In this pilot study, we found that treatment with omega-3 fatty acids did not lead to a statistically significant improvement in hyperactivity in children with ASD. Although non-significant, there was a greater reduction in hyperactivity in the treatment vs. the placebo group in this study, which corresponds to a standardized effect size of 0.38 and is considered to be a small treatment effect (McDowell and Newell 1996
). The interpretation of these findings is difficult and highlights the limitations of pilot studies and the inherent challenges of studying the efficacy of CAM therapies for ASD. The most conservative interpretation of this study is that we found no statistically significant treatment effect, and since the study was designed with enough power to find a large treatment effect (84% power to identify a treatment effect size = 1.1), we might conclude that omega-3 fatty acids do not produce a large beneficial effect for reducing hyperactivity, at least among children with ASD who have mild-to-moderate baseline levels of hyperactivity.
However, because pilot studies generally have small sample sizes, the resulting effect estimates are unreliable and therefore decisions regarding the need for future, larger studies should not be based on the results of pilot studies alone (Kraemer et al. 2006
). Small pilot studies are not designed to provide definitive scientific evidence regarding efficacy; their primary purpose is to prepare for larger studies by examining issues such as the availability of eligible subjects, the recruitment methods, the procedures for staff training, the tolerability of treatment, and the collection and storage of data (Kraemer et al. 2006
). This presents a difficult dilemma for the scientific investigation of the efficacy of CAM therapies for ASD. There is little or no high-quality scientific evidence evaluating the safety and efficacy of most CAM therapies for ASD even though these therapies are used by as much as 95% of affected children. Because there is limited scientific evidence for the efficacy of most of these CAM therapies, it is difficult to justify or obtain funding to conduct a large, randomized controlled trial that would provide definitive scientific evidence regarding efficacy. Therefore, most clinical investigations of CAM therapies can only attract small amounts of funding to conduct small pilot studies, and these studies are often (incorrectly) used as the basis for “triage” or decision making regarding the need for future, larger studies. It is a difficult cycle: there is no evidence, so only funding for small studies can be obtained, and these studies do not provide enough evidence to make decisions regarding future studies. So, the question remains, how does one decide whether to conduct larger studies if effect estimates from pilot studies are inaccurate and insufficient?
The answer to this question is complex and involves considerations of other evidence of efficacy of the agent in question, examination of a plausible mechanism of action, the severity of the clinical problem and the availability of other effective treatments. In the case of omega-3 fatty acids for the treatment of hyperactivity for ASD, only one prior, small, pilot randomized controlled trial has been conducted. This study found a non-significant trend of a greater reduction in hyperactivity in patients in the omega-3 group compared to the placebo group (p
= 0.098) (Amminger et al. 2007
). In that study, the standardized effect size for the improvement in hyperactivity was 0.71, about twice the size of the effect estimate observed in the current study (0.38), and this difference is possibly due to the fact that patients in the prior study had higher baseline levels of hyperactivity (baseline ABC hyperactivity score of 33.3 in the omega-3 group of the prior study compared to a baseline score of 16.8 in the current study). It is also possible that the observed effect size in the prior study was not due to treatment with omega-3 fatty acids, but merely due to the fact that patients in the omega-3 group had higher baseline hyperactivity scores than patients in the placebo group (Gilbert 2008
). However, the observation that both the current study and the one prior randomized controlled trial found an effect estimate in the same direction may provide some limited evidence that omega-3 fatty acids could have a small beneficial effect.
Other relevant evidence regarding the potential efficacy of omega-3 fatty acids comes from studies of this supplement in other psychiatric disorders. A recent systematic review examining the evidence for efficacy of omega-3 fatty acids for mental health disorders (conducted by the Agency for Healthcare Research and Quality) noted many potential mechanisms of action of omega-3 fatty acids which might contribute to normal brain development and function (Schachter et al. 2005
). However, there were very few high-quality randomized controlled trials examining efficacy, leading the authors to conclude that there was insufficient evidence to determine whether omega-3 fatty acids are effective for depression, and only limited evidence to suggest that they might be effective for the treatment of schizophrenia. A separate systematic review identified 11 small randomized controlled trials of omega-3 fatty acids in patients with attention-deficit-hyperactivity disorder (ADHD) and found that the overall quality of evidence was poor, preventing definitive conclusions regarding efficacy (Raz and Gabis 2009
). A recent randomized, placebo-controlled trial in 81 young adults who were high-risk for developing psychosis found that patients treated with 12 weeks of omega-3 fatty acids had a much lower risk of progression to a psychotic disorder (4.9% progressed in the omega-3 group vs. 27.5% in the placebo group) (Amminger et al. 2010
). Overall, the prior evidence for efficacy of omega-3 fatty acids in other mental disorders is limited, though there are clearly several plausible biological mechanisms of action and some clinical trial evidence to support a possible beneficial effect in certain conditions.
