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Original Research

Supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in children with autism spectrum disorders: a meta-analysis of randomized controlled trials

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Pages 2531-2543 | Published online: 04 Oct 2017

Abstract

Aim

Deficiency of omega 3 fatty acids may be linked to autism spectrum disorder (ASD). Evidence about the potential therapeutic effects of supplementation of omega 3 fatty acids is lacking in ASD patients.

Methods

We searched major electronic databases from inception to June 21, 2017, for randomized clinical trials, which compared treatment outcomes between supplementation of omega 3 fatty acids and placebo in patients with ASD. An exploratory random-effects meta-analysis of the included studies was undertaken.

Results and conclusion

Six trials were included (n=194). Meta-analysis showed that supplementation of omega 3 fatty acids improved hyperactivity (difference in means =−2.692, 95% confidence interval [CI] =−5.364 to −0.020, P=0.048, studies =4, n=109), lethargy (difference in means =−1.969, 95% CI =−3.566 to −0.372, P=0.016, studies =4, n=109), and stereotypy (difference in means =−1.071, 95% CI =−2.114 to −0.029, P=0.044, studies =4, n=109). No significant differences emerged between supplementation of omega 3 fatty acids and placebo in global assessment of functioning (n=169) or social responsiveness (n=97). Our preliminary meta-analysis suggests that supplementation of omega 3 fatty acids may improve hyperactivity, lethargy, and stereotypy in ASD patients. However, the number of studies was limited and the overall effects were small, precluding definitive conclusions. Future large-scale randomized clinical trials are needed to confirm or refute our findings.

Introduction

Autism spectrum disorder (ASD) is a life-long neurodevelopment disorder, which is a great burden for the affected individuals, caregivers, and societies worldwide.Citation1 The diagnosis of ASD is made predominantly by behavioral observation and is characterized by the presence of at least two core symptoms including restricted, repetitive patterns of behavior, interests, or activities and persistent difficulties in social communication and social interaction.Citation2 The global prevalence of ASD is estimated to be between 0.76%Citation1 and 1.46%.Citation3 The exact etiology of ASD is complex and multifactorial.Citation4 Numerous proposed mechanisms for ASD etiology exist, although none in isolation can explain all causes of the disorder.Citation5

Over the past few decades, there has been an increase in the prevalence of ASD in several countries.Citation6 Although the exact reason remains unknown, some proposed that heightened awareness and change in diagnostic criteria of ASD may partially account for the increase.Citation7Citation9 In contrast, others suggested that changes in environmental (eg, pollution) or nutritional factors may be potential contributors.Citation10,Citation11 Recently, nutritional factors have become a focus of interest because of possible associations with ASD for which they are regarded as possible treatment targets. Since there remains a lack of effective medication for the ASD core symptoms and some effective medications have multiple side effects,Citation12 the possibility of using nutritional supplements to improve ASD-associated symptoms has received much interest.Citation13,Citation14

Polyunsaturated fatty acids (PUFAs) have been a topic of interest for many psychiatric diseases. Accumulating evidence suggested that PUFA deficiency may be linked to some neurodevelopmental disorders, including schizophrenia, attention-deficit/hyperactivities disorder (ADHD), bipolar disorder, and ASD.Citation10,Citation15 PUFAs play an important role in brain functioning because of their anti-inflammatory properties and their ability to maintain appropriate function of brain cell membrane and myelin sheath.Citation10 Since PUFAs cannot be produced by the human body, some studies have suggested that changes in dietary behaviors that caused an imbalance in PUFAs’ consumption may provide an explanation for recent increase in ASD prevalence.Citation10 Omega 3 and omega 6 fatty acids are two of the most well-known PUFAs. While the former predominantly comes from seafood, the sources of the latter are animal or vegetable oils.Citation16 Some studies reported that the optimal ratio of omega 6 to omega 3 consumption should be 1:1 to 4:1.Citation17 However, recent changes in dietary habits may cause an increase in omega 6 fatty acid intake that may predispose some individuals with genetic vulnerability to certain psychiatric diseases.Citation18 Therefore, many clinical trials have started to investigate the therapeutic potential of supplementation of omega 3 fatty acids in treating patients with psychiatric diseases.Citation15

A recent meta-analysis found that supplementation of omega 3 fatty acids produced a small reduction in emotional liability and oppositional behaviors in ADHD patients.Citation19 Although symptoms of ASD manifest mainly as social dysfunction, many ASD patients also suffer from other emotional or behavioral problems including hyperactivity and poor impulsivity.Citation20 A high prevalence of anxiety disorders and ADHD was also found among ASD patients in previous studies.Citation21,Citation22

To the best of our knowledge, there have been two meta-analyses so far to assess the effects of supplementation of omega 3 fatty acids in ASD patient.Citation23,Citation24 The first meta-analysis, which included only two clinical trials with a very small total sample size (n=40), failed to show any benefits of supplementation of omega 3 fatty acids compared to placebo.Citation23 A more recent meta-analysis by Horvath et al,Citation24 which included more clinical trials, demonstrated no significant positive impact of supplementation of omega 3 fatty acids on most subscales of the Aberrant Behavior Checklist (ABC), despite an improved lethargy subscale. The authors concluded that supplementation of omega 3 fatty acids did not benefit patients with ASD. However, although five trials were included in the latter study, only patients from two out of the five trials (n=82) were included for the assessment of treatment outcomes (ie, change in ABC hyperactivities) in the omega 3 groups compared to those in the placebo groups. Moreover, the authors did not include non-English studies.Citation25 In this updated meta-analysis, we aimed to conduct a comprehensive systematic review that investigated all studies on the effects of supplementation of omega 3 fatty acids with placebo controls in ASD patients.

