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Attention Disorders

Efficacy and Safety of Omega-3/6 Fatty Acids, Methylphenidate, and a Combined Treatment in Children
With ADHD
Eduardo Barragán, Dieter Breuer and Manfred Döpfner
Journal of Attention Disorders published online 24 January 2014
DOI: 10.1177/1087054713518239

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JADXXX10.1177/1087054713518239Barragán et al.Barragán et al.

Article
Journal of Attention Disorders

Efficacy and Safety of Omega-3/6 Fatty

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DOI: 10.1177/1087054713518239

Treatment in Children With ADHD jad.sagepub.com

Eduardo Barragán1, Dieter Breuer2, and Manfred Döpfner2

Abstract
Objective: To compare efficacy of Omega-3/6 fatty acids (Equazen eye q™) with methylphenidate (MPH) and combined
MPH + Omega-3/6 in children with ADHD. Method: Participants (N = 90) were randomized to Omega-3/6, long-acting
MPH, or combination for 12 months. ADHD symptoms were assessed using the ADHD Rating Scale and Clinical Global
Impressions–Severity (CGI-S) scale. Results: ADHD symptoms decreased in all treatment arms. Although significant
differences favoring Omega + MPH over Omega-3/6 alone were found for ADHD Total and Hyperactivity-Impulsivity
subscales, results on the Inattention subscale were similar. CGI-S scores decreased slowly and consistently with Omega-3/6,
compared with a rapid decrease and subsequent slight increase in the MPH-containing arms. Adverse events were
numerically less frequent with Omega-3/6 or MPH + Omega-3/6 than MPH alone. Conclusion: The tested combination
of Omega-3/6 fatty acids had similar effects to MPH, whereas the MPH + Omega combination appeared to have some
tolerability benefits over MPH.

Keywords
ADHD, children, methylphenidate, nonpharmacological treatment, omega fatty acids

ADHD is associated with failure at school and serious
behavioral problems in children, and is the most frequently
reported psychiatric disorder of childhood (American
Academy of Pediatrics, 2000). The worldwide prevalence
of ADHD is estimated at 5.3% (Polanczyk, de Lima, Horta,
Biederman, & Rohde, 2007). In Latin America, it affects
3% to 7% of the population and is considered to be a public
health problem (Barragán-Pérez et al., 2007). ADHD is the
most frequent in children of school age and is usually more
common among boys than girls (Döpfner et al., 2008).
Management of ADHD involves a comprehensive treat-
ment approach using drug and nondrug therapies, with psy-
chopharmacological approaches constituting the
cornerstone of treatment. Stimulants, such as amphetamines
and methylphenidate (MPH), are the most frequently used
class of medications (Olfson, 2004). In addition, nonstimu-
lant medications, such as atomoxetine, tricyclic antidepres-
sants, alpha-adrenergic agonists, and modafinil, may also
have a role to play (López, 2006).
Although effective, pharmaceutical treatment of ADHD
has its disadvantages, including adverse events and the nega-
tive opinions of some parents and clinicians regarding the use
of medication (Berger, Dor, Nevo, & Goldzweig, 2008;
Graham et al., 2011). There is therefore interest in exploring
nonpharmacological therapies for ADHD, such as dietary and
psychological interventions. (Döpfner, 2010; Sonuga-Barke
et al., 2013). Dietary options that have been investigated
include restriction of specific food groups (e.g. sugars, salicy-
lates, and artificial colorings), or the ingestion of high doses of
vitamins and dietary minerals (Buitelaar et al., 2012; Millichap
& Yee, 2012; Rucklidge, Johnstone, & Kaplan, 2009).
It has been suggested that deficiency of long-chain poly-
unsaturated fatty acids (PUFAs) may be involved in the
development of ADHD (Colquhoun & Bunday, 1981;
Richardson, 2006). Omega-3 and Omega-6 PUFAs are inte-
gral parts of neuronal cell membranes in the brain and may
have a role in facilitating the transmission of signals between
neurons (Sinn, Bryan, & Wilson, 2008). Multiple clinical tri-
als of supplementation using Omega-3 and/or Omega-6 fatty
acids have been performed (Bloch & Qawasmi, 2011;
Sonuga-Barke et al., 2013). Meta-analyses of these trials
have reported significant reductions in symptoms of ADHD
(Bloch & Qawasmi, 2011; Sonuga-Barke et al., 2013), with
individual trials reporting significant improvements in
1
The Federico Gómez Children’s Hospital of Mexico
2
University Hospital Cologne, Germany
Corresponding Author:
Eduardo Barragán, Department of Neurology, Hospital Infantil de
México Federico Gómez, Dr. Marquez 162, col doctores delegación
Cuauhtemoc, Mexico City, C.P. 062720, Mexico.
Email: neurodoc@prodigy.net.mx

