385 to 0.232)
0.081 (–0.318 to 0.481)
0.165 (–0.922 to 1.252)
0.172 (–0.487 to 0.831)
0.200 (–0.065 to 0.465)
0.217 (–0.219 to 0.652)
0.306 (–0.364 to 0.976)
0.382 (0.082 to 0.683)
0.477 (–0.308 to 1.261)
0.607 (0.126 to 1.088)
0.610 (0.062 to 1.158)
1.010 (0.153 to 1.868)
1.650 (1.220 to 2.079)
2.459 (1.994 to 2.923)
0.374 (0.081 to 0.666)
There was a significant improvement in anxiety symptoms in patients receiving omega-3 PUFAs than in those not receiving omega-3 PUFAs (k, 19; Hedges g, 0.374; 95% CI, 0.081-
0.666; P= .01).
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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Figure 3. Forest Plot of Subgroup Meta-analysis
–4 2 40
Hedges g (95% CI)
–2
Relative
Weight, %
Worse effect
by omega-3 PUFAs
Better effect
by omega-3 PUFAs
Participants, No.
Source
15.68
Sauder et al,55 2013
No specific clinical conditions
25.46
van de Rest et al,60 2008
26.75
16.86
Cohen et al,51 2014
15.25
Omega-3
52
196
177
40
34
36
53
79
46
6
18
109
17
86
12
26
11
88
63
Control
26
106
178
40
34
24
57
81
49
5
16
109
16
86
12
26
11
38
61
P Value
.22
.08
.19
.33
.01
.95
.57
.57
.63
.69
.77
.61
.14
.37
.01
.02
.01
<.001
<.001
.23
.03
Matsuoka et al,49 2015
100.00
7.33
7.78
7.96
7.70
5.11
6.78
8.06
6.73
7.98
6.28
7.20
5.99
7.61
7.49
100.00
Cornu et al,48 2018
Widenhorn-MÜller et al,53 2014
Fux et al,47 2004
Bellino et al,50 2014
Rogers et al,59 2008
Watanabe et al,47 2018
Gabbay et al,57 2012
Nishi et al,54 2013
Pomponi et al,52 2014
Kiecolt-Glaser et al,36 2011
Overall
Overall
Specific clinical diagnoses
Haberka et al,35 2013
Buydens-Branchey et al,34 2008
Yehuda et al,61 2005
Sohrabi et al,56 2013
Hedges g (95% CI)
–0.290 (–0.759 to 0.178)
–0.214 (–0.450 to 0.023)
–0.139 (–0.347 to 0.069)
0.217 (–0.219 to 0.652)
0.607 (0.126 to 1.088)
–0.008 (–0.266 to 0.250)
–0.149 (–0.659 to 0.362)
–0.107 (–0.479 to 0.264)
–0.077 (–0.385 to 0.232)
0.081 (–0.318 to 0.481)
0.165 (–0.922 to 1.252)
0.172 (–0.487 to 0.831)
0.200 (–0.065 to 0.465)
0.306 (–0.364 to 0.976)
0.382 (0.082 to 0.683)
0.477 (–0.308 to 1.261)
0.610 (0.062 to 1.158)
1.010 (0.153 to 1.868)
1.650 (1.220 to 2.079)
2.459 (1.994 to 2.923)
0.512 (0.119 to 0.906)
Freund-Levi et al,58 2008
An underlying specific clinical diagnosis or not
A
Different mean omega-3 PUFA dosages
B
–4 2 40
Hedges g (95% CI)
–2
Relative
Weight, %
Worse effect
by omega-3 PUFAs
Better effect
by omega-3 PUFAs
Participants, No.
Source
10.60
Sauder et al,55 2013
Sauder et al,55 2013
Dosage <2000 mg/d
11.62
van de Rest et al,60 2008
11.66
11.43
Cohen et al,51 2014
11.15
Omega-3
26
196
177
79
46
40
26
88
63
26
36
53
6
18
109
17
86
12
34
11
Control
26
106
178
81
49
40
26
38
61
26
24
57
5
16
109
16
86
12
34
11
P Value
.16
.08
.19
.63
.69
.33
.03
<.001
<.001
.09
.48
.57
.57
.77
.61
.01
.02
.02
.23
.01
.14
.37
Matsuoka et al,49 2015
11.02
10.56
11.04
10. 91
100.00
8.42
9.05
13.62
2.57
6.14
18.89
5.97
16.96
4.60
9.84
3.94
100.00
Cornu et al,48 2018
Widenhorn-MÜller et al,53 2014
Fux et al,33 2004
Bellino et al,50 2014
Rogers et al,49 2008
Watanabe et al,47 2018
Gabbay et al,57 2012
Nishi et al,54 2013
Pomponi et al,52 2014
Kiecolt-Glaser et al,36 2011
Overall
Overall
Dosage ≥2000, mg/d
Haberka et al,35 2013
Buydens-Branchey et al,34 2008
Yehuda et al,61 2005
Sohrabi et al,56 2013
Hedges g (95% CI)
–0.386 (–0.927 to 0.154)
–0.214 (–0.450 to 0.023)
–0.139 (–0.347 to 0.069)
–0.077 (–0.385 to 0.232)
0.081 (–0.318 to 0.481)
0.217 (–0.219 to 0.652)
0.610 (0.062 to 1.158)
1.650 (1.220 to 2.079)
2.459 (1.994 to 2.923)
0.457 (–0.077 to 0.991)
–0.193 (–0.730 to 0.344)
–0.149 (–0.659 to 0.362)
–0.107 (–0.479 to 0.264)
0.165 (–0.922 to 1.252)
0.172 (–0.467 to 0.831)
0.200 (–0.065 to 0.465)
0.306 (–0.364 to 0.976)
0.382 (0.082 to 0.683)
0.477 (–0.308 to 1.261)
0.607 (0.126 to 1.088)
1.010 (0.153 to 1.868)
0.213 (0.031 to 0.395)
Freund-Levi et al,58 2008
A, Subgroup meta-analysis of the anxiolytic effect of omega-3 polyunsaturated fatty
acids (PUFAs) based on an underlying specific clinical diagnosis or not. The anxiolytic
effect of omega-3 PUFAs wasnot signif icant in the subgroup of participants without
specific clinical conditions (k, 5; Hedges g, –0.008; 95%CI, –0.266 to 0.250; P= .95) but
was significant in the subgroup of participants with specific clinical diagnoses (k, 14;
Hedges g, 0.512; 95% CI, 0.119-0.906;P= .01). Furthermore, the association of
treatment with reduced anxiety symptoms of omega-3 PUFAswere significantly
stronger in subgroups with specific clinical diagnoses than in subgroups without specific
clinical conditions (P= .03). B, Subgroup meta-analysis of the anxiolytic effect of
omega-3 PUFAsbased on different mean omega-3 PUFA dosages. The anxiolytic effect
of omega-3 PUFAswas not significant in subgroups of mean omega-3 PUFA dosages less
than 2000 mg/d (k, 9; Hedges g, 0.457; 95% CI, –0.077 to 0.991; P= .09) but was
significant in the subgroup of mean omega-3 PUFA dosage of at least2000 mg /d (k, 11;
Hedges g, 0.213; 95% CI, 0.031-0.395; P= .02).
