Abstract
Background
It has been suggested that impairments associated with autism spectrum disorders (ASD) may be partially explained by deficits of omega‐3 fatty acids, and that supplementation of these essential fatty acids may lead to improvement of symptoms.
Objectives
To review the efficacy of omega‐3 fatty acids for improving core features of ASD (for example, social interaction, communication, and stereotypies) and associated symptoms.
Search methods
We searched the following databases on 2 June 2010: CENTRAL (2010, Issue 2), MEDLINE (1950 to May Week 3 2010), EMBASE (1980 to 2010 Week 21), PsycINFO (1806 to current), BIOSIS (1985 to current), CINAHL (1982 to current), Science Citation Index (1970 to current), Social Science Citation Index (1970 to current), metaRegister of Controlled Trials (20 November 2008) and ClinicalTrials.gov (10 December 2010). Dissertation Abstracts International was searched on 10 December 2008, but was no longer available to the authors or editorial base in 2010.
Selection criteria
All randomised controlled trials of omega‐3 fatty acids supplementation compared to placebo in individuals with ASD.
Data collection and analysis
Three authors independently selected studies, assessed them for risk of bias and extracted relevant data. We conducted meta‐analysis of the included studies for three primary outcomes (social interaction, communication, and stereotypy) and one secondary outcome (hyperactivity).
Main results
We included two trials with a total of 37 children diagnosed with ASD who were randomised into groups that received either omega‐3 fatty acids supplementation or a placebo. We excluded six trials because they were either non‐randomised controlled trials, did not contain a control group, or the control group did not receive a placebo. Overall, there was no evidence that omega‐3 supplements had an effect on social interaction (mean difference (MD) 0.82, 95% confidence interval (CI) ‐2.84 to 4.48, I2 = 0%), communication (MD 0.62, 95% CI ‐0.89 to 2.14, I2 = 0%), stereotypy (MD 0.77, 95% CI ‐0.69 to 2.22, I2 = 8%), or hyperactivity (MD 3.46, 95% CI ‐0.79 to 7.70, I2 = 0%).
Authors' conclusions
To date there is no high quality evidence that omega‐3 fatty acids supplementation is effective for improving core and associated symptoms of ASD. Given the paucity of rigorous studies in this area, there is a need for large well‐conducted randomised controlled trials that examine both high and low functioning individuals with ASD, and that have longer follow‐up periods.
Keywords: Child; Child, Preschool; Female; Humans; Male; Dietary Supplements; Child Development Disorders, Pervasive; Child Development Disorders, Pervasive/diet therapy; Docosahexaenoic Acids; Docosahexaenoic Acids/administration & dosage; Eicosapentaenoic Acid; Eicosapentaenoic Acid/administration & dosage; Fatty Acids, Omega-3; Fatty Acids, Omega-3/therapeutic use; Interpersonal Relations; Randomized Controlled Trials as Topic
Plain language summary
Omega‐3 fatty acids for autism spectrum disorders (ASD)
It has been suggested that difficulties associated with ASD may be explained in part by lack of omega‐3 fatty acids, and that supplementation of these essential fatty acids may lead to improvement of symptoms. The purpose of this review was to assess the evidence for the effectiveness of omega‐3 supplementation for core features of ASD and associated symptoms. We found only two small randomised controlled trials that evaluated omega‐3 fatty acids for ASD. There is insufficient evidence that omega‐3 fatty acids supplementation is an effective treatment for ASD. However, high quality large randomised controlled trials are needed before definite recommendations about this treatment can be made.
Background
Description of the condition
Autism spectrum disorders (ASD) consist of a continuum of neurodevelopmental disorders, usually considered synonymous with pervasive developmental disorders (PDD).These are characterised by impairments in social interaction and communication, and stereotypies, with onset before the age of three (Diagnostic and Statistical Manual of Mental Disorders, fourth edition text revision (DSM‐IV‐TR) (APA 2000)). ASD is an umbrella term used clinically that encompasses all autism‐related disorders including Asperger's disorder, autistic disorder, and PDD not otherwise specified (NOS) (Landa 2008).
Individuals with ASD typically act in socially inappropriate ways and have difficulty understanding the social behaviour of others (Hobson 1998; Jahr 2007). They may have difficulty in social reciprocity, expressing and recognising certain emotions, and understanding the moods of others (Bacon 1998; Wallace 2008; Bal 2010). As such, they are frequently thought to be aloof and unattached. Individuals with ASD also often have language impairments (for example, semantic and pragmatic deficits (Rapin 2003)) and demonstrate abnormal eye contact patterns (for example, maintaining eye contact for too long (Dalton 2005; Clifford 2007; Spezio 2007)). Some individuals with ASD may engage in aberrant behaviours that include motor stereotypies (for example, hand flapping, rocking, body spinning) and self‐injurious behaviours (for example, head‐banging); the latter is often associated with the more severe autism spectrum disorders (APA 2000). Furthermore, individuals with ASD prefer routine to change, and have great difficulty with new experiences (APA 2000). Children with ASD frequently use toys in restricted and peculiar ways, including spinning or flapping objects for extended periods of time (APA 2000); they also prefer isolated play, avoid peer interaction, and have a limited ability for creative symbolic play that involves pretence (APA 2000; Rogers 2005). Deficits in social interaction make it difficult for children with ASD to play and create close relationships with other children, while also putting them at greater risk for bullying (Montes 2007).
Recent estimates report the total prevalence of all ASD to be approximately 66 per 10,000 children in the USA (Rice 2007) and approximately 116 per 10,000 children in the UK (Baird 2006). This appears to indicate an increase in previous estimates, such as those from studies from the early 1970s, which estimated prevalence of autism to be from 0.7 per 10,000 (Treffert 1970) to 4.8 per 10,000 (Wing 1976). Recent revisions to the nomenclature of autism (for example, the addition of the continuum‐based ASD label) have broadened the diagnostic criteria allowing varying degrees of clinical presentations and manifestations of autism‐related disorders to be recognised; increases in the prevalence of autism‐related disorders is said to be due, in part, to such changes in classification (Rutter 2005). It has also been suggested that improved detection of ASD, improved social policies, and increased public awareness have also influenced prevalence estimates (Saracino 2010). Males are three to four times more likely than females to be diagnosed with an ASD (Baird 2006; Rice 2007; Saracino 2010).
Current treatments
Due in part to the heterogeneous nature of ASD and to lack of knowledge of the precise aetiology of this lifelong disorder, none of the many interventions available is capable of providing a 'cure'. The numerous treatments that do exist (for example, behavioural and pharmacological interventions) target symptoms of ASD. Behavioural interventions, such as Applied Behaviour Analysis, typically involve teaching and eliminating social behaviours through reinforcement (Simpson 2001). Pharmacological interventions are often used as adjuncts to target specific behaviours and symptoms of ASD that affect functioning (for example, aggression, hyperactivity, insomnia, and self‐injury (Posey 2001)).