Methods

The meta-analysis was conducted in accordance with the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Table S1 and Figure S1).Citation26 The current meta-analysis followed our unpublished meta-analytic protocol, which fulfilled the requirement of the Institutional Review Board of the Tri-Service General Hospital (TSGHIRB: B-105-12).

Database searches and identification of eligible papers

Two independent authors (Y-SC and P-TT) searched the following electronic databases from inception to June 21, 2017, using the following chosen keywords: ([omega-3 fatty acids OR HUFAs OR eicosapentaenoic acid OR docosahexaenoic acid OR ethyl-eicosapentaenoic acid OR lipoic acid OR linoleic acid] AND [autism OR autism spectrum disorder OR ASD OR Asperger OR Pervasive development disorder OR PPD]) in PubMed, Cochrane Library, and ClinicalTrials.gov and ([omega-3 fatty acids] AND [autism OR autism spectrum disorder]) in ScienceDirect. In addition, to expand our search results, we hand searched the reference lists of specific review/original articles relevant to current topic.Citation10,Citation15,Citation16,Citation23

In the eligibility stage, the above two authors screened the articles via the titles and abstracts and came to consensus for the eligibility list. At the full-text review, the articles were scrutinized against the inclusion criteria and a final list was developed by the two authors. A third reviewer (P-YL) was available for mediation in the case of any inconsistencies.

Inclusion and exclusion criteria

The inclusion criteria were as follows: 1) randomized controlled trials (RCTs), 2) published articles investigating treatment effect of supplementation of omega 3 fatty acids in ASD children versus placebo, and 3) human studies. We considered articles published in any language. The exclusion criteria were as follows: 1) animal studies and 2) non-RCTs not comparing omega 3 supplement versus placebo in ASD children.

Methodological quality appraisal

To investigate the quality of recruited studies, we used the Jadad scale. The Jadad score ranges from 0 (poor quality) to 5 (high quality).Citation27

Primary outcomes

The primary outcome was the changes of ASD severity rating scales or changes in secondary behavioral symptoms of ASD, including the ABC,Citation28 Behavior Assessment System for Children (BASC),Citation29 Clinical Global Impression – Improvement (CGI-I),Citation30 and Social Responsiveness Scale (SRS).Citation31

Secondary outcomes

The secondary outcomes of interest included the dropout rate and rate of discontinuation of treatment due to side effect.

Data extraction and management

The above two authors extracted the target data of primary and secondary outcomes and clinical variables of interest, such as mean age, gender distribution, and duration of omega 3 treatment. For CGI-I, we defined clinical improvement as CGI-I =1 or 2, which was used in most studies to represent significant clinical improvement in symptoms.

When data were not available in the articles, we tried to contact the authors up to two times over a month to request the data.

Meta-analysis

Due to the anticipated heterogeneity, a random-effects meta-analysis model was conducted rather than a fixed-effect one.Citation32 The current meta-analysis was conducted on the platform of Comprehensive Meta-Analysis software, Version 3 (Biostat, Englewood, NJ, USA). For continuous data, we calculated the Hedges’ g and 95% confidence intervals (CIs) for studies using different outcome measures; we used the mean difference and 95% CI to represent the changes of outcome measures when studies used homogenous outcome measures. Finally, we calculated the odds ratio and 95% CIs for categorical data. Two-tailed P-values <0.05 are considered statistically significant.

Heterogeneity, publication bias, and sensitivity test

Heterogeneity was assessed with the Q statistic and corresponding P-value.Citation33 The I2 statistic was interpreted as the proportion of heterogeneity estimated in a study.Citation34 Furthermore, we examined the publication bias with visual inspection of funnel plotsCitation35 and Egger’s regression tests.Citation36 For evidence of publication bias, the Duval and Tweedie’s trim-and-fill procedure, which is a validated model to estimate an effect size, was employed.Citation37 We also conducted sensitivity analyses using the one study removal method.Citation38 In brief, this method had been widely used in meta-analysis to detect any potential bias from any one outlier among the recruited studies in one subgroup meta-analysis via the removal of one of the recruited studies in each step.