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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Subgroup Meta-analysis When Focusing on Trials With Omega-3 PUFA Dosages
of Less Than 2000 mg/d or at Least 2000 mg/d
Nine studies with 10 data sets used omega-3 PUFA dosages of less than 2000
mg/d.
35,47,48,51,53,55,56,60,61
The main results revealed that there was no significant difference in the
association of treatment with reduced anxiety symptoms between patients receiving omega-3 PUFA
treatment and those not receiving it (k, 9; Hedges g, 0.457; 95% CI, –0.077 to 0.991; P=.09)
(Figure 3B). Ten studies with 10 data sets used omega-3 PUFA dosages of at least 2000
mg/d.
33,34,36,49,50,52,54,55,57-59
The main results revealed a significantly greater association of
treatment with reduced anxiety symptoms in patients receiving omega-3 PUFA treatment than in
those not receiving it (k, 11; Hedges g, 0.213; 95% CI, 0.031-0.395; P= .02) (Figure 3B). Furthermore,
there was no significantly different estimated effect sizes between these 2 subgroups by the
interaction test (P= .40).
Subgroup Meta-analysis of Trials With an EPA Percentage Less Than 60%
or an EPA Percentage of at Least 60%
There was a significantly greater association of treatment with reduced anxiety symptoms in
participants receiving omega-3 PUFAs than in those not receiving omega-3 PUFAs in the subgroup
with an EPA percentage less than 60% (k, 11; Hedges g, 0.485; 95% CI, 0.017-0.954; P= .04;
Figure 4)
35,49,52,54-61
but no significant difference in the association of treatment with reduced
anxiety symptoms between participants receiving omega-3 PUFAs and those not receiving omega-3
PUFAs in the subgroup with an EPA percentage of at least 60% (k, 9; Hedges g, 0.092; 95% CI,
–0.102 to 0.285; P= .35) (Figure 4).
33,34,36,47,48,50,51,53,60
There were no significantly different
estimated effect sizes between these 2 subgroups by the interaction test (P= .13).
Figure 4. Subgroup Meta-analysis With Different Eicosapentaenoic Acid (EPA)Percentages
–4 2 40
Hedges g (95% CI)
–2
Relative
Weight, %
Worse effect
by omega-3 PUFAs
Better effect
by omega-3 PUFAs
Participants, No.
Source
9.12
Sauder et al,55 2013
EPA percentage <60%
9.71
Van de Rest et al,60 2008
Van de Rest et al,60 2008
8.97
9.44
Cohen et al,51 2014
9.73
Omega-3
52
100
36
53
109
17
86
12
26
86
63
177
96
79
46
6
18
40
34
11
Control
26
106
24
57
109
16
86
12
26
38
61
178
106
81
49
5
16
40
34
11
P Value
.22
.26
.57
.57
.14
.37
.01
.23
.03
<.001
<.001
.04
.19
.35
.63
.61
.02
.35
.33
.01
.69
.77
Matsuoka et al,49 2015
8.33
9.64
7.84
8.83
9.26
9.14
100.00
20.05
17.07
15.69
12.36
2.83
6.49
11.25
10.00
4.26
100.00
Cornu et al,48 2018
Widenhorn-MÜller et al,53 2014
Fux et al,33 2004
Bellino et al,50 2014
Rogers et al,59 2008
Watanabe et al,47 2018
Gabbay et al,57 2012
Nishi et al,54 2013
Pomponi et al,52 2014
Kiecolt-Glaser et al,36 2011
Overall
Overall
EPA percentage ≥60%
Haberka et al,35 2013
Buydens-Branchey et al,34 2008
Yehuda et al,61 2005
Sohrabi et al,56 2013
Hedges g
(95% CI)
–0.290 (–0.759 to 0.178)
–0.157 (–0.430 to 0.116)
–0.149 (–0.659 to 0.362)
–0.107 (–0.479 to 0.264)
0.200 (–0.065 to 0.465)
0.306 (–0.364 to 0.976)
0.382 (0.082 to 0.683)
0.477 (–0.308 to 1.261)
0.610 (0.062 to 1.158)
1.650 (1.220 to 2.079)
2.459 (1.994 to 2.923)
0.485 (0.017 to 0.954)
–0.139 (–0.347to 0.069)
–0.131 (–0.406 to 0.144)
–0.077 (–0.385 to 0.232)
0.081 (–0.318 to 0.481)
0.165 (–0.922 to 1.252)
0.172 (–0.487 to 0.831)
0.217 (–0.219 to 0.652)
0.607 (0.126 to 1.088)
1.010 (0.153 to 1.868)
0.092 (–0.102 to 0.285)
Freund-Levi et al,58 2008
Subgroup meta-analysis of the anxiolytic effects of omega-3 polyunsaturated fatty acids
(PUFAs) based on different EPApercentages. The anxiolytic effects of omega-3 PUFAs
were significant in the subgroup with an EPA percentage less than 60% (k, 11; Hedges
g = 0.485;95% CI, 0.017 to 0.954;P= .04) but not significant in the subgroups with an
EPA percentage of at least 60% (k, 9; Hedges g, 0.092; 95% CI, –0.102 to
0.285; P= .35).
