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. 2022 Aug 30;13(6):2217–2236. doi: 10.1093/advances/nmac084

Unsaturated Fatty Acids in Mental Disorders: An Umbrella Review of Meta‐Analyses

Xuping Gao 1,2, Xin Su 3, Xue Han 4, Huiyan Wen 5, Chen Cheng 6, Shiwen Zhang 7, Wanlin Li 8, Jun Cai 9, Lu Zheng 10, Junrong Ma 11, Minqi Liao 12, Wanze Ni 13, Tao Liu 14, Dan Liu 15, Wenjun Ma 16, Shasha Han 17, Sui Zhu 18, Yanbin Ye 19,, Fang-fang Zeng 20,
PMCID: PMC9776730  PMID: 36041185

ABSTRACT

Unsaturated fatty acids might be involved in the prevention of and improvement in mental disorders, but the evidence on these associations has not been comprehensively assessed. This umbrella review aimed to appraise the credibility of published evidence evaluating the associations between unsaturated fatty acids and mental disorders. In this umbrella review, systematic reviews and meta-analyses of studies comparing unsaturated fatty acids (including supplementation, dietary intake, and blood concentrations) in participants with mental disorders with healthy individuals were included. We reanalyzed summary estimates, between-study heterogeneity, predictive intervals, publication bias, small-study effects, and excess significance bias for each meta-analysis. Ninety-five meta-analyses from 29 systematic reviews were included, encompassing 43 studies on supplementation interventions, 32 studies on dietary factors, and 20 studies on blood biomarkers. Suggestive evidence was only observed for dietary intake, in which higher intake of fish was associated with reduced risk of depression (RR: 0.78; 95% CI: 0.69, 0.89) and Alzheimer disease (RR: 0.74; 95% CI: 0.63, 0.87), and higher intake of total PUFAs might be associated with a lower risk of mild cognitive impairment (RR: 0.71; 95% CI: 0.61, 0.84). Evidence showed that PUFA supplementation was favorable but had weak credibility in anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), dementia, mild cognitive impairment, Huntington's disease, and schizophrenia (P-random effects <0.001–0.040). There was also weak evidence on the effect of decreased circulating n–3 (ɷ-3) PUFAs among patients on risk of ADHD, ASD, bipolar disorder, and schizophrenia (P-random effects <10−6–0.037). Our results suggest that higher levels of unsaturated fatty acids may relieve symptoms or reduce the risk of various mental disorders; however, the strength of the associations and credibility of the evidence were generally weak. Future high-quality research is needed to identify whether PUFA interventions should be prioritized to alleviate mental disorders.

Keywords: mental disorders, unsaturated fatty acids, n–3 PUFA, umbrella review, meta-analysis


Statement of Significance: The credibility of published evidence on the association between unsaturated fatty acids and mental disorders remains controversial. Our findings suggest the overall credibility of evidence is low, in which suggestive/weak evidence indicates the protective effect of high consumption of unsaturated fatty acids or fish and weak evidence indicates the broad differences in circulating unsaturated fatty acids and the potential value of omega-3 polyunsaturated fatty acid supplementation interventions for various mental disorders.

Introduction

Currently, mental disorders remain among the top 10 leading causes of disease burden worldwide (1). The Global Burden of Diseases Study (GBD) 2019 showed that the proportion of global disability-adjusted life-years (DALYs) attributed to mental disorders increased from 3.1% to 4.9% between 1990 and 2019 (1). In 2020, only 52% of the WHO's 194 member states met the target related to mental health promotion and prevention programs, which was considerably below the 80% target (2). The global conflict between the increasing burden of mental disorders and the insufficient investment in mental health highlights the growing need to evaluate effective prevention and management strategies for mental disorders (1–3).

Unsaturated fatty acids, as one of the most important dietary nutrients, might be associated with neurodevelopment and brain function, as well as behavior and mental health (4, 5). Characterized by the number and position of double carbon bonds, unsaturated fatty acids include MUFAs, n–3 PUFAs [including ɑ-linolenic acid (ALA; 18:3n−3), EPA, and DHA], and n–6 PUFAs [including linoleic acid (LA; 18:2n–6) and arachidonic acid (AA; 20:4n−6)]. In early life, obtaining adequate DHA and AA from the mother is essential for the myelination and proper neurodevelopment of the fetus (6, 7). In addition, n–3 PUFAs and n–6 PUFAs are highly enriched in brain tissue (8) and participate in numerous biological processes in the brain (e.g., metabolism, neurotransmission, synaptogenesis, and inflammation) (4, 5, 9, 10). Various mental disorders such as Alzheimer disease (AD), dementia, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), mood disorders, and schizophrenia have been suggested to be associated with altered levels and functions related to unsaturated fatty acids in the brain (8, 11–15).

To date, a large number of meta‐analyses have been conducted to assess the role of unsaturated fatty acids in mental disorders from multiple perspectives, but the available evidence remains controversial. The assessment of various kinds of bias (e.g., publication bias, reporting bias, residual confounding bias, and researcher allegiance) in these meta-analyses was often insufficient (16), which might result in overestimated efficacy or false significance (17, 18). Moreover, the appraisal of the evidence has not been formally determined across different mental disorders. To overcome these limitations, we conducted an umbrella review of the relevant meta-analyses, which have increasingly consolidated the highest level of evidence on this topic (19). We aimed to systemically assess the role of unsaturated fatty acids as alternative or complementary (adjunctive) interventions, dietary factors, or peripheral biomarkers for various mental disorders, and generate hierarchies of evidence.

Methods

Literature search strategy and eligibility criteria

We conducted an umbrella review to systematically review and evaluate all available systematic reviews and meta-analyses on the topic of unsaturated fatty acids in mental disorders. PubMed, Embase, PsycINFO, and the Cochrane Database of Systematic Reviews were searched for papers published between database inception and 20 April 2022, and no language restriction was applied. The complete search strategy is provided in the Supplemental Methods. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (20), 2 investigators (XG and XS) independently screened titles, abstracts, and full texts to identify potentially relevant systematic reviews (Figure 1). We also manually searched the reference lists from relevant studies to reduce missing records in database searches. In case of discrepancies, a third investigator (FZ) was involved, and consensus was reached by discussion.

FIGURE 1.

FIGURE 1

Study selection profile.

We included systematic reviews and meta-analyses that evaluated the role of unsaturated fatty acids as interventions, risk factors, or biomarkers for all types of mental disorders and evaluations of unsaturated fatty acids, including but not limited to nutritional supplements, dietary intake, or blood concentrations. For eligible systematic reviews, mental disorders should be assessed using structured psychiatric diagnostic interviews or validated or commonly used rating scales. Systematic reviews without study-level effect sizes and 95% CIs were excluded. When 2 or more systematic reviews existed for the same association or comparison, we included the most recent systematic review with the largest number of individual studies providing study-level estimates, in agreement with umbrella review methodology (21). For systematic reviews that did not report sufficient data for reanalysis, we contacted the corresponding authors to obtain the necessary data.

Data extraction and quality assessment

From each included systematic review, we extracted information on the first author, publication year, number of included studies, outcomes, reported unsaturated fatty acids, and summary meta-analytic estimates. The following information was extracted from each individual study: publication year, study design (i.e., cohort design, case–control design, or clinical trial design), population (i.e., children, adolescents, middle-aged adults, or older adults), sample size, reported unsaturated fatty acids, outcomes and corresponding assessment criteria, and maximally adjusted study-specific estimates [i.e., mean difference (MD), standardized mean difference (SMD; including Hedges’ g and Cohen's d), OR, or RR] with 95% CIs.

The methodological quality of the included systematic reviews was critically appraised using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews), a 16-item rating scale with good interrater reliability and usability (22). AMSTAR 2 is not intended to generate an overall score; instead, it rates the confidence of systematic reviews into 4 broad categories (high, moderate, low, and critically low) based on review design, literature screening, data extraction, and individual study quality assessment (22).

Data analysis

We followed the analytic approach that was developed and reproduced in previous umbrella reviews (23–26). The pooled effect size, 95% CI, and P value of each meta-analysis were re-estimated in their original form under random-effects models using the DerSimonian and Laird method (27). The statistical significance P-value threshold of pooled effect estimates was set at <0.05, and additional P-value thresholds were set at <10−3 and <10−6 to assess the credibility of evidence (28, 29). For between-study heterogeneity, we performed Cochran's Q tests (30) (P < 0.10 indicated the existence of heterogeneity) and calculated the I2 statistic (31) (I2 ≥ 50% represented high inconsistency).