Meta-regression and subgroup meta-analysis

In an effort to find out the potential sources of heterogeneity and confounding effects, we conducted meta-regression and subgroup meta-analyses. At first, if there are at least five sets of datasets, we performed meta-regression with the unrestricted maximum likelihood method for clinical variables of interest. Second, when there were at least three studies, we would perform subgroup meta-analysis.Citation39

Results

Study selection

The search results are displayed in . Among the 34 articles entering full-text evaluation, 28 articles meeting the exclusion criteria were excluded (reasons summarized in Table S2). Finally, six articles were included in the current meta-analysis ().Citation25,Citation40Citation44 Among them, although there were two studies conducted by the same authors, the study design and participants were different. Therefore, they were regarded as two different datasets.Citation41,Citation43

Figure 1 Flowchart of the selection strategy for the current meta-analysis.

Figure 1 Flowchart of the selection strategy for the current meta-analysis.

Table 1 Summary of characteristics of studies in current meta-analysis

Of the six articles, four articles provided data on changes of ABC scalesCitation25,Citation41,Citation43,Citation44 (omega 3 participants =57, mean age =7.7, mean female proportion =9.3%; placebo participants =52, mean age =8.7, mean female proportion =14.6%), three articles provided changes of BASCCitation40,Citation42,Citation43 (omega 3 participants =56, mean age =5.2, mean female proportion =16.1%; placebo participants =56, mean age =5.3, mean female proportion =21.5%), four articles provided changes of CGICitation40Citation43 (omega 3 participants =85, mean age =5.9, mean female proportion =14.1%; placebo participants =84, mean age =5.9, mean female proportion =19.1%), and three articles provided changes of SRSCitation25,Citation41,Citation43 (omega 3 participants =50, mean age =7.3, mean female proportion =9.3%; placebo participants =47, mean age =8.4, mean female proportion =14.6%). Among the four studies that provided change of ABC scales, only one article provided both teachers’ rating and parents’ rating and most of other studies provided parents’ rating only. Therefore, we included only parents’ rating in our meta-analysis.

Methodological quality of included studies

For the six studies, the average Jadad score was 4.67 with a standard deviation of 0.52 (Table S3).

Meta-analysis investigating changes in ASD severity in patients treated with omega 3 or placebo

Primary outcome: changes of ABC

Among the four eligible articles (n=109) comparing changes of ABC scale severity between ASD children treated with omega 3 and those treated with placebo, there were only borderline significance of better treatment effects of the omega 3 treatment group in ABC scores of hyperactivities (k=4, Hedges’ g=−0.348, 95% CI =−0.716 to 0.021, P-value =0.064; difference in means =−2.692, 95% CI =−5.364 to −0.020, P=0.048) () without significant heterogeneity (Q value =1.553, df=3, P-value =0.670, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2A) or Egger’s regression (t value =0.943, df=2, two-tailed P-value =0.445). Improvements in ABC lethargy (k=4, Hedges’ g=−0.447, 95% CI =−0.817 to −0.077, P-value =0.018; difference in means =−1.969, 95% CI =−3.566 to −0.372, P=0.016) () were also noted; there was no any significant heterogeneity (Q value =1.597, df=3, P-value =0.660, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2B) or Egger’s regression (t value =0.639, df=2, two-tailed P-value =0.588). Furthermore, omega 3 resulted in improved ABC scores for stereotypy (k=4, Hedges’ g=−0.404, 95% CI =−0.773 to −0.035, P-value =0.032; difference in means =−1.071, 95% CI =−2.114 to −0.029, P=0.044) () without significant heterogeneity (Q value =0.962, df=3, P-value =0.810, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2C) or Egger’s regression (t value =0.162, df=2, two-tailed P-value =0.886). Finally, this meta-analysis did not find any significant difference in ABC scores for inappropriate speech (k=4, Hedges’ g=−0.199, 95% CI =−0.629 to 0.232, P-value =0.366; difference in means =−0.210, 95% CI =−1.161 to 0.741, P=0.665) (), which did not have any significant heterogeneity (Q value =3.716, df =3, P-value =0.294, I2=19.268%, τ=0.198) or publication bias via inspection of funnel plot (Figure S2D) or Egger’s regression (t value =2.905, df=2, two-tailed P-value =0.101); similarly, there was no significant difference in treatment effect between omega 3 and placebo on ABC irritability (k=4, Hedges’ g=0.016, 95% CI =−0.348 to 0.380, P-value =0.931; difference in means =0.122, 95% CI =−2.020 to 2.265, P=0.911) () without significant heterogeneity (Q value =0.029, df=3, P-value =0.999, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2E) or Egger’s regression (t value =0.821, df=2, two-tailed P-value =0.498).

Figure 2 Meta-analysis of difference of primary outcome, in aspects of (A) changes of ABC, (B) clinical improvement, and (C) changes of SRS total scores, in ASD children treated with omega 3 and placebo.