Description of the intervention
Omega 3 and 6 supplementation
Essential fatty acids are polyunsaturated fatty acids that the human body does not produce and are necessary for normal development and functioning of the brain and the immune system (Yehuda 2005). There are several key types of essential fatty acids. Fish and seafood are major sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are types of long chain omega‐3 fatty acids. Flaxseed, grains, and soya beans are sources of alpha‐linolenic acids (ALA), which are short chain omega‐3 fatty acids. ALA can be converted in the body to EPA and DHA, but this is an inefficient process; it is estimated that less than 5% of ALA in humans is converted to EPA or DHA (Brenna 2002). Vegetable oils are a source of linolenic acid (LA), which is a type of omega‐6 fatty acid; animal fats are also a source of omega‐6. Optimal consumption of omega‐6 to omega‐3 should be 1:1 to 4:1 (Simopoulos 2002). Most modern diets far exceed this ratio, which has been linked with vulnerability to health deficiencies and disorders of mental health (Simopoulos 2003).
How the intervention might work
Omega‐3 deficits or imbalances in the omega‐3:omega‐6 ratio have been linked to various neurodevelopmental disorders, such as attention deficient/hyperactivity disorder, dyslexia, and dyspraxia (Freeman 2000; Vancassel 2001). Randomised controlled trials of omega‐3 supplementation have been conducted for the treatment of attention deficit/hyperactivity disorder, depression, and schizophrenia (Nemets 2002; Peet 2002a; Peet 2002b; Richardson 2002; Su 2003; Richardson 2005).
The premise behind any potential therapeutic benefit from omega‐3 is that the modern diet is deficient in omega‐3 fats or contains too many omega‐6 fats relative to omega‐3s (so called "fatty‐acid imbalance"). Contributing to this imbalance is increased consumption of foods that are processed to have omega‐3 fats removed, often through hydrogenation, in order to prolong food shelf life. Whilst the exact mechanism by which omega‐3 might be of benefit in ASD is not yet fully hypothesised, it is known that certain highly unsaturated fatty acids play key roles in brain structure and function but must be derived from dietary sources (Yehuda 1999). Some believe that more traditional diets contained a greater amount of wild‐harvested seafood and fats from grass‐fed animals. Further sources high in omega‐3 fats were oils from flax and soy bean, and olives. In contrast, the modern diet gets much of its fat from vegetable oils, which are high in omega‐6 fats. It is believed that farmed seafood and grain‐fed animals, especially dairy cows, contain less omega‐3 fats (French 2000; Hauswirth 2004). In addition to this modern malady is the theory that certain families may have a higher need for omega‐3 fats or have inefficiencies in metabolism, so require greater dietary intake. This theory is thought to account for clusters of neurological impairment in families (Simopoulos 2003). However, the evidence base on optimal dose and type of omega‐3 fatty acids supplementation to treat ASD is currently lacking. Although it is generally believed that daily intake of omega‐3s should not exceed three grams, dose‐ranging studies are needed to assess optimal intake, which may differ based on characteristics such as weight, age, and severity of the disorder (Richardson 2006).
Reports of the benefits of omega‐3 fats to treat ASD are not conclusive. One case report (Johnson 2003b) and one non‐comparative cohort study (Patrick 2005b) cited improvements in language skills and learning. Another study (Bell 2004) described parents reports of improvement in general health, cognitive function, motor skills, sleeping, concentration, eye contact and sociability, and a reduction in aggression, irritability, and hyperactivity.
Why it is important to do this review
No curative interventions exist for ASD, and while some treatments may have benefits in ameliorating certain symptoms, they do not result in full remission of symptoms and, in the case of drug therapies, may be accompanied by undesirable side effects such as insomnia, weight gain (Jesner 2010), sadness, withdrawal symptoms, and prolonged seizure (Williams 2010). Parents of children with ASD often act in desperation to find a "cure" for their child. The perseverance of parents in seeking out different modalities is demonstrated by the fact that 74% of children with ASD try complementary and alternative medicines (CAM) (Hanson 2007), compared to 12% of typically‐developing children (Barnes 2008). Most of these treatments are unsupported by evidence; this absence of sound evidence may lead to the continued use of an ineffective or harmful treatment. Fatty acid supplementation is one CAM that has lately been receiving more and more attention in light of study findings that suggest individuals with ASD have fatty acid deficits (Vancassel 2001; Bell 2004; Meguid 2008b; El‐Ansary 2011) that may be overcome with supplementation (Meguid 2008b). To assess the potential benefits and harms of this treatment, a systematic review of RCTs that examine the effect of omega‐3 fatty acids for the treatment of ASD is needed.
Objectives
To review the efficacy of omega‐3 fatty acids for improving core features of ASD (for example, social interaction, communication, and stereotypies) and associated symptoms.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCT) in which any type and any dose of omega‐3 fatty acids supplementation is compared with placebo; the supplementation may be used as an adjunctive treatment (for example, used in addition to behavioural or pharmacological interventions).
Types of participants
Participants of any age diagnosed with an ASD by either established diagnostic criteria (for example, DSM‐IV) or standardised, established instruments (for example, the Childhood Autism Rating Scale).
Types of interventions
Any type and any dose of omega‐3 fatty acids supplementation. Treatment types include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha‐linolenic acids (ALA).
Types of outcome measures
Primary outcomes
Improvement in the following areas, using any measure.
Social interaction.
Communication.
Stereotypy.
Secondary outcomes
Improvements in the following areas, using any measure.
Aggression.
Hyperactivity.
Insomnia.
Self‐injury.
Quality of life for individual and/or family.
Where possible, outcomes have been divided into short term (less than 3 months), medium term (three to six months), and long term (over six months).
Search methods for identification of studies
We first searched databases for this review in December 2008 and repeated these searches in June 2010 to find any new studies published in the intervening period. We did not search Dissertation Abstracts in 2010 because changes at the editorial base meant it was no longer available.
Electronic searches
We searched the following databases.
Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library (2010, Issue 2), searched 2 June 2010. MEDLINE 1950 to May Week 3 2010 (searched 2 June 2010). EMBASE 1980 to Week 21 2010 (searched 2 June 2010). PsycINFO via OVID:1806 to December Week 2008 (searched 5 December 2008). PsycINFO via EBSCOHost:1887 to 2 June 2010 (searched 2 June 2010). BIOSIS1985 to 2 June 2010 (searched 2 June 2010). CINAHL1982 to 2 June 2010 (searched 2 June 2010). Dissertation Abstracts International (searched 10 December 2008). Science Citation Index: 1970 to current (searched 2 June 2010). Social Science Citation Index: 1970 to current to 2 June 2010 (searched 2 June 2010). metaRegister of Controlled Trials (searched 20 November 2008). ClinicalTrials.gov (searched 10 December 2010).
The search terms used for each database are in Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, Appendix 7 and Appendix 8. No language or date restrictions were imposed.
Searching other resources
We searched reference lists from the retrieved articles for relevant trials not already identified.
To identify further relevant published and unpublished trials, we contacted authors of included trials and asked if they knew of any new or unpublished trials.
Since the use of omega‐3 fatty acids to treat ASD is a fairly recent intervention, and frequently occurs outside mainstream medicine, it is possible that trials have been conducted by pharmaceutical and vitamin companies and not published in peer‐reviewed journals. To help identify such trials, we searched the World Wide Web for trials using both scientific and trade names. Common and trade names of omega‐3 preparations identified for us by consumers included: Efalex, fish oil, Nordic Naturals Ultimate Omega, omega‐3 oils, cod liver oil, EPA, linseed oil, flaxseed oil, coromega, DHA, and Eye‐Q.