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2 Journal of Attention Disorders 
several domains, including total symptoms, inattention, and
reading/writing disorders (Richardson & Montgomery,
2005; Sinn & Bryan, 2007). Overall, the best results have
been seen with combination therapy involving Omega-3
(eicosapentaenoic acid [EPA], docosahexaenoic acid
[DHA]) and Omega-6 (gamma-linolenic acid [GLA]) fatty
acids (Schuchardt, Huss, Stauss-Grabo, & Hahn, 2010;
Transler, Eilander, Mitchell, & van de Meer, 2010). However,
data comparing PUFAs with MPH are limited, as are studies
evaluating combinations of PUFAs with MPH. As the mech-
anisms by which MPH and PUFAs act may be different,
there may be additional benefits from combination therapy.
The search for alternatives to pharmacological treat-
ments for resolving attention problems with fewer side
effects is a priority in Latin-American countries. In Mexico,
for example, there are no clinical studies with dietary sup-
plements that show improvement in the symptoms of the
ADHD. The aim of the present study was therefore to assess
the efficacy and safety of a specific Omega-3/6 combina-
tion, alone and in combination with MPH, for the treatment
of ADHD in Mexican children.
Method
Objectives
The main objectives of this pilot study were to (a) assess the
effects of Omega-3/6, MPH, and combined MPH and
Omega-3/6 in terms of symptom reduction and impairment
in treatment-naïve children with ADHD; (b) compare these
effects between the different treatment arms; (c) assess the
clinical significance of the effects by calculating the per-
centage of patients responding to therapy; and (d) assess the
safety and tolerability of the three treatments.
Study Design
The trial was performed at the Neurology Department of the
Hospital Infantil de México Federico Gómez (National Health
Institute for Children in Mexico) as a randomized pilot trial.
Participants were randomized (unblinded) by means of an
aleatorized table to receive MPH, Omega-3/6, or combination
therapy with MPH + Omega-3/6. During a 12-month evalua-
tion period, clinical assessments were made at five time
points: at baseline (t1), after 1 month (t2), after 3 months (t3),
after 6 months (t4), and after 12 months (t5). MPH doses were
titrated during the first 4 weeks of the evaluation period.
Participants
Participants were referred to the Neurology Department of the
Hospital Infantil de México Federico Gómez between October
2009 and December 2010. They were required to be 6 to 12
years of age with newly diagnosed ADHD of any subtype
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(diagnosed according to the Diagnostic and Statistical Manual
of Mental Disorders [4th ed., text rev.; DSM-IV-TR]; American
Psychiatric Association, 2000). The presence of any associ-
ated condition (comorbidity) was assessed by clinical inter-
view according to DSM-IV-TR criteria, and the investigator
also made a medical evaluation, including weight, height,
cephalic perimeter, neurologic evaluation, sleep patterns, and
other symptoms or signs. Written informed consent to partici-
pate was given by the parents or tutors, and the trial was
approved by the local ethical review board.
Exclusion criteria included neurologic disorders (epi-
lepsy, brain damage, mental retardation), autism or perva-
sive developmental disorders, known hypersensitivity to
components of Omega-3/6, previous pharmacological treat-
ment for ADHD, ongoing chronic conditions (e.g., asthma),
or medication for chronic conditions. Children not receiv-
ing school assistance were also excluded from the study.
Study Treatment
The Omega-3/6 fatty acid supplement used for the trial was
Equazen eye q™ (provided by Vifor Pharma, Switzerland).
Patients received three capsules twice daily, corresponding
to a daily dose of 558 mg EPA, 174 mg DHA, and 60 mg
GLA. This product and dosage were chosen based on effi-
cacy and tolerability results from previous clinical trials
(Johnson, Ostlund, Fransson, Kadesjo, & Gillberg, 2009;
Richardson & Montgomery, 2005; Sinn & Bryan, 2007).
The MPH preparation used in the study was long-acting
Metadate CD® (Shire Pharmaceuticals Mexico SA). Patients
in the MPH arm received an initial daily dose of 0.3 mg/kg/
day, increased to 0.5 mg/kg/day after the first 2 weeks of the
titration period. The dose was subsequently increased to a
maximum of 1 mg/kg/day depending on response and toler-
ability. Dose adjustments were made weekly.
Assessments
Clinical assessments were made at five time points: base-
line, 1 month, 3 months, 6 months, and 12 months. ADHD
symptoms were assessed using the Spanish version of the
ADHD Rating Scale (DuPaul, Power, Anastopoulos, &
Reid, 1998), rated by the parents, and the Clinical Global
Impressions–Severity (CGI-S) scale. The latter is a seven-
point scale from 1 (normal, not ill) to 7 (among the most
extremely ill patients), and was rated separately by the
investigator and the parents. Adverse events were evaluated
at each clinic appointment, with their possible relationship
to study treatment assessed by an independent investigator.
Statistical Analysis
Because this was an exploratory pilot study, no formal sam-
ple-size calculation was carried out. The main analyses
Barragán et al.
Table 1. Methylphenidate (MPH) Dosages at Baseline, Month 1,
and Month 3 in Patients Receiving MPH Monotherapy or MPH +
Omega-3/6 Combination Therapy.
significance
n M (SD) mg/kg T df (two-tailed)*
Baseline
MPH 30 0.48 (0.10) −0.41 58
MPH + Omega 30 0.49 (0.10)
Month 1
MPH 29 0.98 (0.11) 6.56 56
MPH + Omega 29 0.79 (0.11)
Month 3
MPH 23 1.03 (0.12) 7.25 49
MPH + Omega 28 0.80 (0.10)
*Statistical significance assumed if p ≤ .05.
were intention-to-treat (ITT) analyses with the last observa-
tion carried forward for patients who dropped out.
Multivariate (3 × 5 factorial) analyses of variance
(MANOVAs) with one between-subject factor (treatment:
MPH, Omega-3/6, MPH + Omega-3/6) and one within-
subject factor (assessment time points t1 to t5) were con-
ducted for each of the outcome parameters to assess
symptom course during treatment in each of the treatment
arms and analyze differences in symptom course between
the three arms. To test for differences between the treatment
arms at Month 12, MANCOVAs were calculated with base-
line score as covariate. Treatment responders were defined
as patients with at least 30% symptom reduction from base-
line to Month 12. Pre- to post-effect sizes were calculated
using the formula: d = (Meanpost − Meanpre)/SDpre.
Results
Participants
Of the 107 patients screened, 90 met the inclusion and
exclusion criteria and were randomized to study treatment
(30 per treatment arm) and included in the ITT population.