To enable comparison of the effects of various interventions on the same outcome, we further re-estimated unstandardized MDs as SMDs by the method of Cohen and converted all SMDs into equivalent ORs based on Hasselblad and Hedges’ method (32–34). Subsequently, we estimated the 95% prediction intervals, which specify the uncertainty as to whether the effect will persist in a future study examining the same research question (35, 36). Prediction intervals excluding the null value (i.e., 1 in the case of RRs or ORs) infer that the effect would be expected in a new study (35, 36). Egger's regression asymmetry test was used to identify potential publication bias (37). The presence of small-study effects was established at an Egger's P < 0.10, with the estimate of the largest component study (the study with the smallest SE) being more conservative than the summary estimate based on random-effects models (23–26).

We evaluated the excess significance to examine whether the observed number of studies (O) with nominally statistically significant results (P < 0.05) in each meta-analysis was larger than their expected number (E) (38). For each meta-analysis, the expected number of significant studies was estimated from the sum of the statistical power estimates for each individual study (26), using an algorithm from a noncentral t distribution and the effect size of the largest study in each meta-analysis as the plausible power for the tested association (39). For each meta-analysis, the significance threshold of the excess significance bias was set at P < 0.10. Excess significance for single meta-analysis was established at P < 0.10 (1-sided P < 0.05 with O > E, as previously proposed). All statistical analyses were performed using Stata version 14.0 (StataCorp). The P values were all 2-tailed.

Determining the credibility of evidence

In accordance with previous umbrella reviews (23–26, 40), the following criteria were used to determine the level of evidence: 1) P < 10−6 based on random-effects meta-analysis, 2) >1000 participants, 3) P < 0.05 of the largest study, 4) between-study heterogeneity with I² < 50%, 5) no evidence of small-study effects, 6) 95% prediction interval that excluded the null value, and 7) no excess significance bias. Based on the results of statistical analyses, we categorized the credibility of each evidence as class I (convincing evidence that met all criteria), class II (highly suggestive evidence that met 1 to 3 of the criteria), class III (suggestive evidence criteria that required only a P < 0.001 by random-effects and >1000 participants), class IV (weak evidence that required only a P < 0.05 under random-effects), and no significant evidence (P ≥ 0.05 under random-effects).

Results

A total of 2714 records were identified through a systematic database search. After duplicate removal and the inspection of titles and abstracts, 127 full-text articles were screened for eligibility. Ultimately, 29 systematic reviews involving 96 meta-analyses met the umbrella review inclusion criteria and were included for reanalysis (Figure 1) (11–15, 41–64). Details of the excluded reviews with the reasons for exclusion are provided in the Supplemental Results. From the included systematic reviews, we extracted information on the role of the assessed unsaturated fatty acids and mental disorders of interest (Table 1). Among these systematic reviews, 43 meta-analyses assessed the efficacy of unsaturated fatty acid supplementation interventions, 32 meta-analyses assessed the effect of unsaturated fatty acid intake, and 20 meta-analyses assessed differences in peripheral unsaturated fatty acid concentrations between healthy controls and patients with mental disorders.

TABLE 1.

Characteristics and quality assessments of eligible meta-analyses evaluating the associations between unsaturated fatty acids and mental disorders1

