Efficacy of Polyunsaturated Fatty Acids (PUFA) in the Treatment of Attention Deficit Hyperactivity Disorder

Abstract

Objective: We aimed to investigate the efficacy of polyunsaturated fatty acids (PUFAs) as an adjuvant treatment in patients with ADHD receiving methylphenidate as well as its side effects. Method: This randomized clinical trial was conducted on 40 ADHD patients aged between 6 and 12 years. Both treatment and placebo groups received methylphenidate. Treatment arm also received omega-6 once daily. The Parent ADHD Rating Scale was used to evaluate disease improvement. Results: The Parent ADHD Rating Scale scores of the two groups were similar at baseline. Although total score and scores of three categories decreased significantly in both groups, total score and scores of inattention, hyperactivity, and impulsivity were not significantly different between the groups. Conclusion: The results did not support the efficacy of PUFA in the treatment of ADHD, and adding PUFAs to the therapeutic regimen of ADHD is not recommended at the moment.

Keywords

ADHD polyunsaturated fatty acids (PUFAs)

Introduction

ADHD is the term used to describe persistent pattern of inattention, hyperactivity, and impulsivity in children (Diagnostic and Statistical Manual of Mental Disorders [4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000]). This condition is the most common behavioral disorder among school-aged children affecting 5% to 12% of this population worldwide (Arnold, 2000). Boys are affected 2 to 9 times more than girls (Barbaresi et al., 2002). Psychostimulant drugs such as methylphenidate are now first-line treatment in these children. Although the response rate to stimulants may be as high as 85% if two stimulants are tried, these drugs are associated with some adverse effects such as insomnia and decreased appetite. (Biederman, Spencer, & Wilens, 2004; Tcheremissine & Salazar, 2008). These adverse effects are more common with higher doses of these drugs. Adding supplements to the treatment regimen can reduce psychostimulant drug dosage and consequently decrease such adverse effects (Biederman et al., 2004; Tcheremissine & Salazar, 2008).

Since the introduction of the association between low plasma levels of polyunsaturated fatty acids (PUFAs) and ADHD (Colquhoun & Bunday, 1981), many studies have investigated this association. Some studies have assessed blood levels of these fatty acids among ADHD patients and have confirmed low of them (Colter, Cutler, & Meckling, 2008; Stevens et al., 1995). Regarding this finding, several clinical trials have evaluated the effectiveness of PUFAs as a new treatment option in ADHD patients. Results of latter studies have been inconclusive (Bélanger et al., 2009; Richardson & Puri, 2002; Voigt et al., 2001) Furthermore, recent systematic reviews have refused to give definite opinion in this case and postponed it to the future evidence (Raz & Gabis, 2009).

This study aimed to investigate the efficacy of PUFAs as an adjuvant in treatment of ADHD patients receiving methylphenidate as well as its side effects.

Method and Materials

Study Design

This randomized, double-blind clinical trial was conducted between June 2009 and March 2010 in Imam Hussein Hospital in Tehran, Iran. The trial was registered in Iranian Registration of Clinical Trials with the registration number IRCT138803122000N1 and approved by the Ethics Committee of Behavioral Sciences Research Center at Shahid Beheshti University of Medical Sciences, Tehran, Iran. After definite diagnosis of ADHD, the study design and goals were explained for the parents, and a written informed consent was obtained from patient’s parent or guardian.

Participants

A total of 40 ADHD patients aged between 6 and 12 years were enrolled in the study. The sample was randomly selected based on random numbers table from the outpatient clinic of child psychiatry. Patients were given numbers using order of attendance in clinic, and those with desired numbers were included in study. All participants were interviewed by two subspecialists in child and adolescent psychiatry, and ADHD diagnosis was confirmed based on DSM-IV (4th ed.; American Psychiatric Association, 1994) criteria. The Parent ADHD Rating Scale was used to evaluate the patients. All included patients also scored more than 20 based on the Parent ADHD Rating Scale. Patients with any psychiatric disorder, except for oppositional defiant disorder (ODD) and learning disability (LD), based on Kiddi Scheduled for Affective Disorders & Schizophrenia (K-SADS) questionnaire as well as those with intelligence quotient (IQ) less than 70; use of any psychotropic substance, opioid, or other drugs affecting central nervous system in two previous weeks; any significant neurologic disease; and use of any combination containing PUFAs more than once weekly were excluded from the study.