If omega-3 fatty acids are effective for reducing hyperactivity in ASD, the mechanism of action is not clear, but the laboratory measurements in this study suggest some possible lines of inquiry. As expected, there were differences in the changes of fatty acid profiles in treated vs. placebo patients, most notably with an increase in omega-3 fatty acids among treated patients. Also, five fatty acid measurements showed correlations with changes in hyperactivity, suggesting that, at least for some individuals, a change in fatty acid profile may be necessary to elicit a positive behavioral response. Two of three previous studies reported lower levels of omega-3 fatty acids in children with autism compared to controls (Bell et al. 2004
; Bu et al. 2006
; Vancassel et al. 2001
), but this is the first study to show that changes in specific fatty acid levels correlate with changes in a behavioral outcome. Similarly, baseline levels of five of the measured fatty acids were correlated with a reduction in hyperactivity among treated patients. Future research is needed to determine if these specific fatty acids might be useful for predicting response to therapy.
The primary limitation of this study is the small sample size, which (as noted above) results in a limited power to detect small to moderate treatment effects. The study was also limited by the relatively mild level of hyperactivity in both the placebo and omega-3 treatment groups. The goal of the study was to examine the effect of omega-3 fatty acids in unselected children with ASD, where the prevalence of hyperactivity is already quite high. For example, in a survey of 487 children with ASD, the prevalence of symptoms related to hyperactivity was very high: difficulty concentrating (49%); easily distracted (60%); fidgets, wiggles, and squirms (42%); overactive (41%); and short attention span (54%) (Lecavalier 2006
). However, because our enrolled population had only mildly elevated levels of hyperactivity, future studies should consider setting a threshold level of hyperactivity as an inclusion criterion to ensure a greater level of severity and therefore more opportunity to detect improvement in hyperactivity with treatment. A suitable goal might be to select children with at least a one standard deviation increase in a baseline measure of hyperactivity such as the Aberrant Behavior Checklist hyperactivity subscale.
In summary, this pilot study revealed no statistically significant effects of omega-3 fatty acids on hyperactivity or the core symptoms of autism after 12 weeks of treatment. However, because the study was a pilot study with a relatively small sample size, the estimate of treatment effect is unreliable, and this study alone does not provide definitive evidence regarding the efficacy of omega-3 fatty acids. Based on this study and the scientific literature to date, we believe it is not possible to determine whether omega-3 fatty acids are effective for treating hyperactivity in ASD. However, there are a number of compelling reasons to suggest that a larger study is indicated. Both the current study and one prior study did find small, non-significant improvements in hyperactivity in the omega-3 group compared to the placebo group. Also, in the current study, changes in hyperactivity were correlated with changes in certain fatty acids levels, suggesting a possible mechanism of action. The treatment was well-tolerated and resulted in no serious side effects. Omega-3 fatty acids are widely used, relatively inexpensive, and have substantial evidence establishing safety in children. Further, hyperactivity is a very common problem among children with ASD. A recent survey of 479 parents of children with ASD found that 46% of children had used stimulant medications by adolescence, suggesting that almost half of children with ASD have hyperactivity that is troubling enough to require a trial of stimulant medication (Goin-Kochel et al. 2007
). Current drug treatment of hyperactivity in children with ASD has limited efficacy and is associated with significant side effects (Aman and Langworthy 2000
). In order to definitively determine if omega-3 fatty acids are a useful treatment option for hyperactivity in children with ASD, a larger randomized controlled trial with sufficient power to identify a clinically relevant benefit is needed.