Study, year (ref) Population Mental disorders Outcomes Outcome assessments No. of studies (participants, n) Study design Intervention/comparison Effect metrics AMSTAR 2 rating2
Unsaturated fatty acids supplementation
 Xu et al., 2022 (64) Adults Schizophrenia Symptoms Positive and Negative Syndrome Scale 6 (317) Randomized controlled studies EPA/DHA/EPA+DHA vs. placebo MD ●●○○Low
 Appleton et al., 2021 (56) Adults Depression Depressive symptoms, adverse events, quality of life Beck Depression Inventory, Montgomery Asberg Depression Rating Scale, Hamilton Depression Rating Scale, and others 34 (1924) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD, OR ●●●●High
 de Andrade Wobido et al., 2021 (57) Children Autism spectrum disorder Symptoms Aberrant Behavior Checklist, Social Responsiveness Scale 13 (372) Clinical trial, community trial n–3 and n–6 fatty acids supplementation vs. placebo SMD ●●●●High
 Goh et al., 2021 (58) Adults Schizophrenia Symptoms Positive and Negative Syndrome Scale and General Psychopathology Scale 14 (950) Randomized controlled studies n–3 fatty acids supplementation vs. placebo or non-supplementation SMD ●●●●High
 Händel et al., 2021 (59) Children Attention-deficit/hyperactivity disorder Symptoms, behavioral difficulties, quality of life Multiple psychopathology scales assessed the parent-reported core symptoms, teacher-reported core symptoms, parent-reported behavioral difficulties, teacher-reported behavioral difficulties, quality of life (including diarrhea, gastrointestinal discomfort, and nausea) 31 (1775) Randomized controlled studies n–3 and n–6 fatty acids supplementation vs. placebo and/or regular diet SMD ●●●●High
 Suradom et al., 2021 (60) Pregnant and postpartum women Depression Prevention and treatment of depression severity Edinburgh Postnatal Depression Scale, Postpartum Depression Screening Scale,Center for Epidemiological Studies–Depression Scale 11 (3181) Randomized controlled studies n–3 and n–6 fatty acids supplementation vs. placebo SMD ●●○○Low
 Xu et al., 2021 (61) Elderly Mild cognitive impairment Symptoms Mini-Mental State Examination 3 (96) Randomized controlled studies Unsaturated fatty acids vs. antioxidant or non-supplementation MD ●○○○Critically low
 Araya-Quintanilla et al., 2020 (52) The elderly Alzheimer disease Symptoms Narcissistic Personality Inventor, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale–Cognitive section 6 (758) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD ●○○○Critically low
 Luo et al., 2020 (53) Adults Depression Depressive symptoms Hamilton Depression Rating Scale or others 10 (910) Randomized controlled studies n–3 and n–6 fatty acids supplementation (≥2000 mg/d and <2000 mg/d) vs. placebo SMD ●○○○Critically low
 Mocking et al., 2020 (54) Pregnant and postpartum women Perinatal and postpartum depression Depressive symptoms Edinburgh Postnatal Depression Scale; Hamilton Depression Rating Scale; Montgomery-Asberg Depression Rating Scale, or others 18 (4052) Randomized controlled studies n–3 and n–6 fatty acids supplementation vs. placebo or regular diet SMD ●●●●High
 Zhang et al., 2020 (55) The elderly Mild cognition decline Cognition Mini-Mental State Examination 7 (434) Randomized controlled studies n–3 and n–6 fatty acids supplementation vs. placebo WMD ●○○○Critically low
 Devoe et al., 2019 (48) Youth (age between 13 and 33) Psychosis Symptoms Scale for the Assessment of Positive Symptoms, Brief Psychiatric Rating Scale, the Positive and Negative Syndrome Scale, the Scale of Prodromal Symptoms, and the Comprehensive Assessment of At-Risk Mental States 3 (347) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD ●●○○Low
 Morsy et al., 2019 (49) Adults Huntington's disease Total motor score; total motor score-4 Unified Huntington disease rating scale (UHDRS) or other evaluations 4 (782) Randomized controlled studies Ethyl-EPA vs. placebo MD ●●●○Medium
 Zhang et al., 2019 (51) Children Depression Depressive symptoms The Children's Depression Rating Scale (CDRS), revised CDRS, Beck Depression Inventory, and Children's Depression Inventory 4 (153) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD ●○○○Critically low
 Su et al., 2018 (47) Adults Anxiety Symptoms Clinician-administered post-traumatic stress disorder scale, Child Behavior Checklist anxiety subscale, children's Yale-Brown obsessive-compulsive scale, depression, anxiety, and stress scales, generalized anxiety disorder questionnaire, Hospital Anxiety and Depression Scale anxiety subscale, Hamilton anxiety rating scale, impact of event scale–revised, and Yale-Brown obsessive-compulsive scale 19 (1203) Clinical trials n–3 fatty acids supplementation vs. placebo or education Hedges' g ●●●●High
 Rosenblat et al., 2016 (45) Adults Bipolar depression Symptoms Bipolar Depression Rating Scale, Clinical Global Impressions Scale, Clinical Global Impressions Scale–Improvement–Bipolar, Clinical Global Impressions Scale–Improvement–Depression, Clinical Global Impressions Scale–Improvement–Mania, Clinical Global Impressions Scale–Severity–Bipolar, Clinical Global Impressions Scale–Severity–Depression, Clinical Global Impressions Scale–Severity–Mania, Hamilton Depression Rating Scale, Inventory of Depressive Symptomatology–Clinical Rating Scale, Montgomery–Asberg Depression Rating Scale, Quality of Life Enjoyment and Satisfaction Scale, Social and Occupational Functioning Assessment Scale, and Young Mania Rating Scale 4 (140) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD ●●○○Low
 Tan et al., 2016 (46) Children Specific learning disorders Adverse effects (gastrointestinal disturbances) 2 (116) Randomized controlled studies, quasi-RCTs PUFA vs. placebo RR ●●●●High
 Cooper et al., 2015 (42) Children Attention-deficit/hyperactivity disorder Symptoms and brain functions Wechsler Intelligence Scale for Children, test of variables of attention, digit span backwards (recalling a string of numbers backwards), immediate or delayed word recall, Wide Range Achievement Test, or others 24 (8658) Randomized controlled studies n–3 fatty acids supplementation vs. placebo SMD ●○○○Critically low
 Yang et al., 2015 (43) Women Depression Depressive symptoms Comprehensive evaluation (including Montgomery–Asberg Depression Rating Scale, Hamilton Depression Rating Scale, Clinical Global Impression, Beck Depression Inventory, or Geriatric Depression Scale) 8 (267) Randomized controlled studies DHA and EPA vs. placebo SMD ●●●●High
Dietary unsaturated fatty acids intake
 Kosti et al., 2022 (63) The elderly Dementia,Alzheimer disease Risk of dementia/Alzheimer disease Cambridge Mental Disorders of the Elderly Examination, Clinical Dementia Rating Diagnostic and Statistical Manual of Mental Disorders-III-Revised, Geriatric Mental State Schedule, Mini-Mental State Examination Wechsler Memory Scale Revised 9 (440,572) Cohort Highest intake of fish vs. reference group RR ●●●●High
 Zhu et al., 2021 (62) The elderly Alzheimer disease Risk of Alzheimer disease NR 14 (54,177) Cohort Highest intake of n–3 fatty acids vs. reference group RR ●●○○Low
 Qu et al., 2019 (50) Adults Parkinson disease Risk of Parkinson disease NR 9 (778,571) Cohort, case-control Highest intake of n–3 and n–6 fatty acids vs. reference group RR ●○○○Critically low
 Grosso et al., 2016 (44) Adults Depression Risk of depression Center for Epidemiologic Studies–Depression, Composite International Diagnostic Interview Short Form, Depression, Anxiety and Stress Scales, Geriatric Depression Scale, Edinburgh Post-partum Depression Scale, and Munich-Composite International Diagnostic Interview 16:15 (255,076) Cohort, case-control Highest intake of n–3 fatty acids and fish vs. reference group RR ●○○○Critically low
 Zhang et al., 2016 (15) The elderly Alzheimer disease; cognitive decline; dementia; mild cognitive impairment; Parkinson disease Risk of cognitive impairment NR 21 (181,580) Cohort Highest intake of n–3 fatty acids and fish vs. reference group RR ●●●●High
 Tsai et al., 2014 (41) Adults Suicide Suicide mortality 3 (205,357) Cohort Highest intake of n–3 or n–6 fatty acids vs. reference group RR ●○○○Critically low
Circulating unsaturated fatty acids
 Mazahery et al., 2017 (11) Children Autism spectrum disorder Circulating n–3, n–6 fatty acids and ratios between n–3/n–6 fatty acids 15 (1193) Case-control Autism spectrum disorder vs. typically developing control SMD ●●●●High
 McNamara et al., 2016 (12) Youth Bipolar disorder Circulating n–3 and n–6 fatty acids 6 (265) Case-control Bipolar disorder vs. typically developing control SMD ●○○○Critically low
 Zhang et al., 2016 (15) The elderly Alzheimer disease; dementia; cognitive decline Risk of cognitive impairment 21 (181,580) Cohort A 1% increment of blood DHA concentrations RR ●●●●High
 Hawkey et al., 2014 (13) Children Attention-deficit/hyperactivity disorder Circulating n–3 fatty acids 9 (586) Case-control Attention-deficit/hyperactivity disorder vs. typically developing control Hedges' g ●●●○Medium
 van der Kemp et al., 2012 (14) The elderly Schizophrenia Circulating n–3 and n–6 fatty acids 14 (873) Cohort, case-control Schizophrenia vs. typically developing control Cohen's d ●○○○Critically low
1

AMSTAR 2, A Measurement Tool to Assess Systematic Reviews; MD, mean difference; NR, not reported; RCT, randomized controlled trial; ref, reference; SMD, standardized mean difference; WMD, weighted mean difference.

2

AMSTAR 2 used 16 items to assess methodological quality of systematic reviews on the basis of the validity of review design, literature screening, data extraction, and individual study quality assessment. Details of the quality assessment for eligible reviews were provided in Supplemental Table 1.

Of the 29 systematic reviews identified, 11 had high-quality ratings according to the AMSTAR 2 scoring system (11, 15, 43, 46, 47, 54, 56–59, 63), 2 had moderate quality ratings (13, 49), and 16 received a low or critically low-quality rating (Table 1) (12, 14, 41, 42, 44, 45, 48, 50–53, 55, 60–62, 64). AMSTAR 2 detected that, in 8 reviews, the methods were not established prior to the conduct of the review and 10 reviews did not provide the list of excluded studies with justification of the exclusions (details are reported in Supplemental Table 1).

Unsaturated fatty acid supplementation interventions for mental disorders

A total of 43 meta-analyses assessed the efficacy of unsaturated fatty acid supplementation on improving mental disorders, including AD, mild cognitive impairment, anxiety, bipolar disorder (BP), depression, perinatal depression, postpartum depression, ADHD, ASD, specific learning disorders, Huntington's disease, schizophrenia, and psychosis. However, only 12 reanalyses reported a nominally statistically significant summary effect using random-effects models (P < 0.05), and only one 95% prediction interval excluded the null value (Table 2). Significant heterogeneity (I2 > 50%) was observed in all statistically significant comparisons, with the exception of the meta-analysis on the efficacy of an n–3 PUFA or n–6 PUFA supplementation intervention for ASD, Huntington's disease, and schizophrenia (Table 2). The risk of small-study effects bias was observed in 2 comparisons, whereas excess of significance bias was detected in 8 comparisons. However, 17 comparisons consisted of less than 5 individual studies, in which case the power of the test was reduced.

TABLE 2.

Quantitative synthesis and evidence grading for meta‐analyses of unsaturated fatty acids supplementation interventions for participants with mental disorders1