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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Other Subgroup Meta-analyses of Changes in Anxiety Symptoms in Patients
Receiving and Not Receiving Omega-3 PUFA Treatment
In addition, there was no significant difference in the association of treatment with reduced anxiety
symptoms between participants receiving omega-3 PUFAs and those not receiving omega-3 PUFAs
in the adolescent subgroup (aged <18 years) (k, 3; Hedges g, 0.020; 95% CI, –0.209 to 0.250;
P= .86),
48,53,57
in the adult subgroup (aged 18 years but <60 years) (k, 11; Hedges g, 0.388; 95%
CI, –0.012 to 0.788; P= .06),
33,35,36,47,49-51,54-56,59
or in the elderly subgroup (aged 60 years) (k,3;
Hedges g, –0.112; 95% CI, –0.406 to 0.181; P= .45).
52,58,60
These insignificant results might be due
to the smaller sample sizes in each subgroup.
Discussion
To our knowledge, this is the first systematic review and meta-analysis to examine the anxiolytic
effects of omega-3 PUFAs in individuals with anxiety symptoms. The overall findings revealed
modest anxiolytic effects of omega-3 PUFAs in individuals with various neuropsychiatric or major
physical illnesses. Although participants and diagnoses were heterogeneous, the main finding of this
meta-analysis was that omega-3 PUFAs were associated with significant reduction in anxiety
symptoms compared with controls; this effect persisted vs placebo controls. Furthermore, the
association of treatment with reduced anxiety symptoms of omega-3 PUFA were significantly higher
in subgroups with specific clinical diagnoses than in subgroups without clinical conditions.
Interestingly, the results are also consistent with our recent findings that somatic anxiety is
associated with omega-3 PUFA deficits and the genetic risks of PUFA metabolic enzyme cytosolic
phospholipase A2 in major depressive disorder
62,63
and interferon α–induced neuropsychiatric
syndrome.
63,64
Brain membranes contain a high proportion of omega-3 PUFAs and their derivatives
and most animal and human studies suggest that a lack of omega-3 PUFAs in the brain might induce
various behavioral and neuropsychiatric disorders,
16,65-70
including anxiety-related
behaviors.
12,18,19,32,49,71
Emerging evidence suggests that omega-3 PUFAs interfere with and possibly
control several neurobiological processes, such as neurotransmitter systems, neuroplasticity, and
inflammation,
12,72
which is postulated to be the mechanism underlying anxiety and depression.
In our analysis, most of the included studies showed a positive Hedges gtoward a beneficial
effect of omega-3 PUFAs in anxiety reduction, although not all findings were statistically significant.
However, after merging of these effect sizes from all of the included studies, the main result showed
significant findings in our meta-analysis. Despite the significant heterogeneity, no significant
publication bias was found among these 19 studies.
To evaluate the potential placebo effect, we made further subgrouping analyses. In the
subgroups of studies using placebo controls, the omega-3 PUFAs still revealed a consistent positive
anxiolytic association with anxiety symptoms. These phenomena meant that the anxiolytic effect of
omega-3 PUFAs is probably not entirely owing to the placebo effect.
Further, according to subgroup results based on the presence of specific clinical diagnoses or
not, the association of omega-3 PUFA treatment with reduced anxiety symptoms was significantly
higher in subgroups with specific clinical diagnoses than in subgroups without clinical conditions.
Among 6 studies included in a meta-analysis of the effect of omega-3 PUFAs on depressive
symptoms, the analysis showed a nearly null effect of omega-3 PUFAs on depressive symptoms in
healthy participants.
73
Although the reason for the null effect of omega-3 PUFAs on anxiety and
depressive symptoms remains unclear, certain pathophysiological conditions might be required for
omega-3 PUFAs to exert an association of treatment with reduced anxiety symptoms.
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. In addition,
participants receiving supplements containing less than 60% EPA showed a significant association,
but not those receiving supplements containing 60% or more EPA. The depression literature
supports the clinical benefits of EPA-enriched formulations (60% or 50%) compared with
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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placebo for the treatment of clinical depression.
9,13,73-75
This opposite effect of EPA-enriched
formations on anxiety and depression is intriguing and possibly linked to a distinct underlying
mechanism of omega-3 PUFAs. Exploration of the effects of omega-3 PUFAs on anxiety symptoms is
just beginning and studies assessing the dose response anxiolytic effects of omega-3 PUFAs have
not yet been performed. Further phase 2 trials of anxiety symptoms among participants with
neuropsychiatric illness or physical illness should aim to determine the optimal dose.
Although there was significant heterogeneity among the included studies (Cochran Q, 178.820;
df, 18; I
2
,89.934%;P< .001), the sensitivity test suggested that the main significant results of the
meta-analysis would not change after removal of any of the included studies. However, through
direct inspection of the forest plot, we detected the potential influence of some outliers, such as the
studies by Sohrabi et al
56
and Yehuda et al.
61
These 2 studies evaluated anxiety symptoms with a
visual analog scale of anxiety and test anxiety severity, which are seldom used in psychiatric research
and lack a definite report to prove their equivalent sensitivity and specificity to some other
frequently used anxiety rating scales, such as depression, anxiety, and stress scales or the Hamilton
anxiety rating scale. Therefore, these studies might have affected the interpretation of the current
meta-analysis.
Finally, to investigate the potential confounding effects of some clinical variables, we tried to
conduct further exploratory subgroup analyses based on age. However, there were no significant
findings from these subgroups. These results might be due to the smaller sample sizes after
subgrouping.