Notes: (A) The treatment effect is significantly better by omega 3 than by placebo in subscales of lethargy (P=0.018) and stereotypy (P=0.032), trend of better response by omega 3 than by placebo in hyperactivity (P=0.064), but no any significance between omega 3 and placebo in inappropriate speech (P=0.366) or irritability (P=0.931). (B) There was no any significant difference of clinical improvement between children with ASD receiving omega 3 and those receiving placebo (P=0.569). (C) There was trend of better response by placebo than by omega 3 in changes of SRS total scores (P=0.066).
Abbreviations: ABC, Aberrant Behavior Checklist; ASD, autism spectrum disorder; CGI-I, Clinical Global Impression – Improvement; CI, confidence interval; SRS, Social Responsiveness Scale.
Figure 2 Meta-analysis of difference of primary outcome, in aspects of (A) changes of ABC, (B) clinical improvement, and (C) changes of SRS total scores, in ASD children treated with omega 3 and placebo.
Figure 2 Meta-analysis of difference of primary outcome, in aspects of (A) changes of ABC, (B) clinical improvement, and (C) changes of SRS total scores, in ASD children treated with omega 3 and placebo.

Sensitivity test

Sensitivity analyses with one study removal test revealed that there was no change in the results of the meta-analysis of hyperactivities, inappropriate speech, and irritability scores. However, in the aspect of ABC stereotypy, the main result of meta-analysis became nonsignificant after the removal of study by Bent et al (2014)Citation41 (Hedges’ g=−0.346, 95% CI =−0.870 to 0.179, P-value =0.197) or became only borderline significance after the removal of study by Amminger et al (2007)Citation44 (Hedges’ g=−0.354, 95% CI =−0.745 to 0.038, P-value =0.077). Besides, the significant result of meta-analysis of ABC lethargy would become insignificant after removing data by Bent et al (2014)Citation41 (Hedges’ g=−0.277, 95% CI =−0.799 to 0.246, P-value =0.300).

Meta-regression

There were insufficient data to perform meta-regression analyses.

Primary outcome: changes of BASC

Although three eligible articles compared changes in BASC scale severity between ASD children treated with omega 3 and those treated with placebo, only two studies provided information on BASC externalizing/internalizing problemsCitation40,Citation43 and BASC functional communication/social,Citation40,Citation42 precluding meta-analysis. Nevertheless, these studies found no significant difference in total BASC scale or most BASC subscales between placebo and omega 3 groups. However, one study found significant favorable improvements in BASC functional communication according to teacher’s report in omega 3 groups.Citation42 On the contrary, one study found a significantly less favorable change in BASC social skill by parents’ report in omega 3 groupCitation42 and another study found a significant worsening of BASC externalizing problems in the omega 3 group.Citation40

Primary outcome: differences of clinical improvement as measurement of CGI

In the four eligible articles (n=169), the results of meta-analysis revealed that there was no significant difference in clinical improvement as reflected in CGI-I between omega 3 and placebo (odds ratio =1.255, 95% CI =0.574 to 2.748, P=0.569) (). There was no significant heterogeneity (Q value =2.350, df=3, P-value =0.503, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2F) or Egger’s regression (t value =0.449, df=2, two-tailed P-value =0.697).

Sensitivity test

No change in the overall results was noted after the removal of any one of the recruited study.

Meta-regression

Due to the paucity of data, meta-regression was not possible.

Primary outcome: changes of SRS

Among the three eligible articles (n=97), there was only borderline improved response by placebo in SRS total scores than those by omega 3 (k=3, Hedges’ g=0.367, 95% CI =−0.025 to 0.758, P-value =0.066; difference in means =3.143, 95% CI =−0.090 to 6.376, P=0.057) () without significant heterogeneity (Q value =0.269, df=2, P-value =0.874, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2G) or Egger’s regression (t value =3.118, df=1, two-tailed P-value =0.198) was noted.

Sensitivity test

No change in the overall result was noted after the removal of any one of the recruited study.

Meta-regression

There were insufficient data for meta-regression analysis.

Secondary outcomes: dropout rate

Among the five eligible studies, no difference in dropout rate between children receiving omega 3 and those treated by placebo was noted (odds ratio =0.853, 95% CI =0.257 to 2.830, P=0.795) (). There was no significant heterogeneity (Q value =7.052, df=4, P-value =0.133, I2=43.275%, τ=0.880) or publication bias via inspection of funnel plot (Figure S2H) or Egger’s regression (t value =0.722, df=3, two-tailed P-value =0.522).

Figure 3 Meta-analysis of difference of (A) dropout rate and (B) rate of discontinuation from study due to side effect in ASD children treated with omega 3 and placebo.

Notes: (A) There was no any significant difference between the dropout rate in ASD children receiving omega 3 and those receiving placebo (P=0.795). (B) There was no any significant difference between the rate of discontinuation from study due to side effect between ASD children receiving omega 3 and those receiving placebo (P=0.707).
Abbreviations: ASD, autism spectrum disorder; CI, confidence interval.
Figure 3 Meta-analysis of difference of (A) dropout rate and (B) rate of discontinuation from study due to side effect in ASD children treated with omega 3 and placebo.

Sensitivity test

No change in the overall result was noted after the removal of any one of the recruited study.

Meta-regression

Meta-regression analysis revealed no significant association between dropout rate and clinical variables, including mean age (P=0.462), female proportion (P=0.848), and duration of omega 3 treatment (P=0.658). However, there was significantly positive association between dropout rate and daily dosage of omega 3 (slope =1.804, k=5, P=0.031), that is, the higher the daily dosage of omega 3, the higher dropout rate in the omega 3 treatment groups.