Study, year (ref) Mental disorders Outcomes Unsaturated fatty acids supplementation No. of studies (participants, n) Original effect metrics Random-effects summary estimate (95% CI) Random-effects P I 2, % Converted as equivalent OR (95% CI) 95% Prediction interval Egger's test> P Largest study estimate (95% CI) Significant studies Grading
O/E P
Xu et al., 2022 (64) Schizophrenia Positive and Negative Syndrome Scale total scores EPA/DHA/EPA+DHA 6 (317) MD −3.274 (−5.449, −1.098) 0.003 22.2 0.326 (0.061, 1.751) (0.001, 144.492) 0.22 1.11 (0.49, 2.52) 1/0.33 0.29 Not significant
Appleton et al., 2021 (56) Depression Depressive symptoms Total n–3 PUFAs 33 (1848) SMD −0.401 (−0.642, −0.160) 0.001 80.7 0.484 (0.313, 0.748) (0.052, 4.482) 0.05 0.83 (0.59, 1.18) 10/2.16 <10−3 Weak
Quality of life Total n–3 PUFAs 12 (476) SMD −0.376 (−0.816, 0.063) 0.093 78.9 0.506 (0.228, 1.121) (0.029, 8.799) 0.26 1.63 (0.72, 3.68) 5/1.52 0.01 Not significant
Adverse events Total n–3 PUFAs 24 (1503) OR 1.267 (0.977, 1.644) 0.075 5.7 (0.840, 1.912) 0.48 1.26 (0.83, 1.91) 2/1.70 0.69 Not significant
de Andrade Wobido et al., 2021 (57) Autism spectrum disorder Aberrant Behavior Checklist Total n–3 and n–6 PUFAs 5 (183) SMD −0.183 (−0.341, −0.025) 0.023 0.0 0.718 (0.540, 0.955) (0.531, 0.970) 0.80 0.79 (0.31, 2.03) 1/1.46 Weak
Social Responsiveness Scale Total n–3 and n–6 PUFAs 5 (238) SMD −0.059 (−0.239, 0.122) 0.524 46.2 0.953 (0.691, 1.314) (0.337, 2.694) <0.01 1.88 (1.36, 4.83) 1/4.11 Not significant
Goh et al., 2021 (58) Schizophrenia Positive and Negative Syndrome Scale total scores Total n–3 PUFAs 9 (443) SMD −0.295 (−0.527, −0.064) 0.012 28.1 0.586 (0.386, 0.891) (0.230, 1.497) 0.81 1.18 (0.55, 2.52) 3/0.55 0.01 Weak
Positive and Negative Syndrome Scale– Positive scale Total n–3 PUFAs 6 (266) SMD −0.105 (−0.349, 0.139) 0.400 0.0 0.827 (0.531, 1.287) (0.442, 1.547) 0.86 0.82 (0.38, 1.75) 0/0.38 Not significant
Positive and Negative Syndrome Scale–Negative scale Total n–3 PUFAs 3 (195) SMD 1.193 (−0.654, 3.039) 0.205 96.7 8.661 (0.306, 245.036) (<0.001, >1000) 0.08 0.67 (0.31, 1.46) 1/0.42 0.37 Not significant
Positive and Negative Syndrome Scale–General Psychopathology scale Total n–3 PUFAs 2 (145) SMD −0.388 (−1.103, 0.327) 0.287 77.7 0.495 (0.136, 1.806) 0.93 (0.44, 2.03) 1/0.10 0.10 Not significant
Händel et al., 2021 (59)2 Attention-deficit/hyperactivity disorder Parent-reported core symptoms Total n–3 and n–6 PUFAs 24 (1754) SMD −0.167 (−0.318, −0.015) 0.031 60.7 0.739 (0.562, 0.972) (0.245, 2.228) 0.04 1.54 (1.36, 3.24) 8/1.04 0.05 Weak
Teacher-reported core symptoms Total n–3 and n–6 PUFAs 10 (640) SMD −0.062 (−0.310, 0.186) 0.626 55.0 0.894 (0.571, 1.401) (0.241, 3.324) 0.26 1.14 (0.59, 2.22) 2/0.58 0.11 Not significant
Parent-reported behavioral difficulties Total n–3 and n–6 PUFAs 7 (682) SMD −0.014 (−0.169, 0.141) 0.859 0.0 0.975 (0.736, 1.291) (0.675, 1.409) 0.73 0.74 (0.41, 1.31) 0/0.89 Not significant
Teacher-reported behavioral difficulties Total n–3 and n–6 PUFAs 5 (377) SMD −0.041 (−0.346, 0.264) 0.791 49.1 0.928 (0.534, 1.612) (0.178, 4.824) 0.38 0.96 (0.49, 1.88) 1/0.25 0.23 Not significant
Quality of life Total n–3 and n–6 PUFAs 2 (191) SMD 0.014 (−0.288, 0.316) 0.929 0.0 1.025 (0.593, 1.771) 0.98 (0.52, 1.88) 0/0.10 Not significant
Suradom et al., 2021 (60) Depression Prevention of depression severity Total n–3 and n–6 PUFAs 10 (1027) SMD −0.033 (−0.201, 0.134) 0.697 23.2 0.942 (0.695, 1.275) (0.493, 1.797) 0.45 1.20 (0.71, 2.03) 1/0.78 0.56 Not significant
Treatment of depression severity Total n-3 and n-6 PUFAs 4 (209) SMD −0.138 (−0.543, 0.268) 0.506 30.7 0.780 (0.374, 1.623) (0.070, 8.640) 0.31 1.54 (0.56, 4.18) 0/0.55 Not significant
Xu et al., 2021 (61) Mild cognitive impairment Mini-Mental State Examination Unsaturated fatty acids 3 (96) MD 0.658 (−0.008, 1.325) 0.053 59.8 3.293 (0.986, 10.995) (<0.001, >1000) 0.44 1.10 (0.33, 3.64) 2/0.16 0.01 Not significant
Araya-Quintanilla et al., 2020 (52) Alzheimer disease Narcissistic Personality Inventor Total n–3 PUFAs 2 (543) SMD −0.342 (−1.077, 0.393) 0.362 93.7 0.539 (0.142, 2.037) 0.28 (0.19, 0.41) 1/1.99 Not significant
Mini-Mental State Examination Total n–3 PUFAs 3 (283) SMD 0.582 (−0.434, 1.597) 0.262 0.0 2.865 (0.456, 18.016) (<0.001, >1000) 0.79 2.06 (0.19, 22.09) 0/1.34 Not significant
Alzheimer's Disease Assessment Scale– Cognitive section Total n–3 PUFAs 3 (239) SMD 1.096 (−1.031, 3.224) 0.312 96.9 7.275 (0.155, 342.043) (<0.001, >1000) 0.11 216.09 (99.23, 470.60) 1/2.99 Not significant
Luo et al., 2020 (53)2 Depression Depressive symptoms Total n–3 and n–6 PUFAs (≥2000 mg/d) 4 (160) SMD −0.941 (−1.581, −0.301) 0.004 66.9 0.182 (0.057, 0.580) (0.001, 22.190) 0.05 0.54 (0.24, 1.18) 3/0.73 0.02 Weak
Depressive symptoms Total n-3 and n-6 PUFAs (<2000 mg/d) 7 (985) SMD −0.630 (−1.186, −0.075) 0.026 90.8 0.319 (0.117, 0.874) (0.010, 9.976) 0.13 0.82 (0.58, 1.16) 2/0.68 0.14 Weak
Mocking et al., 2020 (54) Perinatal depression Depressive symptoms Total n–3 and n–6 PUFAs 14 (3781) SMD −0.072 (−0.188, 0.045) 0.227 19.0 0.879 (0.712, 1.084) (0.571, 1.352) 0.95 0.83 (0.67, 1.04) 1/1.71 0.68 Not significant
Postpartum depression Depressive symptoms Total n–3 and n–6 PUFAs 4 (423) SMD −0.656 (−1.690, 0.378) 0.213 92.7 0.305 (0.047, 1.982) (<0.001, >1000) 0.10 0.03 (0.01, 0.06) 2/3.99 Not significant
Zhang et al., 2020 (55) Mild cognitive impairment Mini-Mental State Examination Total n–3 PUFAs 7 (434) WMD 0.852 (0.039, 1.665) 0.040 52.2 1.646 (1.009, 2.685) (0.424, 6.395) 0.55 0.98 (0.59, 1.62) 1/0.35 0.30 Weak
Devoe et al., 2019 (48) Psychosis Attenuated psychotic symptoms Total n–3 PUFAs 3 (347) SMD −0.309 (−0.878, 0.261) 0.288 81.1 0.572 (0.204, 1.604) (<0.001, >1000) 0.74 0.91 (0.57, 1.46) 1/0.17 0.16 Not significant
Morsy et al., 2019 (49) Huntington disease Total motor score Ethyl-EPA 2 (285) MD −2.720 (−4.763, −0.677) 0.009 0.0 0.071 (0.001, 3.786) 0.52 (0.35, 0.79 2/1.42 1.00 Not significant
Total motor score-4 Ethyl-EPA 2 (285) MD −2.225 (−3.843, −0.607) 0.007 9.7 0.025 (0.008, 0.080) 0.01 (0.01, 0.03) 2/1.99 1.00 Weak
Zhang et al., 2019 (51) Depression in children Depressive symptoms Total n–3 PUFAs 4 (153) SMD −0.119 (−0.533, 0.296) 0.575 30.5 0.807 (0.381, 1.709) (0.069, 9.412) 0.03 1.22 (0.43, 3.49) 1/0.25 0.23 Not significant
Su et al., 2018 (47)2 Anxiety Symptoms Total n–3 PUFAs 19 (1203) Hedges' g −0.374 (−0.666, −0.081) 0.012 89.9 0.508 (0.300, 0.863) (0.049, 5.300) 0.10 1.29 (0.88, 1.87) 6/2.11 0.01 Weak
Rosenblat et al., 2016 (45) Bipolar depression Depressive symptoms Total n–3 PUFAs 4 (140) SMD −0.364 (−0.735, 0.007) 0.054 8.3 0.517 (0.265, 1.012) (0.092, 2.895) 0.79 0.48 (0.20, 1.14) 0/0.83 Not significant
Tan et al., 2016 (46) Specific learning disorders Adverse effects PUFAs 2 (116) RR 1.402 (0.237, 8.281) 0.710 0.0 1.402 (0.237, 8.281) 2.05 (0.19, 21.7) 0/0.63 Not significant
Cooper et al., 2015 (42)2 Attention-deficit/hyperactivity disorder Attention (omission errors) Total n–3 PUFAs 6 (387) SMD −0.129 (−0.327, 0.069) 0.200 0.0 0.792 (0.554, 1.132) (0.477, 1.314) 0.82 0.76 (0.43, 1.3) 0/0.54 Not significant
IQ Total n–3 PUFAs 5 (706) SMD 0.139 (−0.07, 0.351) 0.200 23.3 1.286 (0.876, 1.888) (0.513, 3.221) 0.96 1.00 (0.55, 1.82) 1/0.25 0.23 Not significant
Inhibition Total n–3 PUFAs 12 (951) SMD −0.037 (−0.217, 0.143) 0.687 38.9 0.935 (0.675, 1.295) (0.396, 2.208) 0.49 0.74 (0.43, 1.27) 1/1.36 Not significant
Mean reaction time Total n–3 PUFAs 11 (1107) SMD −0.001 (−0.118, 0.117) 0.997 12.8 0.999 (0.808, 1.236) (0.684, 1.460) 0.86 1.29 (0.89, 1.85) 1/1.16 Not significant
Reaction time variability Total n–3 PUFAs 2 (114) SMD 0.290 (−0.709, 1.289) 0.569 82.1 1.691 (0.277, 10.319) 0.68 (0.25, 1.92) 1/0.24 0.22 Not significant
Reading Total n–3 PUFAs 8 (1433) SMD 0.014 (−0.062, 0.090) 0.722 0.0 1.025 (0.894, 1.176) (0.864, 1.218) 0.22 1.04 (0.79, 1.34) 0/0.42 Not significant
Short-term memory Total n–3 PUFAs 14 (2188) SMD 0.067 (−0.013, 0.147) 0.101 28.5 1.129 (0.976, 1.306) (0.793, 1.608) 0.41 1.00 (0.72, 1.39) 2/0.70 0.15 Not significant
Spelling Total n–3 PUFAs 6 (974) SMD 0.031 (−0.090, 0.153) 0.614 5.1 1.058 (0.849, 1.319) (0.738, 1.517) 0.90 0.95 (0.66, 1.34) 0/0.32 Not significant
Working memory Total n–3 PUFAs 8 (1410) SMD 0.089 (−0.007, 0.185) 0.068 3.6 1.175 (0.988, 1.397) (0.917, 1.505) 0.02 0.96 (0.74, 1.27) 1/0.42 0.35 Not significant
Yang et al., 2015 (43)2 Depression in women Depressive symptoms EPA+DHA 8 (267) SMD −0.648 (−1.120, −0.175) 0.007 78.4 0.310 (0.132, 0.728) (0.018, 5.344) 0.09 0.53 (0.24, 1.20) 6/1.70 <0.01 Weak
1