The study population was randomly assigned into two groups. At the beginning of the study, demographic data, Parental ADHD Rating Scale, and K-SADS questionnaire were filled in for each patient. Before initiation of the treatment, the patients were precisely examined especially for their weight, blood pressure, and heart rate. Treatment group received methylphenidate and capsules containing docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and omega-6, whereas the control group received placebo beside methylphenidate. The patients were followed for 10 weeks, and the Parent ADHD Rating Scale and Drugs Side-Effect questionnaire were filled in for them every 2 weeks.

Treatment Protocol

Both groups received methylphenidate with the dose of 0.3 mg/kg/day in two divided doses that was increased to 1 mg/kg/day during 2 weeks. The treatment arm also received 430 mg capsules containing 241 mg DHA, 33 mg EPA, and 180 mg omega-6 (Minami Company, Belgium) once daily. The control arm received identical placebo capsules from the same company with the same order. Both regimens in each group were initiated at the same time by a subspecialist in children and adolescent psychiatry. Patients and investigator were blind about the study groups (treatment or placebo). Dose adjustment of the methylphenidate was performed based on patient’s response and development of side effects weekly. Considering these two measures, final decision for dose adjustment was made by the psychiatrist in charge of patient.

Outcome Measurement

The Parent ADHD Rating Scale questionnaire was filled in on the Weeks 2, 4, 6, 8, and 10 for each patient during the study, and acceptable response was defined as 25% decrease in ADHD symptoms compared with the beginning of the study. Development of side effects was also monitored using Side-Effect questionnaire based on the history taken from the patient and parents and therapist’s observations.

Statistical Analysis

Data analysis was done using the statistical software SPSS, Version 18.0 for Windows (SPSS Inc., Chicago, Illinois). Numerical variables were presented as mean (SD), whereas nominal and categorized variables were summarized by absolute frequencies and percentages.

For comparing the baseline measurements between the two groups (age, sex, dose of methylphenidate, and number of responders), chi-square test, t test, and Mann–Whitney U test were used whenever appropriate. Wilcoxon’s test was used to compare the scores of various follow-ups in one group during the time. Analysis of covariance (ANCOVA) was used to compare the scores between the two groups with adjustment for the baseline scores.

Final comparison of the two groups’ scores during the study was performed using mixed model analysis. Adjustment for the effect of age, gender, and dose of methylphenidate was done using the same analysis. Mann–Whitney U test was used for comparing the number of side effects between the two groups during the study. All p values were two-tailed, with statistical significance defined by p value ≤.05.

Results

This double-blind, randomized clinical trial was carried out on patients aged between 6 and 12 years between June 2009 and March 2010 in Iran.

Baseline Characteristics

A total of 40 patients were included in this study. Mean age of the patients was 9.1 ± 2 with an M:F ratio of 3:1. ODD was present in 21 (52.5%) patients. Some patients had anxiety symptoms, but none of these symptoms were severe enough to fulfill anxiety disorder criteria. Mean age and M:F ratio in the treatment group were 9 ± 2 and 4:1 as well as 9.2 ± 2 and 7:3 in the control group. Prevalence of ODD was 11 (55%) and 10 (50%) in the treatment and control group, respectively. The mean age, sex ratio, and frequency of ODD were not significantly different between the two groups (p > .05).

The Parent ADHD Rating Scale Total Score

Patients Parental ADHD Rating Scale’s total score was obtained at the beginning and at the 2nd, 4th, 6th, 8th, and 10th weeks (Table 1). Although the total score decrease was statistically significant within each group between visits (p < .001), it was not significant between groups (p > .05). The greatest decrease in total score was in the treatment arm in the 10th week of study, which was 65.7% (from 34 to 14). Level of decrease in total score between every 2 weeks was higher in the treatment arm in all visits except for the Week 8, but it was not statistically significant (mixed model analysis, p = .282) even after adjustment for the effect of age, gender, and dose of methylphenidate in the analysis (mixed model analysis, p value = .289).

Table 1.

Mean and Standard Deviation of Parental ADHD Rating Scale Total Score in Treatment and Control Arm of Study, and Results of Statistical Analysis Comparing Total Scores of Two Groups in Each Visit.

Visit	First visit	2nd week	4th week	6th week	8th week	10th week
Treatment group
Total score (M ± SD)	34 ± 6	25 ± 7	18 ± 9	15 ± 9	16 ± 10	13 ± 9
^aPercentage of change		25.5	48.1	52.9	55.6	65.7
Control group
Total score (M ± SD)	37 ± 6	29 ± 6	23 ± 7	18 ± 8	15 ± 7	13 ± 7
^aPercentage of change		16.7	42.1	54.8	60.8	62.7
^bp value (comparing two groups)	.135	.085	.096	.551	.509	.919

Note. ANCOVA = analysis of covariance.