Secondary outcomes: difference of rate of discontinuation due to side effects

Meta-analysis demonstrated no significant difference in the rate of discontinuation due to side effects between children receiving omega 3 and those treated by placebo (odds ratio =0.734, 95% CI =0.147 to 3.666, P=0.707) () without significant heterogeneity (Q value =1.964, df=2, P-value =0.375, I2<0.001%, τ<0.001) or publication bias via inspection of funnel plot (Figure S2I) or Egger’s regression (t value =1.794, df=1, two-tailed P-value =0.324).

Sensitivity test

No change in the overall result was noted after the removal of any one of the recruited study.

Meta-regression

There were insufficient data for meta-regression analysis.

Subgroup meta-analysis in treatment duration <1 or >1 year

There were insufficient data for subgroup meta-analysis comparing treatment duration of >1 or <1 year.

Discussion

Our preliminary meta-analysis recruited six studies in total (refer for the characteristics of main outcome in each study) and suggests that supplementation of omega 3 fatty acids may improve scores on the ABC hyperactivity, ABC lethargy, and ABC stereotypy subscales (n=109). However, no significant differences in clinical improvement as measurement of CGI-I (n=169) or SRS total scores (n=97) were found between the omega 3 and placebo groups. The results of our study largely resemble those of two previous meta-analyses, although our study showed additional benefits of supplementation of omega 3 fatty acids on improving ABC hyperactivity and stereotypy subscales. In fact, the previous meta-analyses suggested that omega 3 groups had a more favorable outcome on ABC hyperactivity subscale, but the result was not significant.Citation24 The meta-analysis by Horvath et al included only two trials for each ABC subscale meta-analysis, because the results of the ABC assessments were separated into two groups: parents’ ratings (n=82) and teachers’ or clinicians’ ratings (n=69). The main difference between this study and the more recent meta-analysis by Horvath et al is that our study had a larger sample size for each ABC subscale meta-analysis (n=109 versus n=82). It is possible that the effects of supplementation of omega 3 fatty acids on ABC hyperactivity and ABC stereotypy were not detected in the previous meta-analyses, because the sample size was too small.

Table 2 Summary of clinical features of participants in included studies

Most studies included in our meta-analysis used dosages of omega 3 between 1.3 and 1.5 g/day with duration of treatment ranging from 6 to 24 weeks. Only one study used a much lower dosage of omega 3 (200 mg/day), but that study was only included for assessment of CGI-I due to a lack of other outcome data.Citation42 Only one author declared competing interest among all the included trials.Citation40 Most trials in our meta-analysis had fair study quality (average Jadad scores: 4.67), and there was no evidence of publication bias or significant heterogeneity between trials. However, most participants were males and younger than 12 years and most trials excluded nonverbal participants or those with severe intellectual disabilities; therefore, the study results may only be applicable to small subgroups of ASD patients.

Our meta-analysis suggests that supplementation of omega 3 fatty acid had a significant positive effect on ABC hyperactivity (k=4, difference in means =−2.692, 95% CI =−5.364 to −0.020, P=0.048), ABC lethargy (k=4, difference in means =−1.969, 95% CI =−3.566 to −0.372, P=0.016), and ABC stereotypy (k=4, difference in means =−1.071, 95% CI =−2.114 to −0.029, P=0.044) subscales when compared with the placebo (n=109). However, the effect sizes were small for all three outcome measurements (Hedges’ g=−0.348, 95% CI =−0.716 to 0.021, P-value =0.064 for ABC hyperactivities; Hedges’ g=−0.447, 95% CI =−0.817 to −0.077, P-value =0.018 for ABC lethargy; Hedges’ g=−0.404, 95% CI =−0.773 to −0.035, P-value =0.032 for ABC stereotypy). The ABC scale was initially designed to assess treatment effects on severely mentally retarded individualsCitation28 but gradually adopted as an outcome measure used by pharmacological studies for autism treatment.Citation45,Citation46 When compared with SRS scores, the ABC was also frequently used for behavioral problems in other diagnostic groups such as disruptive behavioral disorders or intellectual disabilitiesCitation47,Citation48 and can provide more information on externalizing problems, such as hyperactivities and irritability.Citation49 Our meta-analysis showed significant positive treatment effects of supplementation of omega 3 fatty acids relative to placebo not only on core symptoms of autism such as lethargy (social withdrawal) and stereotypy but also on other related secondary behavioral problems such as hyperactivity. Previous meta-analyses also found positive treatment effect on the ABC hyperactivity subscales (MD: 3.46, 95% CI: −0.97 to 7.70 and MD: 2.09, 95% CI: −0.91 to 5.09), but the results were not statistically significant.Citation23,Citation24 Similarly, although most studies showed trend favoring omega 3 groups on the ABC hyperactivity subscale, none of the results reached statistical significance. However, after combining the results of these studies, we found that supplementation of omega 3 fatty acids had significant treatment effect on the ABC hyperactivity subscale. In fact, the potential benefit of supplementation of omega 3 fatty acids on reducing hyperactivity was not only observed in ASD patients, several clinical trials focusing on ADHD also found greater reduction in hyperactivity with supplementation of omega 3 fatty acids.Citation50,Citation51 It was also proposed that children with hyperactivity may have difficulty in absorbing omega 3 fatty acids, which is essential for normal brain function.Citation52 However, our study only showed an average of 2.69 points better improvement in the ABC hyperactivity subscale, with baseline score of 14.6–33.3 out of a total of 45 points in the included studies, and this treatment effect on hyperactivity was small when compared with treatment with risperidone (11.42 points greater improvement relative to placebo), aripiprazole (7.93 points greater improvement relative to placebo), or methylphenidate (9.6 points greater improvement relative to placebo) in other trials.Citation47,Citation53Citation56 Moreover, the effects’ size for improvement in ABC hyperactivity subscale was small and only reached borderline significance (Hedges’ g=−0.348, 95% CI =−0.716 to 0.021). Nevertheless, even though the improvement in hyperactivity with supplementation of omega 3 fatty acids in ASD patients was small compared with other medications, supplementation of omega 3 fatty acids was safer and had fewer side effects. Therefore, supplementation of omega 3 fatty acids may still be worth trying if the result could be confirmed by further studies.