All summary estimates were recalculated based on a random-effects model using the method of DerSimonian and Laird. The 95% prediction interval and Egger's test were not evaluated if available studies were <3. For excess of significance, the P value was not evaluated if the observed number of studies was smaller than expected. E, expected number of studies with positive finding; MD, mean difference; O, observed number of studies with positive finding; ref, reference; SMD, standardized mean difference; WMD, weighted mean difference.

2

The direction of comparison was normalized to supplementation group versus non-supplementation group.

None of the 43 meta-analyses had convincing, highly suggestive, or suggestive strength of evidence according to the quantitative umbrella review criteria. In addition, the strength of the evidence was weak for 10 meta-analyses (Table 2). Weak evidence suggested that n–3 PUFA and n–6 PUFA supplementation could significantly reduce depressive symptoms in patients with depression (SMD: –0.941 to –0.401; equivalent OR: 0.182 to 0.484; P-random effects: 0.001–0.026). Weak evidence also suggested that n–3 PUFA and n–6 PUFA supplementation could significantly reduce Aberrant Behavior Checklist total scores in patients with ASD (SMD: –0.183; equivalent OR: 0.718; P-random effects: 0.023), and reduce parent-reported core symptoms in patients with ADHD (SMD: –0.167; equivalent OR: 0.739; P-random effects: 0.031). For n–3 PUFA supplementation intervention (Figure 2), there was weak evidence for its efficacy in reducing Positive and Negative Syndrome Scale total scores in patients with schizophrenia (SMD: –0.295; equivalent OR: 0.586; P-random effects: 0.012), efficacy in reducing motor scores in patients with Huntington's disease (MD: –2.225; equivalent OR: 0.025; P-random effects: 0.007), efficacy in reducing symptoms of patients with anxiety (Hedges’ g: –0.374; equivalent OR: 0.508; P-random effects: 0.012), and efficacy in improving Mini-Mental State Examination scores in patients with mild cognitive impairment (WMD: 0.852; equivalent OR: 1.646; P-random effects: 0.040).

FIGURE 2.

FIGURE 2

Efficacy of n–3 unsaturated fatty acid supplementation interventions for mental disorders with evidence grading. SMD, standardized mean difference.

Dietary unsaturated fatty acid intake and the risk of mental disorders

A total of 32 meta-analyses assessing the dietary unsaturated fatty acid intake and the risk of mental disorders, such as AD, dementia, mild cognitive impairment, Parkinson disease, depression, and suicide, were recalculated. Only 5 meta-analyses reported a marginally statistically significant summary effect using random-effects models (P < 0.05), and all 95% prediction intervals of the meta-analyses included the null value, which indicated no associations (Table 3). Significant heterogeneity (I2 > 50%) was observed in associations of fish consumption with risk of depression and intake of EPA and DHA with risk of depression (Table 3). The risk of small-study effects bias was only observed in 2 associations, whereas excess of significance bias was detected in 2 associations. However, most associations (26/32) consisted of fewer than 5 individual studies, in which case the power of the test was reduced.

TABLE 3.

Quantitative synthesis and evidence grading for meta‐analyses evaluating the associations between unsaturated fatty acids intake and risk of mental disorders1