Data collection and analysis
Analysis methods planned in our protocol that we will use in updates of this review can be found in Table.
1. Analysis methods planned in our protocol that will be used in updates of this review.
| Measures of treatment effect |
We will analyse binary outcomes by calculation of the risk ratio (RR) and its 95% confidence interval (CI). For continuous data, we will calculate mean differences (MD) and 95% confidence intervals if studies use the same rating scales. We will calculate the standardised mean difference (SMD) with 95% confidence intervals if studies use different scales to measure the same outcomes. |
| Unit of analysis issues |
Cluster‐randomised trials
We will assess included trials to determine unit of randomisation, and whether or not this unit of randomisation is consistent with the unit of analysis. Where cluster randomisation has been used, we will extract and use an intraclass correlation coefficient (ICC) to modify results. Where no ICC is given, and a unit of analysis error appears to exist, we will contact trial authors and ask them to provide an ICC or raw data to enable calculation of an ICC. Where ICCs cannot be calculated, we will extrapolate a range of ICCs from similar studies and use them in sensitivity analysis. Cross‐over trials Where cross‐over trials meet the inclusion criteria, we will extract mean and standard error of paired t‐tests in meta‐analysis using the generic inverse variance function. We will note the potential bias from carry‐over effects in the Risk of Bias table, and we will use sensitivity analysis to assess the impact of this on treatment effect. |
| Dealing with missing data |
We will contact the original investigators to request missing data. We will perform intention‐to‐treat analyses in binary data comparisons when missing data are due to participant drop‐out, lack of compliance, etc, and we will conduct sensitivity analyses to assess the effect of including suboptimal data. |
| Assessment of heterogeneity |
We will assess clinical heterogeneity by comparing the between‐trials distribution of participant characteristics, trial characteristics, and intervention characteristics (for example, treatment type and dose). We will evaluate statistical heterogeneity using I2 and the Chi2 test of heterogeneity (with statistical significance set at P < 0.10). We will consider I2 values less than 40% as indicating low heterogeneity, values between 41% and 69% as indicating moderate heterogeneity, and values greater than 70% as indicating substantial heterogeneity. We will perform a random‐effects model meta‐analysis if substantial heterogeneity is found. |
| Assessment of reporting biases |
If sufficient studies are found, we will use funnel plots to investigate the relationship between intervention effect and study size. Asymmetry of a funnel plot may indicate, inter alia, publication bias or poor methodological quality (Egger 1997). We will explore possible reasons for any asymmetry found. |
| Data synthesis |
We will undertake meta‐analyses using both fixed‐effect and random‐effects models. |
| Subgroup analysis and investigation of heterogeneity |
We will examine clinical heterogeneity, if found, in subgroup analyses. If appropriate, we will conduct subgroup analyses for treatment dosage, treatment type (for example, EPA or DHA), treatment duration, and different age groups (adults vs. children, preschool vs. school‐age). |
| Sensitivity analysis |
We will conduct sensitivity analyses to investigate the influence of trials at risk of greater bias. For example, cross‐over trials, trials where allocation concealment is inadequate, intention‐to‐treat analysis is not done or is unclear, and blinding is not done or is unclear. |
Selection of studies
All authors independently assessed the titles and the abstracts of the downloaded citations. We obtained the full text of a study that met, or was likely to meet, the predefined inclusion criteria. The Characteristics of excluded studies table contains the reasons why studies were excluded.
Data extraction and management
The authors extracted from the included studies the following information, which is presented in the Characteristics of included studies table:
study methods and setting;
participant details;
intervention details;
outcomes.
No disagreements arose.
Assessment of risk of bias in included studies
We assessed the risk of bias in the included studies using the tool described in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008). The following domains were assessed:
sequence generation;
allocation concealment;
blinding;
incomplete outcome data;
selective reporting;
other bias.
A 'Risk of bias' table was created for the included studies, which indicates the study's performance in each of the above domains. The categories are defined as: low risk of bias; high risk of bias; unclear risk of bias (i.e. uncertain/unknown risk of bias).
Measures of treatment effect
Binary data
We did not include any binary data in this review.
Continuous data
We calculated mean differences (MD) using a 95% confidence interval (CI), since the included studies used the same rating scale.
Unit of analysis issues
We did not identify any unit of analysis issues: randomisation, reporting, and analysis in the included studies were all per individual participant.
Dealing with missing data
We contacted trial investigators when insufficient data were reported; we received no data.
Assessment of heterogeneity
We evaluated statistical heterogeneity using I2 and the Chi2 test of heterogeneity (with statistical significance set at P < 0.10). Chi2 tests were not significant and I2 values were less than 40%, indicating low heterogeneity. Clinical heterogeneity is discussed in the review.
Assessment of reporting biases
Due to a lack of included trials, we did not use funnel plots to investigate the relationship between intervention effect and study size.
Data synthesis
We conducted meta‐analysis using both a random‐effects model and a fixed‐effect model for the following outcomes.
Primary outcomes
Social interaction.
Communication.
Stereotypy.
Secondary outcomes
Hyperactivity.
Additional outcomes not specified in our protocol
Irritability.
The random‐effects model and the fixed‐effect model yielded similar results; since there was no significant statistical heterogeneity among the trials, we have only provided results of the slightly more conservative fixed‐effect model.
Subgroup analysis and investigation of heterogeneity
Due to a lack of data, we did not conduct subgroup analysis.
Sensitivity analysis
Due to an insufficient number of studies, we did not conduct sensitivity analysis.
Results
Description of studies
Results of the search
Our search strategy identified 202 citations, of which 13 were deemed to be potentially eligible based on the title or abstract; we obtained full‐text copies of these 13 studies and inspected them. After all full‐text copies had been reviewed, we included two studies (Amminger 2007; Bent 2011) and excluded six studies (Johnson 2003a; Patrick 2005a; Meguid 2008a; Politi 2008; Meiri 2009; Johnson 2010). Four studies are ongoing (NCT00467818; NCT01248130; NCT01248728; NCT01260961), and one is awaiting classification (NCT00577447); we have not yet received data for this study from the trialists.
Included studies
The studies included in this review were reported to be randomised and double‐blind (Amminger 2007; Bent 2011).
Participants
A total of 40 participants were randomised in the two trials: Amminger 2007 randomised 13 children who had been diagnosed with autistic disorder, based on DSM‐IV criteria, the ADI‐R, and the ADOS (all males; mean age of 10.5 years in the experimental group and 12.1 years in the control group); while Bent 2011 randomised 27 children who were diagnosed with autism spectrum disorder, based on the ADOS, the SCQ, and DSM‐IV TR criteria (24 males and three females; mean age of 5.8 years). One trial was conducted in Vienna, Austria at a centre for long‐term treatment of autistic children (Amminger 2007), and the other study was conducted in the United States at the University of California, Davis (Bent 2011).