As for individual study results on ABC lethargy and stereotypy, one study showed significant improvements in the omega 3 group compared to the placebo group on both the ABC lethargy and ABC stereotypy subscales,Citation41 one study showed significant improvements in the omega 3 group compared to the placebo group only on ABC lethargy subscaleCitation25 and two studies did not find any significant difference between placebo and omega 3 groups.Citation43,Citation44 Overall, our meta-analysis showed a significant but small improvement on both subscales. Specifically, the ABC lethargy subscale in omega 3 groups had an average of 1.969 points improvement, with baseline scores 5.4 to 30 out of a total of 48 points among studies. The ABC stereotypy subscale in omega 3 groups had an average of 1.071 points better improvement, with baseline scores 2.8 to 14.4 out of a total of 21 points among studies. However, the effect sizes were also small for both ABC lethargy subscale (Hedges’ g=−0.447, 95% CI =−0.817 to −0.077, P-value =0.018) and ABC stereotypy subscale (Hedges’ g=−0.404, 95% CI =−0.773 to −0.035, P-value =0.032). Due to the relatively small improvement and lack of previous report about such treatment effects, these results need further investigation.

Our meta-analysis found no significant difference in clinical improvement as measurement of CGI-I between omega 3 and placebo (CGI-I =1 or 2) between placebo and omega 3 groups (n=169). Although a greater number of participants appeared to produce a positive response in most trials except one,Citation43 none of these results reached statistical significance.Citation41Citation43 It is possible that effects of supplementation of omega 3 fatty acids were too small to produce significant result on the CGI-I score as improvement in ABC hyperactivity, lethargy, and stereotypy. Similarly, our meta-analysis and none of the included studies found significant improvement in omega 3 groups in total SRS scores (n=97). Therefore, there is still lack of clear evidence to support the use of omega 3 in improving ASD core symptoms as measured by CGI-I scores or SRS scores.

Our preliminary data suggest that omega 3 is well tolerated among the treatment groups. Gastrointestinal discomfort and irritability were most commonly reported side effects in the omega 3 groups. Nevertheless, our meta-analysis did not find a difference between dropout rate or rate of discontinuation due to side effects between omega 3 and placebo groups. Similarly, none of the studies found significant difference in side effects between placebo and omega 3 groups and none reported serious side effects. However, our meta-regression found that there was significantly positive association between dropout rate and daily dosage of omega 3 (slope =1.804, k=5, P=0.031). Although, little information was provided on the relationship between dosage and side effects on individual studies, this result suggested that higher dosage of omega 3 treatment is associated with higher dropout rate. Further studies may need to explore the relationship between dosage of omega 3 and dropout rate, as this result may indicate that higher dosage of omega 3 treatment is less tolerable due to variety of reasons including medication side effects.

Limitations

There were some limitations in our meta-analysis. First, there were only six trials with a total of 194 participants. The sample size in this meta-analysis is still not sufficient to provide any robust evidence. Besides, we cannot exclude the possibility that certain negative findings in our meta-analysis may be due to the lack of adequate study power. Second, since the longest treatment duration was 24 weeks and the largest dosage of omega 3 was 1.5 g/day, the treatment effect above this dosage or this duration cannot be determined. Third, most of the included studies had many exclusion criteria such as severe medical illness, no language ability, and severe intellectual disability; therefore, the study result may not be applicable to patients with more severe disease and those with nonverbal autism. Fourth, since most participants were allowed to receive behavioral treatments and some trials did not exclude the use of other psychiatric medications, we cannot rule out the possibility that the observed improvement may also come from other interventions. Finally, as some authors only published statistically significant results and did not respond to our email request for more data, we were unable to obtain all the data from included RCTs. It is unclear how this may affect the results of our meta-analysis.