Study, year (ref) Mental disorders Composition No. of studies (participants, n) Effect metrics Random-effects summary estimate (95% CI) Random-effects P I 2, % 95% Prediction interval Egger's test P Largest study estimate (95% CI) Significant studies Grading
O/E P
Kosti et al., 2022 (63) Dementia Higher intake of fish 9 (45,643) RR 0.798 (0.688, 0.925) 0.003 0.0 (0.563, 1.129) 0.08 0.84 (0.71, 1.00) 4/3.50 0.74 Weak
Alzheimer disease Higher intake of fish 8 (444,022) RR 0.737 (0.626, 0.867) <10−3 0.0 (0.479, 1.134) 0.71 0.69 (0.60, 0.80) 5/6.49 Suggestive
Zhu et al., 2021 (62) Alzheimer disease Higher intake of total n–3 PUFAs 4 (11,977) RR 0.883 (0.662, 1.177) 0.396 60.7 (0.370, 2.11) 0.12 1.07 (0.91, 1.25) 1/0.41 0.35 Not significant
Higher intake of total n–6 PUFAs 2 (3427) RR 0.826 (0.549, 1.241) 0.358 55.9 0.76 (0.55, 1.06) 0/1.69 Not significant
Higher intake of PUFAs 3 (8084) RR 0.905 (0.741, 1.105) 0.326 0.0 (0.584, 1.403) 0.68 1.09 (0.79, 1.50) 0/0.43 Not significant
Higher intake of MUFA 4 (8899) RR 1.154 (0.800, 1.664) 0.442 64.50 (0.380, 3.507) 0.78 0.91 (0.77, 1.07) 1/0.56 0.45 Not significant
Higher intake of DHA 3 (3892) RR 0.778 (0.477, 1.267) 0.313 76.20 (0.003, 185.619) 0.67 0.73 (0.57, 0.95) 2/1.66 1.00 Not significant
Higher intake of EPA 3 (3892) RR 0.888 (0.658, 1.198) 0.436 45.08 (0.046, 16.999) 0.15 0.74 (0.57, 0.95) 1/1.58 Not significant
Qu et al., 2019 (50) Parkinson disease Higher intake of total n–3 PUFAs 3 (300,321) RR 0.763 (0.487, 1.194) 0.236 62.2 (0.006, 104.092) 0.50 0.93 (0.76, 1.14) 1/0.39 0.34 Not significant
Higher intake of total n–6 PUFAs 3 (300,321) RR 0.990 (0.667, 1.468) 0.959 55.9 (0.015, 66.907) 0.29 1.23 (1.02, 1.49) 1/1.29 Not significant
Higher intake of PUFAs 4 (326,686) RR 0.864 (0.592, 1.261) 0.449 74.0 (0.173, 4.320) 0.18 1.23 (1.02, 1.49) 2/1.57 0.65 Not significant
Higher intake of MUFA 5 (327,054) RR 1.033 (0.865, 1.235) 0.719 0.0 (0.774, 1.380) 0.24 1.13 (0.94, 1.55) 0/1.00 Not significant
Higher intake of ALA 3 (300,513) RR 0.726 (0.480, 1.099) 0.130 64.6 (0.008, 70.002) 0.22 0.93 (0.77, 1.13) 1/0.39 0.34 Not significant
Higher intake of LA 3 (300,513) RR 0.930 (0.614, 1.409) 0.732 65.6 (0.009, 94.012) 0.05 1.23 (1.02, 1.49) 1/1.33 Not significant
Higher intake of AA 2 (299,985) RR 1.426 (0.753, 2.700) 0.277 80.1 1.08 (0.90, 1.30) 1/0.36 0.32 Not significant
Higher ratio of n–3 to n–6 PUFAs 2 (299,985) RR 0.890 (0.754, 1.051) 0.170 0.0 0.87 (0.73, 1.04) 0/0.82 Not significant
Grosso et al., 2016 (44) Depression Higher intake of total n–3 PUFAs 8 (25,923) RR 0.873 (0.722, 1.055) 0.160 30.9 (0.569, 1.339) 0.86 0.74 (0.58, 0.95) 2/4.57 Not significant
Higher intake of EPA and DHA 7 (77,143) RR 0.782 (0.667, 0.918) 0.003 50.4 (0.508, 1.206) 0.63 0.65 (0.53, 0.80) 3/6.35 Weak
Higher intake of fish 21 (200,422) RR 0.780 (0.688, 0.885) <10−3 61.4 (0.489, 1.244) 0.90 0.76 (0.64, 0.91) 8/15.08 Suggestive
Zhang et al., 2016 (15) Alzheimer disease Higher intake of PUFAs 2 (6844) RR 0.872 (0.334, 2.278) 0.779 27.9 1.07 (0.82, 1.39) 0/0.15 Not significant
Higher intake of DHA 3 (6476) RR 0.546 (0.242, 1.233) 0.145 90.53 (<0.001, >1000) 0.11 1.10 (0.93, 1.31) 2/0.31 0.03 Not significant
Dementia Higher intake of PUFAs 2 (6844) RR 0.870 (0.355, 2.131) 0.760 25.09 1.04 (0.83, 1.29) 0/0.12 Not significant
Higher intake of DHA 2 (5661) RR 0.804 (0.511, 1.263) 0.344 90.81 1.00 (0.89, 1.14) 1/0.10 0.10 Not significant
Mild cognitive impairment Higher intake of PUFAs 3 (3386) RR 0.714 (0.607, 0.841) <10−3 0.0 (0.248, 2.056) 0.70 0.72 (0.61, 0.85) 1/1.05 Suggestive
Parkinson disease Higher intake of DHA 4 (141,551) RR 1.001 (0.974, 1.029) 0.931 0.0 (0.943, 1.063) 0.51 1.01 (0.97, 1.04) 0/0.20 Not significant
Tsai et al., 2014 (41) Suicide Higher intake of total n–3 PUFAs 3 (205,357) RR 1.463 (0.950, 2.251) 0.084 10.1 (0.057, 37.437) 0.97 1.47 (0.88, 2.44) 0/0.55 Not significant
Higher intake of total n–6 PUFAs 3 (205,357) RR 0.887 (0.562, 1.401) 0.607 0.0 (0.0459, 17.149) 0.44 0.82 (0.45, 1.51) 0/0.71 Not significant
Higher intake of EPA and DHA 3 (205,357) RR 1.241 (0.681, 2.263) 0.481 58.2 (0.002, 786.970) 0.21 0.80 (0.49, 1.28) 0/0.29 Not significant
Higher intake of ALA 3 (205,357) RR 1.068 (0.734, 1.556) 0.730 0.0 (0.093, 12.222) 0.01 1.27 (0.78, 2.06) 0/0.30 Not significant
Higher intake of LA 3 (205,357) RR 0.664 (0.418, 1.056) 0.084 0.0 (0.033, 13.410) 0.12 0.54 (0.29, 1.02) 0/2.35 Not significant
Higher intake of AA 3 (205,357) RR 1.190 (0.824, 1.718) 0.354 0.0 (0.110, 12.895) 0.27 1.09 (0.67, 1.77) 0/0.21 Not significant
Higher intake of fish 3 (205,357) RR 0.818 (0.283, 2.364) 0.711 73.7 (<0.001, >1000) 0.71 0.55 (0.31, 0.96) 0/2.39 Not significant
1

All summary estimates were recalculated based on a random-effects model using the method of DerSimonian and Laird. The 95% prediction interval and Egger's test were not evaluated if available studies were <3. For excess of significance, the P value was not evaluated if the observed number of studies was smaller than expected. AA, arachidonic acid; ALA, α-linolenic acid; E, expected number of studies with positive finding; LA, linoleic acid; MD, mean difference; O, observed number of studies with positive finding; ref, reference; SMD, standardized mean difference.

Three meta-analyses had suggestive strength of the associations according to the quantitative umbrella review criteria, and the strength of the evidence was weak for 2 meta-analyses (Table 3). Suggestive evidence indicated that a higher intake of fish could reduce the risk of depression (pooled RR: 0.780; P-random effects: <0.001) and AD (pooled RR: 0.737; P-random effects < 0.001), and a higher intake of dietary PUFAs was associated with a lower risk of mild cognitive impairment (pooled RR: 0.714; P-random effects < 0.001). Moreover, weak evidence showed that a higher intake of dietary EPA and DHA was associated with a lower risk of depression (pooled RR: 0.782; P-random effects: 0.003), and a higher intake of fish might reduce the risk of dementia (pooled RR: 0.798; P-random effects: 0.003).

Unsaturated fatty acids as biomarkers for mental disorders

A total of 20 meta-analyses assessed the difference in circulating unsaturated fatty acids between healthy controls and patients with mental disorders, including AD, dementia, mild cognitive impairment, ADHD, ASD, BP, and schizophrenia. Eight meta-analyses reported a nominally statistically significant summary effect using random-effects models (P < 0.05), and 3 meta-analyses had 95% prediction intervals excluding the null value (Table 4). Significant heterogeneity (I2 > 50%) was observed in 5 statistically significant comparisons, with the exception of the comparison of circulating DHA between patients with BP and controls, the comparison of circulating total n–3 PUFAs between patients with ADHD and controls, and the comparison of circulating docosapentaenoic acid (DPA; 22:5n−3) between patients with schizophrenia and controls (Table 4). The risk of small-study effects bias was observed in 1 comparison, whereas excess of significance bias was detected in 6 comparisons (Table 4). Among these comparisons, 6 meta-analyses consisted of fewer than 5 individual studies, in which case the power of the test was reduced.