Interventions
Omega‐3 fatty acids were administered orally in both trials, either as a capsule (Amminger 2007) or as a pudding (Bent 2011). The doses of omega‐3 fatty acids supplementation ranged from 1.3 g/day (0.7 g of eicosapentaenoic acid and 0.46 g of docosahexaenoic acid) (Bent 2011) to 1.5 g/day (0.84 g of eicosapentaenoic acid and 0.7 g of docosahexaenoic acid). The duration of supplementation was six weeks (Amminger 2007) and 12 weeks (Bent 2011). Placebos of a similar shape and size were used as the control intervention.
Outcomes
The Aberrant Behavior Checklist (ABC) was used in both trials to assess social withdrawal/lethargy, inappropriate speech, stereotypy, hyperactivity, and irritability. One trial (Bent 2011) also assessed hyperactivity with the Behavioral Assessment System for Children (BASC); communication with the Peabody Picture Vocabulary Test (PPVT) and the Expressive Vocabulary Test (EVT), and social interaction with the Social Responsiveness Scale (SRS). Outcome measures used are listed in Table.
2. Outcome measures.
| Measure | Amminger 2007 | Bent 2011 |
| Aberrant Behavior Checklist (ABC) | Yes | Yes |
| Behavioral Assessment System for Children (BASC) | No | Yes |
| Peabody Picture Vocabulary Test (PPVT) | No | Yes |
| Expressive Vocabulary Test (EVT) | No | Yes |
| Social Responsiveness Scale (SRS) | No | Yes |
See also the Characteristics of included studies table.
Excluded studies
We excluded six studies (Johnson 2003a; Patrick 2005a; Meguid 2008a; Politi 2008; Meiri 2009; Johnson 2010) because they were either non‐randomised controlled trials, did not contain a control group, or the control group did not receive a placebo. See the Characteristics of excluded studies table.
Four studies are ongoing (NCT00467818; NCT01248130; NCT01248728; NCT01260961), and one is awaiting classification (NCT00577447). See the Characteristics of ongoing studies table and the Characteristics of studies awaiting classification table.
Risk of bias in included studies
An overview of the risk of bias is illustrated in Figure. See below for more detailed information on risk of bias.
1.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Participants in Amminger 2007 were reported to be randomised, but no details were available on either sequence generation or allocation concealment. Participants in Bent 2011 were randomised using a computer‐generated randomisation list, which was prepared by a third party.
Blinding
In Amminger 2007, we have assumed that participants were blind to treatment condition; however, it is unclear if the researchers or assessors were blinded. In the other trial (Bent 2011), all participants (including their families) and all study personnel (Iincluding clinicians and assessors) were blinded.
Incomplete outcome data
Participants in both trials were lost to follow up (Amminger 2007; Bent 2011). In Amminger 2007, one individual withdrew from the placebo group due to gastrointestinal complaints and lack of improved symptoms. In Bent 2011, two individuals withdrew: one from the treatment group due to dislike of the taste, and one from the placebo group due to anxiety about blood collection, which was required to assess fatty acids levels.
Selective reporting
All outcomes in all trials were reported and covered important clinical domains.
Other potential sources of bias
Other sources of bias do not appear to exist in either trial.
Effects of interventions
For the current version of this review, meta‐analysis was possible for three primary outcomes (social interaction, communication, and stereotypy), one secondary outcome (hyperactivity), and one additional post hoc outcome (irritability).
Primary outcome: Social interaction
Both included trials reported Aberrant Behavior Checklist (ABC) subscale scores for social withdrawal/lethargy (Amminger 2007; Bent 2011). After combining results from both trials, there was no significant difference between the experimental group and the control group on ABC social withdrawal/lethargy scores (MD 0.82, 95% CI ‐2.84 to 4.48, I2 = 0%) (Analysis 1.1;Figure). One trial (Bent 2011) also reported Social Responsiveness Scale (SRS) scores; results indicated no significant difference between the experimental group and the control group on SRS scores (MD ‐2.6, 95% CI ‐7.99 to 2.79).
1.1. Analysis.
Comparison 1 Aberrant Behavior Checklist (ABC), Outcome 1 Social Withdrawal/Lethargy.
2.
Forest plot of comparison: 1 Aberrant Behavior Checklist (ABC), outcome: 1.1 Social Withdrawal/Lethargy.
Primary outcome: Communication
Both included trials reported ABC subscale scores for inappropriate speech (Amminger 2007; Bent 2011). After combining results from both trials, there was no significant difference between the experimental group and the control group on ABC inappropriate speech scores (MD 0.62, 95% CI ‐0.89 to 2.14, I2 = 0%) (Analysis 1.2; Figure). One trial (Bent 2011) also reported Peabody Picture Vocabulary Test (PPVT) scores and Expressive Vocabulary Test (EVT) scores; results indicated no significant difference between the experimental group and the control group on either PPVT scores (MD 0.8, 95% CI ‐8.63 to 10.23) or EVT scores (MD ‐3.6, 95% CI ‐8.84 to 1.64).
1.2. Analysis.
Comparison 1 Aberrant Behavior Checklist (ABC), Outcome 2 Inappropriate Speech.
3.
Forest plot of comparison: 1 Aberrant Behavior Checklist (ABC), outcome: 1.2 Inappropriate Speech.
Primary outcome: Stereotypy
Both included trials reported ABC subscale scores for stereotypy (Amminger 2007; Bent 2011). After combining results from both trials, there was no significant difference between the experimental group and the control group on ABC stereotypy scores (MD 0.77, 95% CI ‐0.69 to 2.22, I2 = 8%) (Analysis 1.3; Figure).
1.3. Analysis.
Comparison 1 Aberrant Behavior Checklist (ABC), Outcome 3 Stereotypy.
4.
Forest plot of comparison: 1 Aberrant Behavior Checklist (ABC), outcome: 1.3 Stereotypy.
Secondary outcome: Hyperactivity
Both included trials reported ABC subscale scores for hyperactivity (Amminger 2007; Bent 2011). After combining results from both trials, there was no significant difference between the experimental group and the control group on ABC hyperactivity scores (MD 3.46, 95% CI ‐0.79 to 7.70, I2 = 0%) (Analysis 1.4; Figure).
1.4. Analysis.
Comparison 1 Aberrant Behavior Checklist (ABC), Outcome 4 Hyperactivity.
5.
Forest plot of comparison: 1 Aberrant Behavior Checklist (ABC), outcome: 1.4 Hyperactivity.
Additional outcome: Irritability
Both included trials reported ABC subscale scores for irritability (Amminger 2007; Bent 2011). After combining results from both trials, there was no significant difference between the experimental group and the control group on ABC irritability scores (MD ‐0.21, 95% CI ‐3.59 to 3.18, I2 = 0%) (Analysis 1.5; Figure).
1.5. Analysis.
Comparison 1 Aberrant Behavior Checklist (ABC), Outcome 5 Irritability.
6.
Forest plot of comparison: 1 Aberrant Behavior Checklist (ABC), outcome: 1.5 Irritability.