Limitations
This article had several limitations and the findings need to be considered with caution. First, our
participant population is too heterogeneous because of our broad inclusion criteria, which might be
true if considering current Diagnostic and Statistical Manual of Mental Disorders or International
Classification of Diseases diagnostic systems. However, the novel Research Domain Criteria consider
anxiety to be one of the major domains in Negative Valence Systems. Trials should be conducted in
populations in which anxiety is the main symptom irrespective of the presence or absence of
diagnosis of anxiety disorder. Second, because of the limited number of recruited studies and their
modest sample sizes, the results should not be extrapolated without careful consideration. Third, the
significant heterogeneity among the included studies (Cochran Q, 178.820; df, 18; I
2
,89.934%;
P< .001) with potential influence by some outlier studies, such as the studies by Sohrabi et al
56
and
Yehuda et al,
61
would be another major concern. Therefore, clinicians should pay attention to this
aspect when applying the results of the current meta-analysis to clinical practice, particularly when
considering the subgroups of these 2 studies (ie, subgroups with specific clinical diagnoses, with
<2000 mg/d, with EPA <60%, and with placebo-controlled trials).
Conclusions
This systematic review and meta-analysis of clinical trials conducted on participants with clinical
anxiety symptoms provides the first meta-analytic evidence, to our knowledge, that omega-3 PUFA
treatment may be associated with anxiety reduction, which might not only be due to a potential
placebo effect, but also from some associations of treatment with reduced anxiety symptoms. The
beneficial anxiolytic effects of omega-3 PUFAs might be stronger in participants with specific clinical
diagnoses than in those without specific clinical conditions. Larger and well-designed clinical trials
should be performed with high-dose omega-3 PUFAs, provided as monotherapy and as adjunctive
treatment to standard therapy.
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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ARTICLE INFORMATION
Accepted for Publication: July 5, 2018.
Published: September 14, 2018. doi:10.1001/jamanetworkopen.2018.2327
Open Access: This is an open access article distributed under the terms of the CC-BY License.©2018SuK-Petal.
JAMA Network Open.
Corresponding Author: Yutaka J.Matsuoka, MD, PhD, Division of Health Care Research, Center for Public Health
Sciences, National Cancer Center Japan, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan (yumatsuo@ncc.go.jp);
Kuan-Pin Su, MD, PhD, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, Taiwan
404 (cobolsu@gmail.com).
Author Affiliations: Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan (Su); Mind-
Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan (Su); College of
Medicine, China Medical University,Taichung, Taiwan (Su, Matsuoka); WinShine Clinics in Specialty of Psychiatry,
Kaohsiung City,Taiwan (Tseng); Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung,
Taiwan (Lin); Chang Gung University College of Medicine, Kaohsiung, Taiwan (Lin); Institute forTranslational
Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan (Lin); Division of
Health Care Research, Center for Public Health Sciences, National Cancer Center Japan, Tokyo, Japan (Okubo,
Matsuoka); Department of Psychiatry, Tri-Service General Hospital, Taipei, Taiwan (T.-Y. Chen); School of Medicine,
National Defense Medical Center, Taipei, Taiwan(T.-Y. Chen); Institute of Brain Science, National Yang-Ming
University,Taipei, Taiwan (T.-Y. Chen); Prospect Clinic for Otorhinolaryngology & Neurology, Kaohsiung, Taiwan
(Y.-W. Chen).
Author Contributions: Dr Tseng had full access to all of the data in the study and takes responsibility forthe
integrity of the data and the accuracy of the data analysis. Drs Su and Tseng contributed equally.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: Su, Tseng, Okubo, Matsuoka.
Drafting of the manuscript: Su, Tseng, Okubo, Y.-W. Chen, Matsuoka.
Critical revision of the manuscript for important intellectual content: Su, Tseng, Lin, Okubo, T.-Y. Chen, Matsuoka.
Statistical analysis: Tseng, Lin, Y.-W. Chen.
Obtained funding: Su, Matsuoka.
Administrative, technical, or material support: Su, T.-Y. Chen.
Supervision: Su, Matsuoka.
Conflict of Interest Disclosures: Dr Su reported 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 Matsuoka
reported receiving donations from Morinaga Milk Industry Co, Ltd outside the submitted work. No other
disclosures were reported.
Funding/Support: The work was supported in part by grant 17H04253, Grant-in-Aid for Scientific Research (B)
from the Japan Society for the Promotion of Science; grant 30-A-17 from the National Cancer Center Research and
Development Fund; grants MOST106-2314-B-039-027-MY, 106-2314-B-038-049, 106-2314-B-039-031,
106-2314-B-039-035,104-2314-B-039-022-MY2, and 104-2314-B-039-050-MY3 from the Ministry of Science
and Technology, Taiwan;grant HRI-EX105-10528NI from the National Health Research Institutes, Taiwan; and
grants CRS-106-063, DMR-107-202, and DMR-107-204 from the China Medical University, Taiwan.
Role of the Funder/Sponsor:The funders had no role in the design and conduc t of the study; collection,
management, analysis, and interpretation of the data; review or approval of the manuscript; and decision to
submit the manuscript for publication.
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SUPPLEMENT.
eAppendix. Excluded Studies and Reasons
eTable. Study Design and Jadad Scores of Recruited Studies
eFigure 1. Whole Flowchart of Current Meta-Analysis
eFigure 2. Funnel Plot of Changes in Anxiety Symptoms in Patients With and Without n-3 PUFA Treatment
eFigure 3. Subgroup MA of Anxiolytic Effect Based Upon Placebo Controlled or Non–Placebo Controlled Design
JAMA Network Open | Psychiatry Association of Omega-3 Polyunsaturated Fatty Acids With Anxiety SymptomSeverity
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... In many cases, the diet was designed to be highly palatable and to induce obesity [22,23]. 39 ...