Conclusion

This preliminary meta-analysis suggests that supplementation of omega 3 fatty acids is well tolerated and may produce a small but positive effect on reducing hyperactivity in ASD patients. However, in the absence of significant improvement in CGI-I score and relatively small sample size, we still cannot draw reliable conclusion about potential effects of supplementation of omega 3 fatty acids on ASD patients. The finding that supplementation of omega 3 fatty acids improves lethargy and stereotypy is also preliminary and needs further investigations. Nevertheless, given relatively few side effects compared to those of other medications, we encourage further trials to continue to explore potential benefit of supplementation of omega 3 fatty acids in ASD patients and also to include wider range of participants such as lower functioning autism and older age groups.

Acknowledgments

The authors declare no funding were received in relation to the subject of this study. Y-SC and P-TT contributed equally as first authors.

Disclosure

The authors report no conflicts of interest in this work.

References

  • BaxterAJBrughaTSErskineHEScheurerRWVosTScottJGThe epidemiology and global burden of autism spectrum disordersPsychol Med201545360161325108395
  • Association APDiagnostic and Statistical Manual of Mental Disorders5th edWashington, DCAmerican Psychiatric Association2013
  • ChristensenDLBaioJVan Naarden BraunKPrevalence and characteristics of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2012MMWR Surveill Summ2016653123
  • ChastePLeboyerMAutism risk factors: genes, environment, and gene-environment interactionsDialogues Clin Neurosci201214328129223226953
  • FakhouryMAutistic spectrum disorders: a review of clinical features, theories and diagnosisInt J Dev Neurosci201543707725862937
  • BoatTFWuJTMental Disorders and Disabilities among Low-Income ChildrenWashington, DCNational Academies Press (US)2015
  • Van Naarden BraunKChristensenDDoernbergNTrends in the prevalence of autism spectrum disorder, cerebral palsy, hearing loss, intellectual disability, and vision impairment, metropolitan atlanta, 1991–2010PLoS One2015104e012412025923140
  • KingMBearmanPDiagnostic change and the increased prevalence of autismInt J Epidemiol20093851224123419737791
  • LundstromSReichenbergAAnckarsaterHLichtensteinPGillbergCAutism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samplesBMJ2015350h196125922345
  • van ElstKBruiningHBirtoliBTerreauxCBuitelaarJKKasMJFood for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disordersNeurosci Biobehav Rev20144536937825025657
  • LamJSuttonPKalkbrennerAA systematic review and meta-analysis of multiple airborne pollutants and autism spectrum disorderPLoS One2016119e016185127653281
  • AccordinoREKiddCPolitteLCHenryCAMcDougleCJPsychopharmacological interventions in autism spectrum disorderExpert Opin Pharmacother201617793795226891879
  • VancasselSDurandGBarthelemyCPlasma fatty acid levels in autistic childrenProstaglandins Leukot Essent Fatty Acids20016511711487301
  • El-AnsaryAKBachaAGAl-AyahdiLYImpaired plasma phospholipids and relative amounts of essential polyunsaturated fatty acids in autistic patients from Saudi ArabiaLipids Health Dis2011106321513514
  • BozzatelloPBrignoloEDe GrandiEBellinoSSupplementation with omega-3 fatty acids in psychiatric disorders: a review of literature dataJ Clin Med201658E6727472373
  • PolitiPRocchettiMEmanueleERondanelliMBaraleFRandomized placebo-controlled trials of omega-3 polyunsaturated fatty acids in psychiatric disorders: a review of the current literatureCurr Drug Discov Technol201310324525321838664
  • SimopoulosAPThe importance of the ratio of omega-6/omega-3 essential fatty acidsBiomed Pharmacother200256836537912442909
  • SimopoulosAPImportance of the ratio of omega-6/omega-3 essential fatty acids: evolutionary aspectsWorld Rev Nutr Diet20039212214579680
  • CooperRETyeCKuntsiJVassosEAshersonPThe effect of omega-3 polyunsaturated fatty acid supplementation on emotional dysregulation, oppositional behaviour and conduct problems in ADHD: a systematic review and meta-analysisJ Affect Disord201619047448226551407
  • MatsonJLNebel-SchwalmMSComorbid psychopathology with autism spectrum disorder in children: an overviewRes Dev Disabil200728434135216765022
  • SimonoffEPicklesACharmanTChandlerSLoucasTBairdGPsychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sampleJ Am Acad Child Adolesc Psychiatry200847892192918645422
  • MattilaMLHurtigTHaapsamoHComorbid psychiatric disorders associated with Asperger syndrome/high-functioning autism: a community- and clinic-based studyJ Autism Dev Disord20104091080109320177765
  • JamesSMontgomeryPWilliamsKOmega-3 fatty acids supplementation for autism spectrum disorders (ASD)Cochrane Database Syst Rev201111CD00799222071839
  • HorvathALukasikJSzajewskaHOmega-3 fatty acid supplementation does not affect autism spectrum disorder in children: a systematic review and meta-analysisJ Nutr2017147336737628077731