Discussion
Summary of main results
Few rigorous studies have been completed and reported to date on omega‐3 fatty acids for ASD; only two trials were included in this review, with a total of 37 participants. The included studies reported data on the primary outcomes of social interaction, communication, and stereotypy, and reported data on the secondary outcome of hyperactivity. No statistically significant improvements were reported, but the largest positive effect for treatment was reported for hyperactivity.
Overall completeness and applicability of evidence
Two trials with a total of 37 children is not sufficient to provide robust evidence. Additionally, the total sample size predominantly comprised males, and all included participants, ranging in age from three to 17 years, displayed moderate to severe symptoms of ASD. (All participants in Amminger 2007 had a diagnosis of autistic disorder, and participants in Bent 2011 had a mean Clinical Global Impression Severity score of 4.4, indicating greater than moderate illness.) As such, these findings are only applicable to a subgroup of individuals with ASD.
Quality of the evidence
The quality of the included trials varied. Although the overall risk of bias in Bent 2011 was considered to be low, the overall risk of bias in Amminger 2007 was uncertain; specifically, the adequacy of blinding, allocation concealment, and random sequence generation in Amminger 2007 was unclear. As such, no robust conclusion can be made with regard to the objective of the review.
Potential biases in the review process
Although we attempted to minimise publication bias by using a comprehensive search strategy and by searching numerous sources, there is the possibility that we may have failed to identify trials or experiments.
Agreements and disagreements with other studies or reviews
A systematic review evaluating the effectiveness of omega‐3 fatty acids for ASD (Bent 2009) was published after the protocol for this review was published. The results of our review mirror and support the recommendations made by Bent 2009; we agree that the effectiveness of omega‐3 fatty acids for ASD cannot be determined, since there is a dearth of scientific evidence for this topic. Although Bent 2009 located many of the same studies as were retrieved by our search, only one randomised controlled trial was included in that review, and no mention was made of the existence of ongoing studies that are currently examining this topic. We are hopeful that the completion of these trials will provide valuable data to better assess whether omega‐3 fatty acids are an effective treatment for ASD. When these trials are completed, 389 individuals aged two to 17 with ASD will have been studied, with a follow‐up period of between six weeks and six months. Hopefully, subgroup information for developmentally and physiologically different age groups and for participants with different diagnostic categories and IQ will also be reported in these trials, so that effectiveness can be assessed for important clinical subgroups.
Authors' conclusions
Implications for practice.
Overall, this review found no current evidence to support the theory that omega‐3 fatty acids supplementation is an effective treatment for individuals with ASD. Results of ongoing trials are awaited.
Implications for research.
Trials with larger sample size are currently in progress. Given the heterogeneous nature of ASD, we hope that these trials will include both lower‐functioning and higher‐functioning individuals with ASD and, if a wide age range is included in the study, provide analyses based on age subgroups for which a different response to treatment may be expected for physiological or developmental reasons. Clarity about the expected outcomes and appropriate choice of outcome measures to detect change, if it exists, is also crucial. Further research is also necessary to explore the effect of various doses and compositions of polyunsaturated fatty acids treatment (for example, EPA/DHA).
What's new
| Date | Event | Description |
|---|---|---|
| 31 October 2011 | Amended | Author contact details changed. |
Acknowledgements
Margaret Anderson, Trials Search Coordinator, Cochrane Developmental, Psychosocial and Learning Problems Group. Jo Abbott, Former Trials Search Coordinator, Cochrane Developmental, Psychosocial and Learning Problems Group. Danielle Wheeler was involved in the early stage of the review.
Appendices
Appendix 1. CENTRAL search strategy
#1 (phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega*) #2 (acid* near/1 eicosa*) or (acid* near/1 docosahex*) or (acid* near/1 fatty) #3 (fish near/3 oil*) #4 (fatty near/3 acid* near/3 n‐3) #5 (membran* near/2 hypothes*) or (membran* near/2 neuronal*) #6 (oil* near/3 flax) or (oil* near/3 linseed):ti #7 MeSH descriptor Docosahexaenoic Acids, this term only #8 MeSH descriptor Fatty Acids explode all trees #9 MeSH descriptor Fish Oils explode all trees #10 MeSH descriptor Linseed Oil explode all trees #11 MeSH descriptor Membrane Lipids explode all trees #12 MeSH descriptor Synaptic Membranes, this term only #13 MeSH descriptor Phospholipids explode all trees 1074 #14 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13) #15 MeSH descriptor Autistic Disorder, this term only #16 MeSH descriptor Child Development Disorders, Pervasive, this term only #17 MeSH descriptor Asperger Syndrome, this term only #18 MeSH descriptor Schizophrenia, Childhood, this term only #19 autis* #20 PDD #21 (pervasive next developmental next disorder*) #22 kanner* #23 (language near/3 delay*) #24 (communicat* or speech) near/3 disorder* #25 childhood next schizophrenia #26 asperg* NOT aspergill* #27 (#15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26) #28 (#27 AND #14)
Appendix 2. EMBASE search strategy
1 (phospholip$ or EFA or EPA or MaxEPA or DHA or ALA or omega$).tw. 2 (acid$ adj1 (eicosa$ or docosahex$ or fatty)).tw. 3 (acid$ adj1 (eicosa$ or docosahex$ or fatty)).tw. 4 (fatty adj3 acid$ adj3 n‐3).tw. 5 (membran$ adj2 (hypothes$ or neuronal$)).tw. 6 (oil$ adj3 (flax or linseed)).tw. 7 Docosahexaenoic Acids/ 8 exp Fatty Acids/ 9 exp Fish Oils/ 10 exp Linseed Oil/ 11 exp Membrane Lipids/ 12 Synaptic Membranes/ 13 exp Phospholipids/ 14 or/1‐13 15 autis$.tw. 16 PDD.tw. 17 pervasive developmental disorder$.tw. 18 kanner$.tw. 19 (language adj3 delay$).tw. 20 childhood schizophrenia.tw. 21 ((communicat$ or speech) adj3 disorder$).tw. 22 (asperg$ not aspergill$).tw. 23 autism/ or asperger syndrome/ or infantile autism/ 24 21 or 17 or 20 or 15 or 22 or 18 or 16 or 19 or 23 25 random$.tw. 26 factorial$.tw. 27 crossover$.tw. 28 cross over$.tw. 29 cross‐over$.tw. 30 placebo$.tw. 31 (doubl$ adj blind$).tw. 32 (singl$ adj blind$).tw. 33 assign$.tw. 34 allocat$.tw. 35 volunteer$.tw. 36 Crossover Procedure/ 37 double‐blind procedure.tw. 38 Randomized Controlled Trial/ 39 Single Blind Procedure/ 40 or/25‐39 41 14 and 24 and 40