Of these, 60 were boys (no statistically significant differ-
ences between the three treatment groups; Cramer’s V =
.06, p = .861). Mean age was 8.27 years (SD = 1.74) with no
statistically significant differences between the three treat-
ment groups (ANOVA F = 0.20, p = .658).
Overall, 51 patients (57%) had a diagnosis of combined-
type ADHD, 32 (36%) had predominantly inattentive type,
and 7 (8%) had the hyperactive-impulsive subtype. There
were no significant differences in the distribution of ADHD
subtypes (Cramer’s V = .103, p = .750). MPH dosages at
baseline and Months 1 and 3 are shown in Table 1. No dif-
ferences in MPH dosages between the MPH arm and MPH
+ Omega-3/6 arm were found at baseline, although doses
were higher in the MPH arm at Months 1 and 3.
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3
Between baseline and Month 12, more withdrawals
occurred in the MPH (n = 10; 33%) and Omega-3/6 (n = 8;
27%) arms compared with the MPH + Omega-3/6 arm (n =
3; 10%; Figure 1).
Efficacy
0.682
As shown in Figure 2, there was a substantial improve-
ment in all outcome parameters during the study. Based on
0.000
3 × 5 factorial MANOVA with repeated measures, a strong
effect of time was found on all outcome parameters, show-
ing a substantial reduction of symptoms and impairment in
0.000 all treatment groups (Table 2, Figure 2). Pre–post effect
sizes ranged between d = −4.77 and d = −0.62. Moreover,
statistically significant Time × Group interaction effects
were found on all outcome parameters, indicating signifi-
cantly different courses in the three treatment groups dur-
ing treatment (Table 3, Figure 2). The effect size of this
interaction effect (eta squared = square sum effect / square
sum total) was between 0.05 and 0.01, indicating small
interaction effects according to the criteria of Cohen
(2013). A priori comparisons revealed statistically signifi-
cant differences on ADHD total score between the MPH
and Omega-3/6 arms across the five assessment time
points (p < .036), with a steeper decline in the first part of
MPH treatment compared with Omega-3/6 (see Figure 2).
Statistical trends were also found between the MPH and
Omega-3/6 arms on the subscores of Inattention (p < .059)
and Hyperactivity-Impulsivity (p < .069). No differences
were found between Omega-3/6 and MPH + Omega-3/6
on ADHD Total score (p < .696), Inattention (p < .429), or
Hyperactivity-Impulsivity (p < .824). However, on the
CGI-S scale, statistically significant differences were
found between Omega-3/6 and MPH + Omega-3/6 (par-
ents, p < .022; clinician, p < .012), with no differences
between MPH and Omega-3/6 (parents, p < .515; clini-
cian, p < .359).
To test for differences between the treatment groups at
Month 12, ANCOVAs were calculated with baseline scores
as covariate. Statistically significant differences between
the treatment arms at Month 12 were found for ADHD Total
and Hyperactivity-Impulsivity, but not for Inattention or
CGI-S (Table 4). A priori comparisons revealed significant
differences between Omega-3/6 and MPH + Omega-3/6 in
ADHD Total score (p = .007) and Hyperactivity-Impulsivity
(p = .009), indicating a stronger effect for combined treat-
ment compared with Omega-3/6. No statistically significant
differences were found between Omega-3/6 treatment and
MPH alone (ADHD Total score, p < .121; Inattention, p <
.184; Hyperactivity-Impulsivity, p < .433).
Responder rates (i.e., ≥30% symptom reduction on
ADHD total score from baseline to Month 12) were the
highest for MPH + Omega-3/6 (93%) followed by MPH
(80%) and Omega-3/6 (60%). The differences in responder
4 Journal of Attention Disorders 
Figure 1. Patient disposition.
*The withdrawal rates in the three groups were marginally significant (χ2 = 4.845; p = .089).
rates between treatment arms were statistically significant
(χ2 = 9.77; p < .008). Responder rates on the clinician-rated
CGI-S (defined as the percentage of ratings 1 or 2) at Month
12 were 6.7% (MPH), 16.7% (Omega-3/6), and 3.3% (MPH
+ Omega-3/6).
Additional analyses in a subgroup of patients who termi-
nated treatment according to protocol revealed results simi-
lar to those in the ITT population, with statistically
significant interaction effects in the MANOVA analyses (p
< .05) and, as expected, somewhat higher pre–post effect
sizes (data not shown).
Safety and Tolerability
Adverse events occurring during the study are shown in
Table 5. The most frequent side effect was hyporexia, which
was reported in 16 patients (53.3%) receiving MPH, 8
patients (26.7%) receiving MPH + Omega-3/6, and 2
patients (6.7%) receiving Omega-3/6 (p = .009 for MPH +
Omega-3/6 vs. MPH). Overall, adverse events were more
commonly reported in patients receiving MPH alone or
with Omega-3/6 (p = .001 for MPH + Omega-3/6 vs. MPH;
Table 5). In patients receiving Omega-3/6 alone, the most
frequently reported adverse events were dyspepsia and diar-
rhea, reported by nine patients (30.0%) and five patients
(16.7%), respectively, after 1 month of treatment. In most
patients, dyspepsia and diarrhea were transient and disap-
peared rapidly after the first treatment month.
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Discussion
The results of this exploratory study suggest that the spe-
cific combination of Omega-3/6 fatty acids tested in the
present trial, although slightly less effective than MPH, is
an effective, well-tolerated treatment for children with
ADHD when used as monotherapy. The combination of
Omega-3/6 with MPH offers no efficacy benefit over MPH
monotherapy but did permit lower doses of MPH (mono-
therapy, 1.0 mg/kg/day; combination, 0.8 mg/kg/day; p <
.001). Combined with the numerically higher responder rate
and lower rate of withdrawal in the combination therapy
group, together with the significantly lower incidence of
adverse events, this suggests that combination therapy may
lead to improved treatment adherence compared with MPH
monotherapy. Although control and reduction of symptoms
were slower in the Omega-3/6 and MPH + Omega-3/6 arms
compared with the MPH arm, scale scores leveled off
toward Week 8 of treatment, suggesting long-term stabiliza-
tion with Omega-3/6 either alone or in combination.
One surprising finding in the present study was the mag-
nitude of the pre–post effect sizes in the three arms. The
pre–post effect size for ADHD total score in the present
study (d = −2.7 to d = −4.4), for example, was considerably
greater than that seen in comparable studies. For example,
Sinn and Bryan (2007) found one of the largest effects of
PUFA, with an effect size of d = 0.49 versus placebo and a
pre–post change in the Omega-3/6 group of about d = 0.7
Barragán et al. 5