TABLE 4.

Quantitative synthesis and evidence grading for meta‐analyses comparing circulating unsaturated fatty acids between participants with and without mental disorders1

Study, year (ref) Mental disorders Outcome No. of studies (participants, n) Original effect metrics Random-effects summary estimate (95% CI) Random-effects P I 2, % Converted as equivalent OR (95% CI) 95% Prediction interval Egger's test P Largest study estimate (95% CI) Significant studies Grading
O/E P
Mazahery et al., 2017 (11) Autism spectrum disorder Circulating n–3 PUFAs 5 (564) SMD −0.164 (−0.536, 0.209) 0.389 73.0 0.744 (0.379, 1.459) (0.073, 7.573) 0.24 0.51 (0.32, 0.82) 3/2.19 0.66 Not significant
Circulating n–6 PUFAs 5 (564) SMD 0.569 (−0.186, 1.323) 0.139 93.2 2.799 (0.715, 10.968) (0.015, 518.050) 0.09 0.59 (0.37, 0.95) 3/1.54 0.17 Not significant
Circulating DHA 14 (1291) SMD −1.607 (−2.482, −0.732) <10−3 97.3 0.055 (0.011, 0.266) (0.000, 43.982) 0.11 0.45 (0.28, 0.72) 11/6.78 0.03 Weak
Circulating EPA 11 (951) SMD −0.437 (−0.901, 0.027) 0.065 90.2 0.453 (0.196, 1.050) (0.019, 10.672) 0.82 1.00 (0.62, 1.60) 3/0.55 0.02 Not significant
Circulating AA 13 (1211) SMD −0.826 (−1.481, −0.172) 0.013 95.5 0.224 (0.068, 0.733) (0.002, 26.555) 0.82 0.45 (0.28, 0.72) 8/6.29 0.41 Weak
The ratio of AA to EPA in blood 9 (525) SMD 0.662 (−0.109, 1.433) 0.093 93.4 3.311 (0.820, 13.367) (0.023, 470.693) 0.97 5.79 (3.18, 10.33) 5/6.32 Not significant
The ratio of AA to DHA in blood 5 (336) SMD −0.080 (−2.223, 2.063) 0.942 98.1 0.865 (0.018, 41.855) (<0.001, >1000) 0.05 127.84 (58.70, 278.41) 4/4.99 Not significant
McNamara et al., 2016 (12) Bipolar disorder Circulating DHA 6 (265) SMD −0.960 (−1.243, −0.676) <10−6 0.0 0.176 (0.105, 0.294) (0.085, 0.364) 0.87 0.17 (0.07, 0.44) 4/5.22 Weak
Circulating EPA 6 (265) SMD −0.455 (−0.882, −0.027) 0.037 56.9 0.438 (0.202, 0.951) (0.045, 4.317) 0.27 0.44 (0.20, 1.22) 2/1.96 1.00 Weak
Circulating LA 4 (199) SMD −0.623 (−1.663, 0.418) 0.241 90.3 0.324 (0.049, 2.129) (<0.001, >1000) 0.28 0.52 (0.19, 1.27) 1/0.94 1.00 Not significant
Circulating AA 6 (265) SMD −0.186 (−0.844, 0.471) 0.579 80.4 0.716 (0.217, 2.361) (0.013, 40.473) 0.69 0.95 (0.38, 2.43) 3/0.31 <0.01 Not significant
Zhang et al., 2016 (15) Alzheimer disease Circulating DHA (a 1% increment of blood DHA concentrations) 3 (1828) RR 0.785 (0.561, 1.098) 0.157 62.75 (0.020, 31.045) 0.16 0.96 (0.88, 1.04) 1/0.16 0.15 Not significant
Dementia Circulating DHA (a 1% increment of blood DHA concentrations) 5 (3099) RR 0.939 (0.864, 1.020) 0.136 57.37 (0.744, 1.185) <0.01 0.99 (0.96, 1.03) 2/0.25 0.02 Not significant
Mild cognitive impairment Circulating DHA (a 1% increment of blood DHA concentrations) 2 (2497) RR 0.846 (0.465, 1.540) 0.585 85.84 1.11 (0.97, 1.26) 1/0.16 0.15 Not significant
Hawkey et al., 2014 (13)2 Attention-deficit/hyperactivity disorder Circulating n–3 PUFAs 9 (586) Hedges' g −0.409 (−0.563, −0.255) <10−6 0.0 0.492 (0.367, 0.659) (0.346, 0.700) 0.25 0.59 (0.41, 1.16) 2/1.91 1.00 Weak
van der Kemp et al., 2012 (14) Schizophrenia Circulating DHA 6 (194) Cohen's d −0.871 (−1.290, −0.452) <10−3 68.1 0.207 (0.097, 0.441) (0.019, 2.269) 0.45 0.485 (0.214, 1.103) 4/1.67 0.06 Weak
Circulating AA 6 (194) Cohen's d −0.767 (−1.390, −0.144) 0.016 85.7 0.249 (0.081, 0.771) (0.005, 12.730) 0.34 0.40 (0.17, 0.91) 4/1.96 0.09 Weak
Circulating LA 4 (113) Cohen's d −0.042 (−0.327, 0.244) 0.774 0.0 0.927 (0.553, 1.554) (0.298, 2.883) 0.57 0.88 (0.39, 2.02) 0/0.21 Not significant
Circulating DPA 4 (113) Cohen's d −0.924 (−1.225, −0.624) <10−6 0.0 0.188 (0.109, 0.323) (0.057, 0.619) 0.79 0.18 (0.08, 0.43) 3/0.04 0.63 Weak
Circulating DTA 3 (78) Cohen's d −0.113 (−0.478, 0.252) 0.544 12.8 0.815 (0.421, 1.577) (0.005, 129.249) 0.32 0.51 (0.17, 1.06) 0/0.27 Not significant
1

All summary estimates were recalculated based on a random-effects model using the method of DerSimonian and Laird. The 95% prediction interval and Egger's test were not evaluated if available studies were <3. For excess of significance, the P value was not evaluated if the observed number of studies was smaller than expected. AA, arachidonic acid; DPA, docosapentaenoic acid; DTA, docosatetraenoic acid; E, expected number of studies with positive finding; LA, linoleic acid; MD, mean difference; O, observed number of studies with positive finding; ref, reference; SMD, standardized mean difference.

2

The direction of comparison was normalized to mental disorder group versus control group.

None of the 20 meta-analyses had convincing, highly suggestive, or suggestive strength of efficacy according to the quantitative umbrella review criteria. In addition, the credibility of the evidence was weak for 8 meta-analyses, which suggested differences in circulating unsaturated fatty acids among ADHD, ASD, BP, and schizophrenia patients and healthy controls (P-random effects <10−6–0.037).

Discussion

This umbrella review included 29 systematic reviews of studies assessing the role of unsaturated fatty acids in numerous mental disorders. Overall, the available evidence has mainly focused on long-chain PUFAs (n–3 PUFAs and n–6 PUFAs), and the effects vary among mental disorders. Current evidence suggests that n–3 PUFA supplementation intervention might have potential value, but the strength of the efficacy and credibility of the evidence were weak overall. Higher intake of unsaturated fatty acids might have protective effects on a limited number of mental disorders (i.e., depression and mild cognitive impairment), and the effect of unsaturated fatty acid intake on many mental disorders has not been evaluated. In addition, we observed broad differences in circulating unsaturated fatty acids between patients with mental disorders and controls. The between-study heterogeneity, limited study populations, prediction intervals including the null value, and risk of excess significance bias were the main factors reducing the overall confidence in the evidence.