Appendix 3. PsycINFO search strategy
PsycINFO searched via EBSCOhost (June 2010)
S38 S36 and S37 S37 ED 20081201‐20100602 S36 S17 and S18 and S35 S35 S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 S34 TI(control*) or AB(control*) S33 TI((trebl* N3 blind*) or (trebl* N3 mask*)) or AB((trebl* N3 blind*) or (trebl* N3 mask*)) S32 TI((tripl* N3 blind*) or (tripl* N3 mask*)) or AB((tripl* N3 blind*) or (tripl* N3 mask*)) S31 TI((doubl* N3 blind*) or (doubl* N3 mask*)) or AB((doubl* N3 blind*) or (doubl* N3 mask*)) S30 TI((singl* N3 blind*) or (singl* N3 mask*)) or AB((singl* N3 blind*) or (singl* N3 mask*)) S29 TI(singl* N3 blind*) or (singl* N3 mask*) S28 TI(prospectiv* N3 stud*) or AB(prospectiv* N3 stud*) S27 TI(evaluat* N3 stud*) or AB(evaluat* N3 stud*) S26 TI(research N3 design*) or AB(research N3 design*) S25 TI(clinical N3 trial*) or AB(clinical N3 trial*) S24 TI(comparative stud*) or AB(comparative stud*) S23 TI(random*) or AB(random*) S22 DE "Followup Studies" S21 DE "Placebo" S20 DE "Treatment Outcomes" OR DE "Psychotherapeutic Outcomes" S19 DE "Treatment Effectiveness Evaluation" S18 S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 S17 S1 or S2 or S3 or S4 or S5 or S6 or S7 S16 ((DE "Autism") or (DE "Aspergers Syndrome")) S15 TI (asperg* not aspergill*) or AB (asperg* not aspergill*) S14 TI ((communicat* N3 disorder*) or ( communicat* N3 speech) ) or AB ((communicat* N3 disorder*) or ( communicat* N3 speech) ) S13 TI(childhood schizophrenia) or AB (childhood schizophrenia) S12 TI (language N3 delay*) or AB (language N3 delay*) S11 TI(kanner*) OR AB (kanner*) S10 TI(pervasive developmental disorder*) or AB(pervasive developmental disorder*) S9 TI (PDD) or AB(PDD) S8 TI (autis*) or AB(autis*) S7 DE "Fatty Acids" OR DE "Arachidonic Acid" OR DE "Capsaicin" OR DE "Phosphatides" or DE "Phosphatides" OR DE "Lecithin" S6 TI ((oil* n3 flax ) or (oil* N3 linseed)) or AB ((oil* n3 flax ) or (oil* N3 linseed)) S5 TI ((membran* N2 hypothes*) or (membran* N2 neuronal*)) or AB ((membran* N2 hypothes*) or (membran* N2 neuronal*)) S4 TI (fatty N3 acid* N3 "n‐3") or AB(fatty N3 acid* N3 "n‐3") S3 TI (fish* N3 oil*) or AB (fish* N3 oil*) S2 TI ((acid* N1 eicosa*) or (acid* N1 docosahex*) or (acid* N1 fatty)) OR AB ((acid* N1 eicosa*) or (acid* N1 docosahex*) or (acid* N1 fatty)) S1 TI (phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega*) or AB(phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega*)
PsycINFO searched via OVID ( December 2008)
1 (phospholip$ or EFA or EPA or MaxEPA or DHA or ALA or omega$).tw. 2 (acid$ adj1 (eicosa$ or docosahex$ or fatty)).tw. 3 (fish adj3 oil$).tw. 4 (fatty adj3 acid$ adj3 n‐3).tw. 5 (membran$ adj2 (hypothes$ or neuronal$)).tw. 6 (oil$ adj3 (flax or linseed)).tw. 7 exp Fatty Acids/ 8 exp Phospholipids/ (419) 9 autis$.tw. 10 PDD.tw. 11 pervasive developmental disorder$.tw. 12 kanner$.tw. 13 (language adj3 delay$).tw. 14 childhood schizophrenia.tw. 15 ((communicat$ or speech) adj3 disorder$).tw. 16 (asperg$ not aspergill$).tw. 17 autism/ or aspergers syndrome/ 18 or/1‐8 19 or/9‐17 20 18 and 19 21 Treatment Effectiveness Evaluation/ 22 exp Treatment Outcomes/ 23 Psychotherapeutic Outcomes/ 24 PLACEBO/ 25 exp Followup Studies/ 26 placebo$.tw. 27 random$.tw. 28 comparative stud$.tw. 29 randomi#ed controlled trial$.tw. 30 (clinical adj3 trial$).tw. 31 (research adj3 design).tw. 32 (evaluat$ adj3 stud$).tw. 33 (prospectiv$ adj3 stud$).tw. 34 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. 35 control$.tw. 36 35 or 27 or 25 or 33 or 32 or 28 or 21 or 26 or 22 or 34 or 30 or 24 or 23 or 31 or 29 37 36 and 20
Appendix 4. MEDLINE search strategy
1 (phospholip$ or EFA or EPA or MaxEPA or DHA or ALA or omega$).tw. 2 (acid$ adj1 (eicosa$ or docosahex$ or fatty)).tw. 3 (fish adj3 oil$).tw. 4 (fatty adj3 acid$ adj3 n‐3).tw. 5 (membran$ adj2 (hypothes$ or neuronal$)).tw. 7 Docosahexaenoic Acids/ 8 exp Fatty Acids/ 9 exp Fish Oils/ 10 exp Linseed Oil/ 11 exp Membrane Lipids/ 12 Synaptic Membranes/ 13 exp Phospholipids/ 14 or/1‐13 15 child development disorders, pervasive/ or asperger syndrome/ or autistic disorder/ or schizophrenia, childhood/ 16 autis$.tw. 17 PDD.tw. 18 pervasive developmental disorder$.tw. 19 kanner$.tw. 20 (language adj3 delay$).tw. 21 childhood schizophrenia.tw. 22 ((communicat$ or speech) adj3 disorder$).tw. 23 (asperg$ not aspergill$).tw. 24 21 or 17 or 20 or 15 or 22 or 18 or 16 or 19 or 23 25 24 and 14 26 randomized controlled trial.pt. 27 controlled clinical trial.pt. 28 randomized.ab. 29 placebo.ab. 30 drug therapy.fs. 31 randomly.ab. 32 trial.ab. 33 groups.ab. 34 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 35 humans.sh. 36 34 and 35 37 25 and 36
Appendix 5. BIOSIS Previews, Science Citation Index and Social Science Citation Index
# 22 #21 AND #11 # 21 #20 OR #19 OR #18 OR #17 OR #16 OR #15 OR #14 OR #13 OR #12 # 20 TS=(pervasive SAME developmental SAME disorder*) # 19 TS=(childhood SAME schizophrenia) # 18 TS=(asperg* NOT aspergill*) # 17 TS=(speech SAME disorder*) # 16 TS=(communicat* SAME disorder*) # 15TS=(language SAME delay) # 14 TS=(kanner*) # 13 TS=(PDD) # 12 TS=(autis*) # 11 #10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1 # 10 TS=(membran* SAME neuronal*) # 9 TS=(oil* SAME linseed) # 8 TS=(oil* SAME flax) # 7 TS=(membran* SAME hypothes*) # 6 TS=(fatty SAME acid* SAME n‐3) # 5 TS=(fish SAME oil*) # 4 TS=(acid* SAME fatty) # 3 TS=(acid* SAME docosahex*) # 2 TS=(acid* SAME eicosa*) # 1 TS=(phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega*)
Appendix 6. CINAHL search strategy