  • YuiKKoshibaMNakamuraSKobayashiYEffects of large doses of arachidonic acid added to docosahexaenoic acid on social impairment in individuals with autism spectrum disorders: a double-blind, placebo-controlled, randomized trialJ Clin Psychopharmacol201232220020622370992
  • LiberatiAAltmanDGTetzlaffJThe PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaborationPLoS Med200967e100010019621070
  • JadadARMooreRACarrollDAssessing the quality of reports of randomized clinical trials: is blinding necessary?Control Clin Trials19961711128721797
  • AmanMGBurrowWHWolfordPLThe Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homesAm J Ment Retard199510032832928554775
  • ReynoldsCRKamphausRWBehavior Assessment System for ChildrenCircle Pines, MNAGS Publishing2004
  • BusnerJTargumSDThe clinical global impressions scale: applying a research tool in clinical practicePsychiatry (Edgmont)2007472837
  • ConstantinoJNThe Social Responsiveness ScaleLos Angeles, CAWestern Psychological Services2002
  • BorensteinMHedgesLVHigginsJPRothsteinHRA basic introduction to fixed-effect and random-effects models for meta-analysisRes Synth Methods2010129711126061376
  • HigginsJPThompsonSGQuantifying heterogeneity in a meta-analysisStat Med200221111539155812111919
  • BorensteinMHigginsJPHedgesLVRothsteinHRBasics of meta-analysis: I2 is not an absolute measure of heterogeneityRes Synth Methods20178151828058794
  • HigginsJPGreenS10.4.3.1 recommendations on testing for funnel plot asymmetryHigginsJPGreenSCochrane Handbook for Systematic Reviews of Interventions. 5.1.0Cochrane Library2011 Available from: http://training.cochrane.org/handbookAccessed September 21, 2017
  • EggerMDavey SmithGSchneiderMMinderCBias in meta-analysis detected by a simple, graphical testBMJ199731571096296349310563
  • DuvalSTweedieRTrim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysisBiometrics200056245546310877304
  • TobiasAAssessing the influence of a single study in meta-analysisStata Tech Bull1999471517
  • DaveyJTurnerRMClarkeMJHigginsJPCharacteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysisBMC Med Res Methodol20111116022114982
  • MankadDDupuisASmileSA randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autismMol Autism201561825798215
  • BentSHendrenRLZandiTInternet-based, randomized, controlled trial of omega-3 fatty acids for hyperactivity in autismJ Am Acad Child Adolesc Psychiatry201453665866624839884
  • VoigtRGMellonMWKatusicSKDietary docosahexaenoic acid supplementation in children with autismJ Pediatr Gastroenterol Nutr201458671572224345834
  • BentSBertoglioKAshwoodPBostromAHendrenRLA pilot randomized controlled trial of omega-3 fatty acids for autism spectrum disorderJ Autism Dev Disord201141554555420683766
  • AmmingerGPBergerGESchäferMRKlierCFriedrichMHFeuchtMOmega-3 fatty acids supplementation in children with autism: a double-blind randomized, placebo-controlled pilot studyBiol Psychiatry200761455155316920077
  • KentJMKushnerSNingXRisperidone dosing in children and adolescents with autistic disorder: a double-blind, placebo-controlled studyJ Autism Dev Disord20134381773178323212807
  • MarcusRNOwenRManosGAripiprazole in the treatment of irritability in pediatric patients (aged 6–17 years) with autistic disorder: results from a 52-week, open-label studyJ Child Adolesc Psychopharmacol201121322923621663425
  • LoyJHMerrySNHetrickSEStasiakKAtypical antipsychotics for disruptive behaviour disorders in children and youthsCochrane Database Syst Rev20129CD00855922972123
  • SchmidtJDHueteJMFodstadJCChinMDKurtzPFAn evaluation of the Aberrant Behavior Checklist for children under age 5Res Dev Disabil20133441190119723376629
  • KarabekirogluKAmanMGValidity of the aberrant behavior checklist in a clinical sample of toddlersChild Psychiatry Hum Dev20094019911018600444
  • SinnNBryanJWilsonCCognitive effects of polyunsaturated fatty acids in children with attention deficit hyperactivity disorder symptoms: a randomised controlled trialProstaglandins Leukot Essent Fatty Acids2008784–531132618514501
  • SinnNBryanJEffect of supplementation with polyunsaturated fatty acids and micronutrients on learning and behavior problems associated with child ADHDJ Dev Behav Pediatr2007282829117435458
  • ColquhounIBundaySA lack of essential fatty acids as a possible cause of hyperactivity in childrenMed Hypotheses1981756736797196985
  • GhanizadehASahraeizadehABerkMA head-to-head comparison of aripiprazole and risperidone for safety and treating autistic disorders, a randomized double blind clinical trialChild Psychiatry Hum Dev201445218519223801256
  • Research Units on Pediatric Psychopharmacology Autism NRandomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivityArch Gen Psychiatry200562111266127416275814
  • AmanMRettigantiMNagarajaHNTolerability, safety, and benefits of risperidone in children and adolescents with autism: 21-month follow-up after 8-week placebo-controlled trialJ Child Adolesc Psychopharmacol201525648249326262903
  • PearsonDASantosCWAmanMGEffects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptomsJ Child Adolesc Psychopharmacol201323533735123782128