Although linking nutrition evidence with practice remains challenging (7, 64–67), the findings of this umbrella review might have clinical practice implications. The availability of a substantial body of experimental evidence generated in unsaturated fatty acid supplementation is a major finding that should inform the establishment of guidelines for the prevention of mental disorders. Mental disorders require complex interdisciplinary treatment grounded in the use of antipsychotic medications (68). However, medical treatment is usually accompanied by a large number of adverse effects, resulting in decreased treatment compliance (69). This has contributed to the development of alternative and complementary (adjunctive) treatments. An ever-growing body of evidence has evaluated the effect of dietary and supplemental unsaturated fatty acids (especially PUFAs) on various mental illnesses, but on the basis of umbrella review criteria none of these effect sizes have reached the maximum in terms of the strength of evidence credibility ratings. Suggestive evidence has shown a protective effect of fish consumption on depression (44) and dietary PUFA intake on mild cognitive impairment (15). Although the credibility in the estimate for efficacy was not optimal, weak evidence supported the efficacy of unsaturated fatty acid supplementation for mental disorders, which demonstrated the need for future high-quality randomized controlled trials evaluating the effects of unsaturated fatty acid supplementation interventions on different mental disorders.

n–6 and n–3 PUFAs have opposite effects on inflammatory modulation (4). n–6 PUFAs, particularly AA, are important precursors of eicosanoids (including prostaglandins, thromboxanes, and leukotrienes), which regulate the inflammatory process in immune cells as inflammatory mediators (4, 8). However, EPA and DHA act as competitive inhibitors of n–6 PUFAs causing a reduction in the synthesis of proinflammatory mediators (70). On the basis of evidence grading, the mental health–related favorable effect of unsaturated fatty acid supplementation was mainly limited to n–3 PUFAs, EPA, and DHA. Moreover, n–3 and n–6 PUFAs are implicated in gene expression and regulate several genes involved in lipid metabolism and inflammatory signaling through nuclear receptors (including farnesoid X receptors, liver X receptors, NF-κB, peroxisome proliferator activated receptors, retinoid X receptors, and sterol regulatory element binding protein 1c) (71). However, n–3 PUFAs show a greater potency in modifying nuclear receptor gene expression than n–6 PUFAs (71). n–3 PUFAs downregulate inflammatory genes and lipid synthesis and stimulate fatty acid degradation (71).

PUFAs are highly enriched in the brain (8) and make up approximately 35% of the lipids in brain (72). Adequate brain DHA and ARA are essential for normal cellular processes, such as transmembrane potential, neurotransmission, and the function of ion channels (10, 73). Altered brain fatty acid composition, metabolism, and fatty acid–derived signaling systems have been associated with mental disorders (8, 74, 75). Weak evidence suggested a broad range of circulating unsaturated fatty acid shortfalls in mental disorders (including ASD, ADHD, BP, and schizophrenia), which indicated the disturbance of fatty acid metabolism and a potential decrease in the absorption of unsaturated fatty acids (11–14). Therefore, unsaturated fatty acid supplementation and the intake of an unsaturated fatty acid–enriched diet have potential value in reversing fatty acid–related imbalances in the brain and might have favorable effects on mental health conditions (4, 5, 8, 64).

The main limitations of this umbrella review include those of the included systematic reviews and, in turn, the limitations of the original studies. The most frequently reported review shortcomings, detected by AMSTAR 2, were the absence of the list of excluded studies and the justification for exclusion studies, a thorough discussion of between-study heterogeneity, and adequate investigation and discussion of publication bias. According to the umbrella review criteria, publication bias and excess significance bias cannot be excluded for some comparisons. We were also unable to quantify the differences in the dose of unsaturated fatty acids among the included meta-analyses. These limitations decreased the strength of the associations and credibility of the evidence. Based on the analytic approach of an umbrella review, analyzing numerous outcomes could increase the risk of making a type I error, and Egger's tests might lack the statistical power to detect bias when few studies are included in the meta-analysis.

Additional limitations were related to the umbrella review methodology because this approach is based on the statistical reanalysis of meta-analyses. By definition, umbrella reviews include only systematic reviews that applied a quantitative approach to data presentation, whereas systematic reviews providing qualitative descriptions of the included studies, without applying meta-analytic techniques, are excluded. However, the absence of a meta-analytical approach is typically motivated by the scarcity of sufficient and homogeneous experimental evidence, which therefore does not reach the minimum clinical and methodological requirements needed for meta-analysis. Another limitation is that we did not analyze whether the efficacy of unsaturated fatty acid supplementation interventions was moderated by the composition and dose of unsaturated fatty acids, the length of follow-up, or by other social, dietary, or lifestyle-related variables (76, 77). The analysis of these variables was not feasible due to the nature of an umbrella review. To avoid data overlapping with exaggerated test power of the actual sample, we excluded a large amount of duplicate or updated studies assessing the same association. Different meta-analyses could have differences in selection criteria and analytical approaches, which might introduce bias to the evaluation of evidence, but we only extracted the main results (i.e., the specific association between unsaturated fatty acids and mental disorders); hence, the latest study with the largest number of individual studies typically provides the most accurate estimate of the true effect size. Finally, based on the aim of this review, we did not include studies evaluating the effects of unsaturated fatty acids on the general population—for example, studies on the neurodevelopment of typically developing children (78–80).

In view of the variability in the strength of the associations and credibility of the evidence, action is required to support further research efforts for different mental disorders. Several initiatives have aimed to improve the capacity of mental health research centers to conduct high-quality nutrition studies. In terms of populations, this review suggests a need for further studies involving children and adolescents, especially in children with mood disorders. A focus on mental health along a continuum from mild psychological distress to a severely disabling condition, as suggested by the Lancet Commission on global mental health and sustainable development (81), seems to be an appropriate and feasible approach, although we note a scarcity of evidence for specific diagnostic conditions, such as sleep disorders. In terms of interventions, considering the effective dose of unsaturated fatty acids, future research efforts should be directed to ascertain which combination and dose is more feasible and effective. In terms of outcomes, the assessment of the long-term effectiveness of n–3 PUFA supplementation would be relevant, including functional and quality-of-life measures, because they were seldom considered by the studies included in this umbrella review.

Given the pressing need for evidence-based answers for people with mental health conditions, and in view of the data on the effect of unsaturated fatty acid supplementation on mental disorders, we recommend that more high-quality studies be conducted to critically evaluate the potential of unsaturated fatty acid supplementation interventions in the prevention and control of mental disorders.

Supplementary Material

nmac084_Supplemental_Files

Acknowledgements

The authors’ responsibilities were as follows—FZ and XG: designed the study; XG, XS, and FZ: performed the literature search and screening and extracted the data; XS, XH, CC, and SZ: conducted the data analyses; XG and XS: created the figures and tables and drafted the manuscript; XG and XS: contributed equally to the manuscript as joint first authors, whereas FZ and YY are the corresponding authors who take responsibility for the integrity of the data and the accuracy of the data analysis; FA and YY: had the final responsibility for the decision to submit for publication; and all authors: had full access to all of the study data, participated in the interpretation of results, critically revised the manuscript, and read and approved the final manuscript.

Notes

Supported by grants from National Natural Science Foundation of China (81602853 and 81801492) and the Medical Research Fund of Guangdong Province (A2020582).

Author disclosures: The authors report no conflicts of interest. The funders of this study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Supplemental Methods, Supplemental Results, and Supplemental Table 1 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/advances/.

XG and XS contributed equally to this work and should be considered as co-first authors.

Abbreviations used: AA, arachidonic acid; AD, Alzheimer disease; ADHD, attention-deficit/hyperactivity disorder; ALA, ɑ-linolenic acid; AMSTAR 2, A Measurement Tool to Assess Systematic Reviews; ASD, autism spectrum disorder; BP, bipolar disorder; LA, linoleic acid; MD, mean difference; SMD, standardized mean difference; WMD, weighted mean difference.

Contributor Information

Xuping Gao, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China; Department of Child and Adolescent Psychiatry, Peking University Sixth Hospital (Institute of Mental Health), National Clinical Research Center for Mental Disorders and NHC Key Laboratory of Mental Health (Peking University Sixth Hospital), Beijing, China.

Xin Su, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Xue Han, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Huiyan Wen, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Chen Cheng, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Shiwen Zhang, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Wanlin Li, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Jun Cai, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Lu Zheng, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Junrong Ma, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Minqi Liao, Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

Wanze Ni, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Tao Liu, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Dan Liu, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Wenjun Ma, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Shasha Han, Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Sui Zhu, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Yanbin Ye, Department of Clinical Nutrition, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Fang-fang Zeng, Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangdong, China.

Data Availability

All data included in this umbrella review were extracted from publicly available systematic reviews.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

nmac084_Supplemental_Files

Data Availability Statement

All data included in this umbrella review were extracted from publicly available systematic reviews.


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