Figure 2. Estimated marginal means over time for (a) ADHD Rating Scale total score, (b) Inattention subscale score, (c)
Hyperactivity-Impulsivity subscale score, (d) CGI-S (parent), and (e) CGI-S (clinician) (last observation carried forward).
Note. CGI-S = Clinical Global Impressions–Severity; MPH = methylphenidate.

using the Conners’ Parent Rating Scale (Diagnostic and
Statistical Manual of Mental Disorders [4th ed.; DSM-IV];
American Psychiatric Association, 1994). Faraone and
Buitelaar (2010), in their meta-analysis of randomized con-
trolled trials using parent ratings, found a standardized
mean difference (SMD, that is, effect size) of 0.73 on
ADHD total scores for stimulant treatment. However, in
randomized controlled trials, effect sizes take into account
the effects of placebo treatment, whereas only pre–post
changes were assessed in our study. In an open-label study,
Döpfner, Breuer, Walter, and Rothenberger (2011) found
pre–post effect sizes of d = 1.41 on parent-rated ADHD
total scores and d = 1.73 on CGI-S scores for patients with
no treatment at t1. Similarly, Van der Oord, Prins,
Oosterlaan, and Emmelkamp (2008) found pre–post effect
sizes of d = 1.53 for MPH treatment on parent-rated ADHD