In comparison to baseline score.

ANCOVA except in first visit in which Mann–Whitney U test has been applied.

The Parent ADHD Rating Scale Score—Inattention Category

Comparison of the Parent ADHD Rating Scale scores in this category (Table 2) showed that there was no statistically significant difference between the two groups in any of visits (p > .05). Decrease between each two visits was statistically significant in both groups (p < .003). Highest level of decrease in this category was in the 10th week in control arm, which was 65.5% (from 18 to 7). Decrease in inattention score was higher in the treatment arm between every two visits except for the 10th week. However, these differences were not statistically significant (mixed model analysis, p = .108) even after considering the effect of age, gender, and dose of methylphenidate (mixed model analysis, p = .365) in the analysis.

Table 2.

Mean and Standard Deviation of Parental ADHD Rating Scale Inattention Score in Treatment and Control Arm of Study, and Results of Statistical Analysis Comparing Inattention Scores of Two Groups in Each Visit.

Visit	First visit	2nd week	4th week	6th week	8th week	10th week
Treatment group
Inattention score (M ± SD)	18 ± 3	13 ± 4	9 ± 5	8 ± 5	7 ± 5	6 ± 5
^aPercentage change		31.6 (41.2)	47.1	50	64.1	65
Control group
Inattention score (M ± SD)	18 ± 4	15 ± 4	12 ± 5	10 ± 5	8 ± 5	7 ± 4
^aPercentage change		20.5	38	53	62	65.5
^bp value (comparing two groups)	.837	.073	.154	.502	.668	.691

Note. ANCOVA = analysis of covariance.

In comparison to baseline score.

ANCOVA except in first visit in which Mann–Whitney U test has been applied.

Parental ADHD Rating Scale Score—Hyperactivity Category

Scores of patients in this category are summarized in Table 3. Difference between the scores of the patients in the two groups was not statistically significant in any of the visits (p > .05), but the decrease between the visits was significant in both groups (p < .001). Except for the 2nd week, decrease in this category in the control arm was higher in comparison with the treatment arm; however, it was not statistically significant (mixed model analysis, p = .246) even after considering the effect of age, gender, and methylphenidate dose (mixed model analysis, p = .910) in the analysis.

Table 3.

Mean and Standard Deviation of Parental ADHD Rating Scale Hyperactivity Score in Treatment and Control Arm of Study, and Results of Statistical Analysis Comparing Hyperactivity Scores of Two Groups in Each Visit.

Visit	First visit	2nd week	4th week	6th week	8th week	10th week
Treatment group
Hyperactivity score (M ± SD)	10 ± 4	7 ± 3	6 ± 3	5 ± 3	4 ± 3	4 ± 3
Percentage of change		30.8	33.3	53.8	66.7	64.6
Control group
Hyperactivity score (M ± SD)	12 ± 4	9 ± 3	6 ± 2	4 ± 2	4 ± 3	4 ± 3
^aPercentage of change		23.1	51.5	60.8	65.1	74.4
^b p value (comparing two groups)	.128	.246	.499	.939	1.000	.811

Note. ANCOVA = analysis of covariance.

In comparison to baseline score.

ANCOVA except in first visit in which Mann–Whitney U test has been applied.

Parental ADHD Rating Scale Score—Impulsivity Category

Scores of the patients in both groups in this category are summarized in Figure 1. Difference observed between the scores of the two arms was not significant in any of visits (p > .05), whereas decrease in the scores in comparison with previous visits was significant in both arms (p < .001). Highest level of decrease in the scores was observed in the 10th week in the treatment group that was 66.7% (from 6 to 3). The level of decrease in the Parent ADHD Rating Scale scores in impulsivity was significantly higher in the group receiving methylphenidate and PUFAs only after adjustments for the effect of age, sex, and dose of methylphenidate (mixed model analysis, p = .031).

Methylphenidate Dose

As methylphenidate dose was adjusted individually for different patients, these adjustments could alter the results of treatment response in both arms. So we separately compared the dose of methylphenidate between the two arms in different visits, and the results showed that difference between the two arms was not significant regarding the dose of methylphenidate (p > .05).

Treatment Response

The number of patients with response to treatment defined as 25% and 50% decrease in the ADHD Rating Scale scores was compared between the two arms. The results are presented in Table 4. This number was not statistically different between the groups in any of visits (p > .05). The mixed model analysis also showed similar result during the whole study between the two arms (p = .764) even after adjustment for age, sex, and methylphenidate dosage (p = .104).