... Eleven studies reported an improvement in anxiety symptoms, the remaining studies were equivocal. Two of three meta-analyses of trials delivering omega-3 fatty acid supplements reported benefit to anxiety symptoms [37][38][39]. While nine of the experimental studies included participants with psychiatric disorders such as eating disorders, substance use disorders and ADHD, only There was an association between higher anxiety symptoms and tryptophan depletion, among human experimental studies. ...
... Eleven studies reported an improvement in anxiety symptoms, the remaining studies were equivocal. Two of three meta-analyses of trials delivering omega-3 fatty acid supplements reported benefit to anxiety symptoms [37][38][39]. While nine of the experimental studies included participants with psychiatric disorders such as eating disorders, substance use disorders and ADHD, only one trial involved participants with anxiety disorders [40]. ...
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Anxiety disorders are the most common group of mental disorders. There is mounting evidence demonstrating the importance of nutrition in the development and progression of mental disorders such as depression; however, less is known about the role of nutrition in anxiety disorders. This scoping review sought to systematically map the existing literature on anxiety disorders and nutrition in order to identify associations between dietary factors and anxiety symptoms or disorder prevalence as well as identify gaps and opportunities for further research. The review followed established methodological approaches for scoping reviews. Due to the large volume of results, an online program (Abstrackr) with artificial intelligence features was used. Studies reporting an association between a dietary constituent and anxiety symptoms or disorders were counted and presented in figures. A total of 55,914 unique results were identified. After a full-text review, 1541 articles met criteria for inclusion. Analysis revealed an association between less anxiety and more fruits and vegetables, omega-3 fatty acids, “healthy” dietary patterns, caloric restriction, breakfast consumption, ketogenic diet, broad-spectrum micronutrient supplementation, zinc, magnesium and selenium, probiotics, and a range of phytochemicals. Analysis revealed an association between higher levels of anxiety and high-fat diet, inadequate tryptophan and dietary protein, high intake of sugar and refined carbohydrates, and “unhealthy” dietary patterns. Results are limited by a large percentage of animal and observational studies. Only 10% of intervention studies involved participants with anxiety disorders, limiting the applicability of the findings. High quality intervention studies involving participants with anxiety disorders are warranted.
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A nutrition-based approach was utilized to examine the effects of fish oil and a polyphenol blend (with or without tomato pomace) on the fecal microbiota and plasma/fecal metabolomes. Forty dogs, aged 5–14 years, were fed a washout food, then randomized to consume a control (fish oil and polyphenol blend without tomato pomace) or test (fish oil and polyphenol blend with tomato pomace) food, then the washout food, and crossed over to consume the test or control food; each for 30 days. Several metabolites differed when comparing consumption of the washout with either the control or test foods, but few changed significantly between the test and control foods. Plasma levels of 4-ethylphenyl sulfate (4-EPS), a metabolite associated with anxiety disorders, demonstrated the largest decrease between the washout food and the control/test foods. Plasma 4-EPS levels were also significantly lower after dogs ate the test food compared with the control food. Other plasma metabolites linked with anxiety disorders were decreased following consumption of the control/test foods. Significant increases in Blautia, Parabacteroides, and Odoribacter in the fecal microbiota correlated with decreases in 4-EPS when dogs ate the control/test foods. These data indicate that foods supplemented with polyphenols and omega-3 fatty acids can modulate the gut microbiota to improve the profile of anxiety-linked metabolites.
... Brain damage Neurotropism and replication capacity in neuronal cultures, brain organoids (Ackermann et al., 2020;Chu et al., 2020;Sun et al., 2020;von Weyhern et al., 2020;Zhang et al., 2020a) Brain protection: Regenerative, neuroprotective and neurotrophic effects -suppressing NF-κB activation -inhibiting ROS production, heme oxygenase 1 activity -attenuating apoptosis (Liu et al., 2014;Lu et al., 2010;Luo et al., 2014;Zhang et al., 2014) Changes in brain parenchyma and vessels -altering the integrity of blood-brain and blood-cerebrospinal fluid barriers -drove inflammation in neurons, brain vasculature and supportive cells (Reichard et al., 2020;Romero-Sánchez et al., 2020) Beneficial effects on neurodegenerative diseases, cerebral ischemia, neurotrauma and other brain disorders Lin et al., 2012;Lin et al., 2010;Luo et al., 2014;Michael-Titus, 2009;Su et al., 2008;Su et al., 2014;Su et al., 2018;Zhang et al., 2011) Cognitive, psychiatric and dysautonomic impairment -hypometabolism in various brain areas such as the right temporal lobe, connected limbic and paralimbic regions including the amygdala and the hippocampus, the brainstem, the cerebellum and the hypothalamus (Guedj et al., 2021;Yan et al., 2021) SPMs have been reported to significantly improve behavioral, neurological and histological outcomes -modulating inflammatory, antioxidative, neurotrophic, and antiapoptotic (Belayev et al., 2011;Blondeau et al., 2009;Horrocks and Farooqui, 2004;Lu et al., 2010;Rao et al., 2007;Shi et al., 2016) Inflammation/ Neuroinflammation ...
... Brain damage Neurotropism and replication capacity in neuronal cultures, brain organoids (Ackermann et al., 2020;Chu et al., 2020;Sun et al., 2020;von Weyhern et al., 2020;Zhang et al., 2020a) Brain protection: Regenerative, neuroprotective and neurotrophic effects -suppressing NF-κB activation -inhibiting ROS production, heme oxygenase 1 activity -attenuating apoptosis (Liu et al., 2014;Lu et al., 2010;Luo et al., 2014;Zhang et al., 2014) Changes in brain parenchyma and vessels -altering the integrity of blood-brain and blood-cerebrospinal fluid barriers -drove inflammation in neurons, brain vasculature and supportive cells (Reichard et al., 2020;Romero-Sánchez et al., 2020) Beneficial effects on neurodegenerative diseases, cerebral ischemia, neurotrauma and other brain disorders Lin et al., 2012;Lin et al., 2010;Luo et al., 2014;Michael-Titus, 2009;Su et al., 2008;Su et al., 2014;Su et al., 2018;Zhang et al., 2011) Cognitive, psychiatric and dysautonomic impairment -hypometabolism in various brain areas such as the right temporal lobe, connected limbic and paralimbic regions including the amygdala and the hippocampus, the brainstem, the cerebellum and the hypothalamus (Guedj et al., 2021;Yan et al., 2021) SPMs have been reported to significantly improve behavioral, neurological and histological outcomes -modulating inflammatory, antioxidative, neurotrophic, and antiapoptotic (Belayev et al., 2011;Blondeau et al., 2009;Horrocks and Farooqui, 2004;Lu et al., 2010;Rao et al., 2007;Shi et al., 2016) Inflammation/ Neuroinflammation ...