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6 Journal of Attention Disorders 

Table 2. Mean (Standard Deviation) for All Outcome Parameters at All Assessment Points, Including Pre–Post Effect Sizes (Cohen’s d).

Scale Treatment Baseline Month 1 Month 3 Month 6 Month 12 Pre–post effect

ADHD Rating Scale MPH 41.43 (4.3) 27.60 (4.98) 26.23 (4.70) 25.43 (4.84) 25.83 (4.67) −3.60
Total score Omega 40.70 (4.82) 33.63 (7.47) 30.27 (7.86) 28.17 (7.92) 27.77 (7.84) −2.68
MPH + Omega 42.03 (4.00) 31.87 (5.77) 27.57 (5.54) 25.50 (5.01) 24.33 (5.09) −4.43
ADHD Rating Scale MPH 21.83 (3.13) 12.97 (2.14) 12.13 (1.72) 11.73 (1.78) 12.03 (1.71) −3.13
Inattention Omega 21.47 (3.20) 15.50 (3.41) 13.27 (2.92) 12.33 (2.83) 12.17 (2.70) −2.90
MPH + Omega 21.57 (2.85) 14.13 (2.52) 12.57 (2.08) 11.70 (2.17) 11.30 (1.95) −3.60
ADHD Rating Scale MPH 19.93 (5.11) 14.60 (3.71) 14.10 (3.74) 13.70 (3.71) 13.80 (3.68) −1.20
Hyperactivity Omega 19.37 (6.07) 18.37 (5.82) 17.00 (5.84) 15.83 (5.78) 15.60 (5.68) −0.62
MPH + Omega 20.60 (5.45) 17.73 (4.32) 14.93 (3.79) 13.80 (3.28) 13.03 (3.44) −1.39
CGI-S (parents) MPH 6.27 (0.74) 3.57 (1.10) 4.27 (1.08) 4.00 (0.98) 4.10 (0.96) −2.93
Omega 6.07 (0.64) 4.83 (1.56) 4.43 (1.17) 3.97 (1.33) 3.63 (1.43) −3.80
MPH + Omega 6.17 (0.53) 3.97 (1.03) 3.30 (0.95) 3.23 (0.86) 3.63 (0.85) −4.77
CGI-S (clinician) MPH 6.30 (0.65) 3.67 (1.21) 4.27 (1.14) 4.00 (1.08) 4.10 (1.06) −3.38
Omega 6.13 (0.63) 4.90 (1.37) 4.57 (1.19) 4.10 (1.32) 3.70 (1.51) −3.87
MPH + Omega 6.17 (0.53) 3.93 (1.01) 3.33 (0.88) 3.23 (0.86) 3.63 (0.85) −4.77

Note. MPH = methylphenidate; CGI-S = Clinical Global Impressions–Severity.