Table 4.

Number and Percentage of Patients Who Showed Less Than 25%, 25% to 50%, and More Than 50% Decrease in Parental ADHD Rating Scale Total Score in Two Groups Between Every Two Visits, and Results of Statistical Analysis Comparing Two Groups in Each Visit Regarding Number of Patients in Each Response Category.

		Groups
Visit	Response level	Control number (%)	Treatment number (%)	^ap value
2nd	Less than 25%	13 (65)	9 (45)	.175
	25-50%	6 (30)	8 (40)
	More than 50%	1 (5)	3 (15)
4th	Less than 25%	7 (35)	4 (20)	.331
	25-50%	6 (30)	8 (40)
	More than 50%	7 (35)	8 (40)
6th	Less than 25%	3 (15)	2 (10)	.972
	25-50%	6 (30)	7 (35)
	More than 50%	11 (65)	11 (65)
8th	Less than 25%	1 (5)	2 (10)	.085
	25-50%	4 (20)	7 (35)
	More than 50%	15 (65)	10 (50)
10th	Less than 25%	1 (5)	1 (5)	.138
	25-50%	2 (10)	6 (30)
	More than 50%	17 (85)	13 (65)

Mann–Whitney U test.

Side Effects

Loss of appetite, agitation, and headache were the most common side effects in both groups. The two arms were not different regarding the number or type of side effects that appeared during the study (p > .05).

Discussion

In the present study, although Parental ADHD Rating Scale scores decreased significantly within both groups after treatment, the total score and the scores of inattention and hyperactivity were not significantly different between the two groups in any follow-up times. The level of decrease in the Parent ADHD Rating Scale scores in impulsivity category was significantly higher in the PUFAs group only after adjustment for the effect of age, sex, and dose of methylphenidate.

Several studies have been conducted to evaluate the effect of PUFAs on ADHD patients. Design of these studies has been variable in many aspects. Two main basic types of studies have been conducted on this topic: open-label trials and randomized clinical trials. Although all former trials have shown some kind of improvement consistently (Germano et al., 2007; Sorgi, Hallowell, Hutchins, & Sears, 2007), results of latter studies have been much contrary (Raz, Carasso, & Yehuda, 2009; Richardson & Puri, 2002; Sinn & Bryan, 2007). In a recent meta-analysis on these clinical trials, a small but significant beneficial effect of omega-3 fatty acid was reported for treatment of ADHD (Bloch & Qawasmi, 2011). Larger scale studies have revealed improvement in at least some measured variables. In a study by Sinn and Bryan (2007), with the largest sample size, improvement was observed in all parents’ report of the ADHD-Related Scale scores. Our sample size of 40 patients is an acceptable number among these studies considering the fact that our drop-out rate was zero during the follow-up. In a number of previous studies such as the study by Sinn and Bryan, all children with the symptoms of ADHD—not definite diagnosis—were included, whereas definite diagnosis of ADHD before inclusion was a noteworthy aspect in our study (Sinn & Bryan, 2007). Duration of follow-up was another characteristic in these studies. The patients were followed for 4 to 17.5 months during these trials (Aman, Mitchell, & Turbott, 1987; Voigt et al., 2001). As a minimum of several weeks seems necessary for fatty acids to effect, we selected a 10-week follow-up period in this study. Longer follow-up period might reveal more dissimilarity between the two groups; however, the only meta-analysis on this topic demonstrated no significant relation between the trial duration and the efficacy of supplementation (Bloch & Qawasmi, 2011).

Type and dose of the administered fatty acids were not identical in different trials. Whereas some studies have used natural combinations (Aman et al., 1987), more recent studies have applied synthetic combinations (Johnson, Östlund, Fransson, Kadesjö, & Gillberg, 2009; Raz et al., 2009; Sinn & Bryan, 2007). The proportion of omega-3 to omega-6 content has not been fixed in various studies. This diversity may explain divergent results. Meta-analysis by Bloch and Qawasmi showed that higher doses of EPA within omega-3 fatty acids supplements were significantly associated with increased efficacy of omega-3 in treatment of ADHD symptoms (Bloch & Qawasmi, 2011). Omega-3 content in our formulation was based on the order of manufacture and was similar to the range utilized by other similar studies.