Article
The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the lasting pandemic of coronavirus disease 2019 (COVID-19) and the post-acute phase sequelae of heterogeneous negative impacts in multiple systems known as the “long COVID.” The mechanisms of neuropsychiatric complications of long COVID are multifactorial, including long-term tissue damages from direct CNS viral involvement, unresolved systemic inflammation and oxidative stress, maladaptation of the renin-angiotensin-aldosterone system and coagulation system, dysregulated immunity, the dysfunction of neurotransmitters and hypothalamus-pituitary-adrenal (HPA) axis, and the psychosocial stress imposed by societal changes in response to this pandemic. The strength of safety, well-acceptance, and accumulating scientific evidence has now afforded nutritional medicine a place in the mainstream of neuropsychiatric intervention and prophylaxis. Long chain omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) might have favorable effects on immunity, inflammation, oxidative stress and psychoneuroimmunity at different stages of SARS-CoV-2 infection. Omega-3 PUFAs, particularly EPA, have shown effects in treating mood and neurocognitive disorders by reducing pro-inflammatory cytokines, altering the HPA axis, and modulating neurotransmission via lipid rafts. In addition, omega-3 PUFAs and their metabolites, including specialized pro-resolvin mediators, accelerate the process of cleansing chronic inflammation and restoring tissue homeostasis, and therefore offer a promising strategy for Long COVID. In this article, we explore in a systematic review the putative molecular mechanisms by which omega-3 PUFAs and their metabolites counteract the negative effects of long COVID on the brain, behavior, and immunity.
... In contrast, cluster headaches, which are uncommon in ME/CFS and GWI, may be interpreted as exteroceptive pain with the arousal of sympathetic fight-flight reactions, motor agitation, and restlessness. The molecular mechanisms of sickness behaviors are complex but may involve IL6, IL1-beta, INF-alpha, and other cytokines as well as modulation of arachidonic acid cytochrome P450 metabolites and phosphatidylinositol derivatives by eicosapentaenoic acid (EPA) and effects on cannabinoid CB2 receptors [135][136][137][138]. EPA may have some benefits for treating anxiety [139] and PTSD [140,141] but has small non-clinical effects compared to placebo in depression [142]. This provides the rationale for testing in ME/CFS [143] and GWI. ...
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms. These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
... A number of trials have found that omega-3 PUFAs might reduce anxiety under serious stressful situations. Case-controlled studies have shown low peripheral omega-3 PUFA levels in patients with anxiety disorders ). on the cell membrane (Chang, Su, Mondelli, & Pariante, 2018;Su et al., 2018). ...
Chapter
The role of the daily diet in public and individual health has been of significant interest since long before the development of nutrition as a scientific discipline.
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Essential fatty acids such as omega-3 polyunsaturated fatty acids (n-3 PUFAs) and omega-6 (n-6) PUFAs are essential for the development and function of the brain. There are three potential mechanisms that link n-3 PUFAs and mental health: (1) Inflammation & Oxidative Stress (2) Microbiota & Immune System (3) Nervous System. In addition, n-3 PUFAs have been used as a treatment for several common psychiatric disorders, including depression, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and dementia. This chapter provides a brief overview of the most updated basic and clinical research findings of n-3 PUFAs in psychiatric disorders. Last but not least, clinical guidelines and the level of evidence of n-3 PUFAs in psychiatric disorders will also be featured in the chapter.
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Somatic symptom disturbance is among the strongest predictors of painful temporomandibular disorder (TMD). Related psychological constructs, such as anxiety and depression, respond therapeutically to omega-3 polyunsaturated fatty acids (PUFAs) in clinical trials. This cross-sectional study investigated associations between the omega-6/omega-3 PUFA ratio and somatic symptom disturbance and depressive symptoms in a community-based sample of 501 adults and determined whether these associations differed between adults with and without TMD or irritable bowel syndrome (IBS). Liquid chromatography tandem mass spectrometry quantified PUFAs in circulating erythrocytes. Somatic symptoms and depression were quantified using Symptom Checklist-90-Revised subscales. Presence or absence of TMD and IBS, respectively, were determined by clinical examination and Rome III screening questions. The standardized beta coefficient for the omega-6/omega-3 long-chain PUFA ratio was 0.26 (95% confidence limits (CL): 0.08, 0.43) in a multivariable linear regression model in which somatic symptom disturbance was the dependent variable. When modelling depressive symptoms as the dependent variable, the standardized beta coefficient was 0.17 (95% CL:0.01, 0.34). Both associations were stronger among TMD cases and IBS cases than among non-cases. Future randomized control trials that lower the omega-6/omega-3 PUFA ratio could consider somatic or depressive symptoms as a therapeutic target for TMD or IBS pain. Perspective : In people with painful TMD or IBS, a high ratio of n-6/n-3 PUFA was positively associated with somatic symptom disturbance and depressive symptoms. Both measures of psychological distress were elevated in people with painful TMD and IBS. Future randomized clinical trials will determine whether lowering the n-6/n-3 ratio is therapeutic for pain.