S38 S24 and S37 S37 S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 S36 PT clinical trial S35 TI((clinical* N3 trial*) or (control* N3 trial*)) or AB((clinical* N3 trial*) or (control* N3 trial*)) S34 TI(placebo* ) or AB (placebo*) S33 (MH "Placebos") S32 AB ((random* N3 alloc*) or (random* N3 assign*)) S31 TI ((random* N3 alloc*) or (random* N3 assign*)) S30 TI ( Randomi?ed )or Ab( Randomi?ed ) S29 AB((singl* and blind*) or (doubl* and blind*) or (tripl* and blind*) or (trebl*and blind*)) S28 TI ((singl* and blind*) or (doubl* and blind*) or (tripl* and blind*) or (trebl*and blind*)) S27 AB ((singl* and mask*) or (doubl* and mask*) or (tripl* and mask*) or (trebl*and mask*)) S26 TI ((singl* and mask*) or (doubl* and mask*) or (tripl* and mask*) or (trebl*and mask*)) S25 (MH "Random Assignment") or (MH "Clinical Trials+") S24 S22 and S23 S23 S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 S22 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 S21 TI(asperg* NOT aspergill* ) or Ab(asperg* NOT aspergill* ) S20 TI(communicat* N3 disorder*) or AB(communicat* N3 disorder*) or TI( speech* N3 disorder*) or AB (speech* N3 disorder*) S19 TI(childhood schizophrenia ) or AB(childhood schizophrenia ) S18 TI(language N3 delay* ) or AB(language N3 delay*) S17 TI(kanner*) or AB(kanner*) S16 TI(pervasive developmental disorder*) or AB(pervasive developmental disorder*) S15 TI(PDD ) or AB(PDD ) S14 TI(autis* ) or AB(autis* ) S13 (MH "Child Development Disorders, Pervasive+") S12 TI(membran* N2 hypothes* ) or Ti(membran* N2 neuronal*) or Ab (membran* N2 hypothes*) or AB(membran* N2 neuronal* ) S11 (MH "Phospholipids+") S10 (MH "Linseed Oil") S9 (MH "Fish Oils+") S8 (MH "Fatty Acids+") S7 TI (oil* N3 flax ) or ab (oil* N3 flax) or TI(oil* N3 linseed) or AB(oil* N3 linseed) S6 TI (fatty N3 acid* N3 "n‐3") or AB (fatty N3 acid* N3 "n‐3 " ) S5 TI(fish N3 oil) or AB(fish N3 oil) S4 AB((acid* N1 eicosa* ) or (acid* N1 docosahex*) or ( acid* N1 fatty )) S3 TI ((acid* N1 eicosa* ) or (acid* N1 docosahex*) or ( acid* N1 fatty )) S2 AB (phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega* ) S1 TI (phospholip* or EFA or EPA or MaxEPA or DHA or ALA or omega* )
Appendix 7. Dissertation Abstracts search terms
fish oil/s fatty acid/s omega 3 Omega 6 docosahexaenoic acid/s eicosapentaenoic acid/s EFA EPA DHA ACA
Appendix 8. metaRegister and ClinicalTrials.gov search terms
omega AND autism
omega AND asperger
Data and analyses
Comparison 1. Aberrant Behavior Checklist (ABC).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Social Withdrawal/Lethargy | 2 | 37 | Mean Difference (IV, Fixed, 95% CI) | 0.82 [‐2.84, 4.48] |
| 2 Inappropriate Speech | 2 | 37 | Mean Difference (IV, Fixed, 95% CI) | 0.62 [‐0.89, 2.14] |
| 3 Stereotypy | 2 | 37 | Mean Difference (IV, Fixed, 95% CI) | 0.77 [‐0.69, 2.22] |
| 4 Hyperactivity | 2 | 37 | Mean Difference (IV, Fixed, 95% CI) | 3.46 [‐0.79, 7.70] |
| 5 Irritability | 2 | 37 | Mean Difference (IV, Fixed, 95% CI) | ‐0.21 [‐3.59, 3.18] |
Comparison 2. Social Responsiveness Scale (SRS).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Social Interaction | 1 | 25 | Mean Difference (IV, Fixed, 95% CI) | ‐2.6 [‐7.99, 2.79] |
2.1. Analysis.
Comparison 2 Social Responsiveness Scale (SRS), Outcome 1 Social Interaction.
Comparison 3. Peabody Picture Vocabulary Test (PPVT).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Communication | 1 | 25 | Mean Difference (IV, Fixed, 95% CI) | 0.80 [‐8.63, 10.23] |
3.1. Analysis.
Comparison 3 Peabody Picture Vocabulary Test (PPVT), Outcome 1 Communication.
Comparison 4. Expressive Vocabulary Test (EVT).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Communication | 1 | 25 | Mean Difference (IV, Fixed, 95% CI) | ‐3.6 [‐8.84, 1.64] |
4.1. Analysis.
Comparison 4 Expressive Vocabulary Test (EVT), Outcome 1 Communication.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Amminger 2007.
| Methods | Randomised controlled trial Duration: 6 weeks |
|
| Participants | Setting: specialised day care centre for long‐term treatment of autistic children, Vienna, Austria Diagnosis: autistic disorder, using DSM‐IV criteria 13 children, all males (7 treatment group, 6 placebo group) Age range: 5‐17 years |
|
| Interventions | 0.84 g/day eicosapentaenoic acid and 0.7 g/day docosahexaenoic acid for 6 weeks (intervention) Placebo (control) |
|
| Outcomes | Irritability, social withdrawal, stereotypy, hyperactivity, and inappropriate speech (Aberrant Behavior Checklist) Adverse effects (UKU Side Effect Rating Scale) |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Although the title and abstract state randomised, no details given |
| Allocation concealment (selection bias) | Unclear risk | No details given |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | Although the title and abstract state double‐blind, no details given |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | One participant dropped out from the placebo group |
| Selective reporting (reporting bias) | Low risk | Results are reported for all outcomes stated in the article; we have no reason to suspect that other outcomes were measured |
| Other bias | Low risk | Other sources of bias in the included trial do not appear to exist |
Bent 2011.
| Methods | Randomised controlled trial Duration: 12 weeks |
|
| Participants | Setting: Davis, California Diagnosis: autism spectrum disorder, using the Autism Diagnostic Observation Scale (ADOS), the Social Communication Questionnaire (SCQ) and by clinical review of DSM‐IV TR criteria 24 males, 3 females (14 treatment group, 13 placebo group) Age range: 3‐8 years |
|
| Interventions | 0.7 g/day eicosapentaenoic acid and 0.46 g/day docosahexaenoic acid for 12 weeks (intervention) Placebo (control) |
|
| Outcomes | Hyperactivity, irritability, stereotypy, social withdrawal/lethargy, inappropriate speech (Aberrant Behavior Checklist) Communication (Peabody Picture Vocabulary Test, Expressive Vocabulary Test) Social interaction (Social Responsiveness Scale) Behaviours: externalising, internalising, behavioral, adaptive skill, hyperactivity (Behavioral Assessment System for Children) Global changes (Clinical Global Impression‐Improvement scale) |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Computer‐generated randomisation |
| Allocation concealment (selection bias) | Low risk | Randomisation by a third party |
| Blinding (performance bias and detection bias) All outcomes | Low risk | "All participants, families, and study personnel (including clinicians and those performing baseline and outcome assessments) were blinded to group assignment for the entire study" |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Loss to follow up: 1 (intervention) and 1 (control) |
| Selective reporting (reporting bias) | Low risk | Results are reported for all outcomes stated in the article; we have no reason to suspect that other outcomes were measured |
| Other bias | Low risk | Other sources of bias in the included trial do not appear to exist |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Johnson 2003a | Case report |
| Johnson 2010 | Control did not receive placebo |
| Meguid 2008a | Non‐randomised controlled trial |
| Meiri 2009 | No control group |
| Patrick 2005a | No control group |
| Politi 2008 | No control group |
Characteristics of studies awaiting assessment [ordered by study ID]
NCT00577447.