Open-labeled studies have consistently shown some kind of improvement after treatment with PUFAs (Germano et al., 2007; Harding, Judah, & Gant, 2003; Joshi et al., 2006; Sorgi et al., 2007), although the results of randomized clinical trials have been too controversial to draw a definite conclusion. A number of trials have shown no improvement in the group receiving essential fatty acids in comparison with the group receiving placebo (Sorgi et al., 2007; Voigt et al., 2001). Minimal to significant improvement has been observed in the remaining studies with PUFAs in the treatment group when compared with the placebo group. In a study by Aman et al. (1987) measuring 42 variables, including Parental and Teacher Rating Scales and eight psychomotor performance tests, significant improvement was observed in only 2 out of 42 outcome variables. In another study by Arnold et al. (1989) using Parental and Teacher Rating Scales, treatment group showed improvement only in the parental assessed hyperactivity scores, whereas all other measures, including ratings by teachers, did not show significant treatment effects. Brue, Oakland, and Evans (2001) conducted a trial on 30 untreated and 30 treated (receiving methylphenidate) children with ADHD. In treated children, those who received fatty acids improvement were significantly more than those who received placebo on the Teacher Assessed Inattention Scale. Attention improvement after treatment with essential fatty acids was also observed in another trial by Stevens et al. (1985). In all, 2 out of 16 measured scales (Conduct, rated by parents, and Attention, rated by teachers) had shown improvement in that study. In Sinn and Bryan’s (2007) study on three ADHD patients’ groups, two groups received essential fatty acids. Improvement was observed in Cognitive Problems/Inattention, Conners’ ADHD Index, Restless-Impulsive (Conners’ Global Index), Oppositional Behavior, and DSM-IV Symptom subscales of inattention and hyperactivity-impulsivity in these two groups in both phases of the study in Parental but not Teacher Rating Scale scores. Higher level of decrease in inattention score was observed in the treatment arm of our study in comparison with the placebo arm, but the difference was not significant. The level of decrease in Impulsivity subscale was significantly higher in the treatment arm of our study only after adjustment. In mentioned meta-analysis, similar effect of PUFAs was just observed in the hyperactivity and inattention categories (Bloch & Qawasmi, 2011). No difference in the number and type of side effects between the two groups in our study shows that addition of PUFAs to the treatment protocol of ADHD does not harm the patients.

In a previous study, children showed more improvements in Parental ADHD Rating Scale scores in comparison with Teacher Rating Scale scores (Sinn & Bryan, 2007). In some studies, clinical improvement of ADHD has been measured by psychomotor performance tests in addition to the Parental ADHD Rating Scale to increase the accuracy of the results (Raz et al., 2009; Voigt et al., 2001). Several studies have also assessed the blood levels of essential fatty acids and its association with clinical changes to increase strength of interpretation (Voigt et al., 2001). These differences can explain the diversity in final results to some extent. Therefore, one of the limitations of our study is the lack of this assessment. However, we only used Parent-Reported questionnaire as the means of outcome measurement in the present study. Teacher-related assessment was not performed because of the season of the study. Addition of the mentioned variables in this study could enrich our results.

Conclusion

The results of many studies have shown improvements in certain aspects of ADHD and in special category of patients by adding PUFAs to the treatment regimen of ADHD patients. Considering the results of present study, we could not recommend adding of PUFAs to the therapeutic regimen of ADHD patients because our study could not confirm beneficial effect of PUFAs in treatment of ADHD. As our study evidence is lacking, future randomized clinical trials with greater sample size and longer follow-up period with assessment of patients by Parent and Teacher Rating Scales are warranted to confirm our results.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the grant from the Behavioral Sciences Research Center of Shahid Beheshti University of Medical Sciences (Tehran, Iran).

Author Biographies

Marzieh Assareh, MD, is Assistant Professor of Child & Adolescent Psychiatry, Department of Psychiatry, Bahonar Hospital, Alborz University of Medical Sciences, Karaj, Iran, and is in the Department of Psychiatry Bahonar Hospital, Alborze University of Medical Sciences, Karaj, Iran. Her research interest is clinical trial in ADHD.

Rozita Davari Ashtiani, MD, is Associate Professor of Child & Adolescent Psychiatry, Department of Psychiatry, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, and Behavioral Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Mojgan Khademi, MD, is Assistant Professor of Child &Adolescent Psychiatry, Department of Psychiatry, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. She is also part of the Behavioral Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Her research interest is study in ADHD.

Shima Jazayeri, MD, PhD, is Assistant Professor in Department of Nutrition & Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Her research interest is study in ADHD.

Alireza Rai, MD, is Assistant Professor of Cardiology Interventionalist, Department of Cardiology, Kermanshah University of Medical Science, Kermanshah, Iran. His research interest is study in omega3.

Mohammadali Nikoo is affiliated with the Farzan Clinical Research Institute, Tehran, Iran.

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