Table 3. Results of Multivariate Analysis of Variance for Time and Time × Group Interaction.

Time Time × Group

F df p* Eta2 F df p* Eta2
ADHD Rating Scale
Total 153.92 4.84 ≤.001 0.48 5.65 8.170 .001 0.02
Inattention 125.56 4.84 ≤.001 0.68 2.14 8.170 .035 0.01
Hyperactivity 34.79 4.84 ≤.001 0.16 5.20 8.170 .001 0.02
CGI-S (parent) 121.68 4.84 ≤.001 0.41 10.60 8.170 .001 0.05
CGI-S (clinician) 116.98 4.84 ≤.001 0.40 11.59 8.170 .001 0.04

Note. eta2 = percentage of variance explained; CGI-S = Clinical Global Impressions–Severity.

*Statistical significance assumed if p ≤ .05.

Table 4. Results of Multivariate Analysis of Covariance With group; however, the SDs were half of those reported in this
Baseline Score as Covariate for Month 12 Outcomes. study. Therefore, the high effect sizes in the present study
Scale F df p result from the fact that effects are not controlled for pla-
cebo effects and that the sample was very homogenous
ADHD Rating Scale regarding ADHD scores, as shown by the small SDs.
Total 3.88 2.86 .024 Nevertheless, the suggestion that Omega-3/6 may be as
Inattention 2.43 2.86 .094 effective as MPH is surprising and needs further replication
Hyperactivity 6.42 2.86 .003 in blinded randomized controlled trials.
CGI-S (parent) 1.32 2.86 .272 Multimodal treatment of ADHD was previously investi-
CGI-S (clinician) 0.94 2.86 .394
gated in the Multimodal Treatment Study of Children with
Note. CGI-S = Clinical Global Impressions–Severity. ADHD (MTA), in which pharmacological treatment was
compared with an intensive behavioral intervention, a com-
bination of pharmacological and behavioral treatment, and
symptoms in their meta-analysis. Newcorn et al. (2008) standard community care (MTA Cooperative Group, 1999).
also used the ADHD Rating Scale in a randomized con- The initial results showed that the medication regimen was
trolled trial comparing the effects of atomoxetine and MPH, superior to behavioral therapy and community care, with no
with similar mean total scores at baseline and a similar significant benefit from the combination of medication and
change from baseline to follow-up in the MPH-treated behavioral therapy, although there were small advantages

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Barragán et al. 7

Table 5. Adverse Events Reported During the Study (Percentage of Patients).

MPH (n = 30) Omega-3/6 (n = 30) MPH + Omega (n = 30) χ2 (MPH vs. MPH + Omega) p
Hyporexia 70.0 6.7 33.3 8.08 .009
Headache 56.7 0 33.3 3.30 .119
Irritability 23.3 0 0 NA
Tension 26.7 0 10.0 2.78 .181
Pallor 33.3 0 36.7 .073 1.000
Palpitation 23.3 0 16.7 .417 .748
Insomnia 20.0 0 0 NA
Tics 6.7 0 0 NA
Tremor 3.3 0 0 NA
Nausea 3.3 0 0 NA
Dyspepsia 0 40.0 0 NA
Diarrhea 0 23.3 0 NA
Others 13.3 16.7 6.7 .741 .671
All adverse events 100.0 60.0 63.3 13.47 .001

Note. MPH = methylphenidate; NA = not applicable.