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Polyunsaturated and monounsaturated fatty acids, respectively known as PUFA and MUFA, are considered bioactive compounds. Nuts and seeds, fish, and other marine products are the main sources of PUFA and MUFA. Epidemiological studies support many health benefits of PUFA and MUFA. Accordingly, this contribution summarizes the general chemical aspects as well as the reported health benefits in cell model systems, animals, and humans attributed to these compounds. The main biological mechanisms involved in the role of MUFA and PUFA are provided and discussed. The protective role of these compounds against cardiovascular diseases has been widely recognized in previous works. However, more studies are needed regarding potential health benefits of MUFA and PUFA against diabetes, cancer, Alzheimer’s disease, and dementia due to current controversies.
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Carotenoids are lipophilic natural yellow to red pigments found in fruits and vegetables. The chemical molecules of these bioactive compounds comprise an extensive chain of conjugated double bonds responsible for the color and their reactivity and antioxidant activity, which are related to several health benefits. The mechanisms of action of the dietary carotenoids will be presented in this chapter considering the existent scientific evidence based on experimental protocols using in vitro assays, animal models, and clinical trials.
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Objective: Clinical trials and inconclusive meta-analyses have investigated the effects of omega-3 supplements in children with Attention-Deficit Hyperactivity Disorder (ADHD). We performed a randomised placebo-controlled trial to evaluate the efficacy of omega-3 fatty acids. Methods: Children aged 6-15 years with established diagnosis of ADHD were randomised 1:1 to receive either supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or a placebo for 3 months. Psychotropic or omega-3-containing treatments were not authorised during the study. The primary outcome was the change in the Attention-Deficit Hyperactivity Disorder Rating Scale version 4 (ADHD-RS-IV). Other outcomes included safety, lexical level (Alouette test), attention (Test of Attentional Performance for Children-KiTAP), anxiety (48-item Conners Parent Rating Scale-Revised-CPRS-R), and depression (Children's Depression Inventory-CDI). Results: Between 2009 and 2011, 162 children were included in five French child psychiatry centres. The mean age was 9.90 (SD 2.62) years and 78.4% were boys. The inclusion ADHD-RS-IV at was 37.31 (SD 8.40). The total ADHD-RS-IV score reduction was greater in the placebo group than in the DHA-EPA group: -19 (-26, -12) % and -9.7 (-16.6, -2.9) %, respectively, p = 0.039. The other components of the Conners score had a similar variation but the differences between groups were not significant. Two patients in the DHA-EPA group and none in the placebo group experienced a severe adverse event (hospitalisation for worsening ADHD symptoms). Conclusion: This study did not show any beneficial effect of omega-3 supplement in children with mild ADHD symptoms.
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Background: Omega-3 (or n-3) polyunsaturated fatty acids (PUFAs) are promising antidepressant treatments for perinatal depression (PND) because of supporting evidence from clinical trials, the advantage in safety, and their anti-inflammatory and neuroplastic effects. Although several observational studies have shown n-3 PUFA deficits in women with PND, the results of individual PUFAs from different studies were inconsistent. Methods: This systematic review and meta-analysis aims to compare the levels of PUFA indices, including eicosapentaenoic acid, docosahexaenoic acid, arachidonic acid, total n-3, total n-6, and the n-6/n-3 ratio between women with PND and healthy control subjects. The meta-analysis included 12 eligible studies available as of December 2016. The effect sizes were synthesized by using a random effects model. In addition, we performed subgroup analysis for the PUFA levels in patients with prenatal and postnatal depression, both of which were compared with healthy control subjects. Results: There were significantly lower levels of total n-3 PUFAs and docosahexaenoic acid and significantly increased n-6/n-3 ratios in PND patients. In the subgroup analyses, there were significantly lower levels of n-3 PUFAs, eicosapentaenoic acid, and docosahexaenoic acid in women with prenatal depression. The n-6/n-3 ratio was significantly increased in both prenatal and postnatal depression subgroups. Conclusions: Our meta-analysis consolidates the important role of n-3 PUFAs in PND. Nutritional medicine is an important strategy to improve the effectiveness of treatment for depression, and our findings provide the strong rationale to conduct clinical trials to test the therapeutic and prophylactic effects of n-3 PUFAs in PND.
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Background: Eicosapentaenoic acid (EPA) is suggested to be protective against posttraumatic stress disorder (PTSD) from two observational studies. We previously conducted a randomized controlled trial and found no effect of docosahexaenoic acid (DHA) for prevention of PTSD. This secondary analysis aimed to determine whether change in blood levels of EPA is associated with PTSD symptoms. Methods: The percentages of EPA, DHA, and arachidonic acid (AA) were measured in erythrocyte membranes at baseline and posttreatment in 110 participants with severe physical injury who were randomly assigned to receive either a daily dose of 1,470mg DHA and 147mg EPA or of placebo for 12 weeks. Associations between change in erythrocyte fatty acid levels during the trial controlling for each baseline level and PTSD severity at 12 weeks were analyzed by treatment arm. Results: In the omega3 supplements arm, changes in EPA+DHA (p=.023) and EPA (p=.001) as well as the EPA:AA ratio (p=.000) and EPA: DHA ratio (p=.013) were inversely correlated with PTSD severity. Change in AA was positively correlated with PTSD severity (p=.001). Limitation: This trial was conducted at a single-center in Japan and PTSD symptoms in most participants were not serious. Conclusions: Increased erythrocyte level of EPA during the trial was associated with low severity of PTSD symptoms in patients receiving omega3 supplements.