| Methods | Randomised controlled trial Duration: 6 months |
| Participants | Setting: Mayo Clinic, Rochester, Minnesota Diagnosis: autistic disorder, DSM‐IV Enrolment: 80 (both males and females) Age: 3‐10 years |
| Interventions | 200 mg of DHA (intervention) Placebo (control) |
| Outcomes | Total plasma fatty acid patterns Global severity (Clinical Global Impressions‐Improvement) Behavior (Behavior Assessment Scale for Children, Aberrant Behavior Checklist) Development (Child Development Inventory) |
| Notes | As this study has been completed, we contacted the trialists for additional information. We received a response indicating that a manuscript for the study is being submitted for review, and that results will be provided once the manuscript has been published. |
Characteristics of ongoing studies [ordered by study ID]
NCT00467818.
| Trial name or title | Omega‐3 fatty acids in the treatment of children with autism spectrum disorders |
| Methods | Randomised controlled trial Duration: 12 weeks |
| Participants | Setting: University of Medicine and Dentistry of New Jersey (UMDNJ) Diagnosis: autism Estimated enrolment: 60 (both males and females) Age: 5‐17 years |
| Interventions | Omega 3 fatty acids will initially be administered to the experimental group in low doses; the dosage will be increased biweekly for each individual as based on his/her weight Placebo (control) |
| Outcomes | Global severity (Clinical Global Impressions‐Improvement) Aggression and irritability (Aberrant Behavior Checklist, Overt Aggression Scale‐Modified) Functional ability (Vineland Adaptive Behavior Scale) Parental stress (Parental Stress Index) |
| Starting date | January 2007 |
| Contact information | Rahkhee Wasiulla University of Medicine and Dentistry of New Jersey (UMDNJ) 732 235 5690 wasiulra@umdnj.edu |
| Notes | Although the starting date for this study was January 2007, clinicaltrials.gov indicates that the study is currently recruiting participants. We contacted the trialists to verify whether or not the study has been completed; we were informed that the study is still ongoing. |
NCT01248130.
| Trial name or title | Omega‐3 fatty acids monotherapy in children and adolescents with autism spectrum disorders |
| Methods | Randomised controlled trial Duration: 18 weeks |
| Participants | Setting: Massachusetts General Hospital, Cambridge, Massachusetts Diagnosis: autism spectrum disorders, DSM‐IV‐TR Enrolment: 40 (both males and females) Age: 6‐17 years |
| Interventions | 1050 mg of EPA and 150 mg of DHA (intervention) Placebo (control) |
| Outcomes | Social responsiveness (Social Responsiveness Scale) Global severity (NIMH Clinical Global Impression Scale for Pervasive Develpopmental Disorders) |
| Starting date | November 2009 |
| Contact information | Dayna M Yorks Massachusetts General Hospital 617 503 1009 dyorks@partners.org |
| Notes | Estimated completion date: November 2012 |
NCT01248728.
| Trial name or title | Omega‐3 fatty acids for treatment of young children with autism |
| Methods | Randomised controlled trial Duration: 24 weeks |
| Participants | Setting: Hollant Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada Diagnosis: autism spectrum disorders, DSM‐IV‐TR Enrollment: 40 (both males and females) Age: 2‐5 years |
| Interventions | 1.5 g of EPA and DHA (intervention) Placebo (control) |
| Outcomes | Autism symptomology (Pervasive Developmental Disorder‐Behavioral Inventory) Global severity (Clinical Global Impression) Functional ability (Vineland Adaptive Behavioral Scales) Preschool language (Preschool Language Scale‐4) |
| Starting date | November 2010 |
| Contact information | Nadia Tanel Holland Bloorview Kids Rehabilitation Hospital 416 425 6220 ext 3456 ntanel@hollandbloorview.ca |
| Notes | Estimated completion date: July 2012 |
NCT01260961.
| Trial name or title | Developing treatment, treatment validation and treatment scope in the setting of an autism clinical trial |
| Methods | Randomised controlled trial Duration: 12 weeks |
| Participants | Setting: University of Medicine and Dentistry of New Jersey (UMDNJ) Diagnosis: autistic disorder, DSM‐IV, ADI, and ADOS Estimated enrolment: 132 (both males and females) Age: 5‐17 years |
| Interventions | 200 mg DHA daily; the dosage will be increased during the study (intervention) Placebo (control) |
| Outcomes | Global severity (Autism Diagnostic Observation Schedule‐Generic and Vineland Adaptive Behavior Scale) Behavioural symptoms and functional ability (Aberrant Behavior Checklist‐Community Version 11) |
| Starting date | November 2010 |
| Contact information | Sherie Novotny University of Medicine and Dentistry of New Jersey (UMDNJ) 732 235 4119 novotns@umdnj.edu |
| Notes | Estimated completion date: December 2011 |
Contributions of authors
All authors contributed equally to each stage in the production of the review.
Declarations of interest
Stephen James ‐ none known. Paul Montgomery ‐ has done consultancy work for the following companies that make fatty acid supplements: Efamol‐Wassen, Ferrosan AS, Martek Biosciences. Katrina Williams ‐ none known.
Edited (no change to conclusions)
References
References to studies included in this review
Amminger 2007 {published data only}
- Amminger GP, Berger GE, Schafer MR, Klier C, Friedrich MH, Feucht M. Omega‐3 fatty acids supplementation in children with autism: A double‐blind randomized, placebo‐controlled pilot study. Biological Psychiatry 2007;61:551‐3. [DOI] [PubMed] [Google Scholar]
Bent 2011 {published data only}
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Johnson 2003a {published data only}
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Meiri 2009 {published data only}
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Patrick 2005a {published data only}
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NCT00577447 {published data only}
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References to ongoing studies
NCT00467818 {published data only}
- Omega‐3 fatty acids in the treatment of children with autism spectrum disorders. http://clinicaltrials.gov.
NCT01248130 {published data only}
- Omega‐3 fatty acids monotherapy in children and adolescents with autism spectrum disorders. http://clinicaltrials.gov.
NCT01248728 {published data only}
- Omega‐3 fatty acids for treatment of young children with autism. http://clinicaltrials.gov.
NCT01260961 {published data only}
- Developing treatment, treatment validation and treatment scope in the setting of an autism clinical trial. http://clinicaltrials.gov.
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