*Events of dyspepsia and diarrhea persisted for ≥ 3 months.

for combination therapy on non-ADHD symptom and posi-
tive functioning. Notably, patients receiving combination
therapy required lower doses of MPH, consistent with our
results. It should be noted, however, that patients in the
MTA study had a lower baseline ADHD severity than those
in the present study. Subsequent analysis of the MTA data-
set using a single outcome score, however, revealed that
combination therapy was significantly superior to the other
treatment arms, effect sizes ranging from small (0.28 vs.
medication only) to moderate (0.70 vs. community treat-
ment; Conners et al., 2001). Similarly, development of a
categorical outcome measure revealed a small but statisti-
cally significant benefit of combination treatment over
medication alone (Swanson et al., 2001). Multimodal ther-
apy in which standard medication with MPH is supple-
mented by nonpharmacological modalities therefore has
considerable potential for the treatment of ADHD.
Strengths of the present study include the three-arm
design, the 12-month duration, and the high retention rate.
Limitations of the study include a possible lack of statistical
power as a result of the exploratory nature of the study, with
no formal sample-size calculation resulting in a small sam-
ple size, especially for a noninferiority study; the non-
blinded trial design; the lack of a placebo arm; and the high
baseline disease severity. The latter can be explained by the
nature of the study center, which is a tertiary institution that
receives a large number of patients with severe ADHD from
other centers. Therefore, we cannot rule out placebo effect,
regression to the mean, or that this was the natural symptom
course. It should also be noted that the maximum permitted
MPH dose of 1 mg/kg may have resulted in low dosing for
some patients. In the analysis, the CGI-S score is presented
in a somewhat unorthodox way because it was rated by
(unblinded) clinicians and parents at each assessment point.
We decided to analyze both CGI-S scores in a similar way
to the ADHD Rating Scale—despite the ordinal level of the
CGI-S scores—to compare the results on different outcome
parameters. The analyses are, however, usually quite robust
against violation of the statistical prerequisites. However,
despite these limitations, the results of this pilot study add
to the body of evidence for the efficacy and tolerability of
the tested Omega-3/6 fatty acid combination (with a higher
EPA/DHA ratio and combined with GLA) in children with
ADHD. It is important to note that, given the importance of
Omega-3/6 composition (Bloch & Qawasmi, 2011;
Schuchardt et al., 2010; Sonuga-Barke et al., 2013; Transler
et al., 2010), these results should not be generalized to other
Omega-3/6 products with different component ratios, which
must be tested in separate clinical trials.
In conclusion, the tested combination of Omega-3/6
fatty acids was slightly less effective than MPH in this
unblinded randomized controlled trial. While no statistical
superiority of the combination of MPH and Omega-3/6
fatty acids compared with MPH was found in terms of effi-
cacy, the combination appeared to have some benefits over
MPH monotherapy in terms of MPH dosing and tolerabil-
ity, which may in turn lead to improvements in compliance.
Further studies are now required to confirm these promising
initial findings.
Acknowledgment
Medical writing support was provided by Daniel Booth (Bioscript
Medical, London, UK) and funded within the scope of an unre-
stricted grant provided by Vifor Pharma.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this

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8 Journal of Attention Disorders 
article: Eduardo Barragán has received unrestricted research fund-
ing from Vifor Pharma to perform the present trial. Dieter Breuer
declares no potential conflicts of interest. Manfred Döpfner has
received consulting income and research support from Lilly,
Medice, Shire, Janssen Cilag, Novartis, and Vifor, and research
support from the German Research Foundation, German Ministry
of Education and Research, and German Ministry of Health. He
has received royalties from books and psychological tests pub-
lished by Guilford, Hogrefe, Beltz, and Huber.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article:
Manfred Döpfner has received consulting income and research
support from Lilly, Medice, Shire, Janssen Cilag, Novartis, and
Vifor, and research support from the German Research Foundation,
German Ministry of Education and Research, and German
Ministry of Health. He has received royalties from books and psy-
chological tests published by Guilford, Hogrefe, Beltz, and Huber.
Eduardo Barragán has received consulting income and research
support from Lilly, UCB, Cilag, Novartis and Vifor, and research
support from the Universidad Nacional Autónoma de México
(UNAM).
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Author Biographies
Eduardo Barragán, MSc, is a professor of pediatric neurology at
the Hospital Infantil de México for the UNAM. He has published
articles on a variety of topics, specifically in ADHD and epilepsy.
Dieter Breuer, Dr. rer. medic., is a research assistant and has pub-
lished articles on assessment and treatment of ADHD and other
mental disorders.
Manfred Döpfner, Prof. Dr., is professor of psychotherapy in
child and adolescent psychiatry. He has published articles on
assessment, prevention, and treatment of ADHD, conduct disor-
ders, anxiety disorders, obsessive compulsive disorders, and tic
disorders.