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A new application for omega-3 fatty acids has recently emerged, concerning the treatment of several mental disorders. This indication is supported by data of neurobiological research, as highly unsaturated fatty acids (HUFAs) are highly concentrated in neural phospholipids and are important components of the neuronal cell membrane. They modulate the mechanisms of brain cell signaling, including the dopaminergic and serotonergic pathways. The aim of this review is to provide a complete and updated account of the empirical evidence of the efficacy and safety that are currently available for omega-3 fatty acids in the treatment of psychiatric disorders. The main evidence for the effectiveness of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has been obtained in mood disorders, in particular in the treatment of depressive symptoms in unipolar and bipolar depression. There is some evidence to support the use of omega-3 fatty acids in the treatment of conditions characterized by a high level of impulsivity and aggression and borderline personality disorders. In patients with attention deficit hyperactivity disorder, small-to-modest effects of omega-3 HUFAs have been found. The most promising results have been reported by studies using high doses of EPA or the association of omega-3 and omega-6 fatty acids. In schizophrenia, current data are not conclusive and do not allow us either to refuse or support the indication of omega-3 fatty acids. For the remaining psychiatric disturbances, including autism spectrum disorders, anxiety disorders, obsessive-compulsive disorder, eating disorders and substance use disorder, the data are too scarce to draw any conclusion. Concerning tolerability, several studies concluded that omega-3 can be considered safe and well tolerated at doses up to 5 g/day.
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The efficacy of omega-3 fatty acids for maintaining a better mental state has not been examined among working populations. We aimed to explore the effectiveness of omega-3 fatty acids for hospital nurses. In a multi-center randomized trial, 80 junior nurses were randomly allocated to either omega-3 fatty acids (1200 mg/day of eicosapentaenoic acid and 600 mg/day of docosahexaenoic acid) or identical placebo pills for 13 weeks. The primary outcome was the total score of the Hospital Anxiety and Depression Scale (HADS), determined by a blinded rater at week 26 from the study enrolment. Secondary outcomes included the total score of the HADS at 13 and 52 weeks; incidence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism; utility scores; and adverse events at 13, 26 and 52 weeks. The mean HADS score at baseline was 7.2. At 26 weeks, adjusted mean scores on the HADS were 6.32 (95% CIs of standard errors: 5.13, 7.52) in the intervention and 6.81 (5.57, 8.05) in the placebo groups, respectively. The coefficient of the group by time interaction was not statistically significant at 0.58 (-1.35, 2.50; P = 0.557). Although the intervention group showed significant superiority on the HADS score at 52 weeks, depression severity at 52 weeks, insomnia severity at 13 weeks, and absolute presenteeism at 26 weeks, no significant superiority or inferiority was observed on the other outcomes. The additive value of omega-3 fatty acids was not confirmed regarding mental state and self-evaluated work efficiency.
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Anxiety symptoms and disorders are common in community settings and primary and secondary care. Symptoms can be mild and transient, but many people are troubled by severe symptoms causing great personal distress and impairing social and occupational function. The societal burden from anxiety disorders is considerable, but many who might benefit from treatment are not recognized or treated by healthcare professionals. Some patients, however, are given unnecessary or inappropriate treatment. Recognition relies on keen awareness of the psychological and physical symptoms of all anxiety disorders, and accurate diagnosis on identification of the specific features of particular disorders. Need for treatment is determined by the severity and persistence of symptoms, level of associated disability and impact on everyday life, presence of coexisting depressive symptoms, and other features such as good response to or poor tolerability of previous treatments. Choice of treatment is influenced by patient characteristics, patient and doctor preferences, and local availability of potential interventions. There is much overlap between different anxiety disorders in evidence-based and effective therapies (e.g. prescription of a selective serotonin reuptake inhibitor or course of individual cognitive behavioural therapy), but there are important differences. It thus helps to become familiar with the characteristic features and evidence base for each disorder.
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Background: Although fatty acid (FA)-supplementation studies are currently being implemented, in fact little is known about FA-profiles in posttraumatic stress disorder (PTSD). Therefore, the present study aimed at comparing FA-concentrations between PTSD-patients and healthy controls. Methods: A cross-sectional study comparing a mixed-gender sample of 49 patients with PTSD due to civilian trauma to 46 healthy controls regarding erythrocyte FAs including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (AA), and nervonic acid (NA). Results: DHA was found to be significantly lower in PTSD-patients compared to controls after adjusting for sociodemographic and dietary factors (p =0.043). Additionally, exploratory analyses showed lower vaccenic acid (p =0.035) and eicosatrienoic acid (p =0.006), but higher erucic acid (p =0.032) in PTSD-patients. The effect of erucic acid remained after adjustment for sociodemographic factors (p =0.047); with the additional adjustment for dietary factors none of these FAs were found to be significant. Limitations: Statistical power for differences with small effect sizes was limited, and dietary assessment could be optimized. Conclusions: We found little evidence for a considerable role of FA-metabolism in PTSD. Apart from lower DHA after adjusting for confounders, no differences were observed in the hypothesized long-chained polyunsaturated FA-concentrations. Additionally, we found few alterations in the long-chained monounsaturated FAs, which may be explained by dietary factors. Nevertheless, the observed small effect sizes and limited extent of the alterations emphasize the importance of further investigating the assumed role of FA-metabolism and its underlying mechanisms in PTSD, before implementing further FA-supplementation studies.
Article
Background: Psychophysiological symptoms (e.g., pounding heart) are known to be a prominent feature of post-traumatic stress disorder (PTSD). Although omega-3 polyunsaturated fatty acids (PUFAs) have a beneficial potential pharmacological effect of preventing these psychophysiological symptoms, no clinical data is yet available. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of Japanese accident survivors. Methods: A total of 83 participants received either omega-3 PUFAs (1470mg docosahexaenoic acid and 147mg eicosapentaenoic acid per day) or placebo within 10 days of the accidental injury. After 12-week supplementation, participants performed script-driven imagery of their traumatic event during monitoring of their heart rate and skin conductance. Results: Analysis revealed that heart rate during both rest and script-driven imagery was significantly lower in the omega-3 group than the placebo group, whereas baseline heart rate was comparable between the two groups. Limitations: The present trial was conducted at a single-center in Japan and psychophysiological symptoms of PTSD in most participants were not serious. Conclusion: These findings suggest that post-trauma supplementation of omega-3 PUFAs might be effective for the secondary prevention of psychophysiological symptoms of PTSD.