Treatment of ADHD with Care as usual versus an Elimination diet:
An exploratory investigation on the biological mechanisms underlying the effects of an elimination diet treatment
in ADHD

Previous work has shown that an elimination diet (ED) might be an effective
treatment for ADHD. However, the mechanism underlying ED*s effects in ADHD are
yet unknown. Converging evidence suggests that the microbiome-gut-brain
interaction, involving neural pathways, as well as immune and endocrine
mechanisms, plays a crucial role in ED*s effects in ADHD.

Changes in microbiome-gut-brain axis have been suggested to play an important
role in neurodevelopmental disorders, such as autism (3). Although direct
evidence is currently lacking in ADHD, converging evidence suggests that
similar alterations in microbiome-gut-brain interaction can contribute to ADHD
symptoms as well. Indeed, not only autism, but also
ADHD has been linked with gastrointestinal abnormalities, which likely reflects
alterations in microbiome composition and function. Furthermore, ADHD has been
associated with alterations in the endocrine and immune pathways. These
alterations in turn have been shown to affect neural development and neural
systems implicated in ADHD, such as the dopaminergic system. In a recent study
in our research group, we have found a relationship between ADHD, microbiome
and brainfunctioning. Since diet plays a crucial role in modulating microbiome
composition, there is good reason to believe that ED*s effects in ADHD are
mediated by alterations in microbiome-gut-brain interactions.

It is extremely relevant to study the mechanisms underlying ED*s effect in
ADHD, and the involvement of the microbiome-gut-brain interaction is the main
suspect of these mechanisms. Characterization of the interaction between the
intestinal microbiome and the patient is important, as it can ultimately inform
clinicians as to potential markers and targets for (preventative) treatment.
Furthermore, this knowledge acquisition is an important step in the development
of novel nutritional/therapeutic interventions tailored at the individual
patient. The previously approved TRACE study (2014-1349) offers an excellent
context for taking this step: the food intake will be strictly controlled in
the ED condition* patients will be monitored over a long term course of 12-18
months on several outcome measures* the size of the sample is relatively large
(n=301).

The main aim of the TRACE-BIOME study is to characterize the role of biomarkers
related to the microbiome-gut-brain pathways in the effect of an ED as a
treatment for ADHD.

The TRACE study is carried out in three child and adolescent psychiatry centers
in the Netherlands: Karakter, Accare and Triversum. Eligible children are
treatment naïve children with ADHD 5-12 years old and willing to be randomized
to either one of the dietary treatments or the care as usual. The assessments
of the TRACE-BIOME study will be synchronized with the three main assessments
of the TRACE study, namely at baseline, after 5 weeks of treatment and 1,5
years after start of treatment. Assessments of the TRACE-BIOME study will take
place immediately following the main assessments of the TRACE study on the same
day, so no extra visit to the clinical center is required.

See TRACE (2014-1349):
-Elimination diet
-Control diet
-Care as usual

There will be no direct benefits for the participants in this TRACE-BIOME
study. By participation, parents and child will help our understanding of the
biological mechanisms involved in the ED*s treatment response, which may
significantly improve future care for patients with ADHD.

The participants in TRACE-BIOME will be asked to provide extra blood. The
venapuncture can be experienced as unpleasant. Note that blood collection by
venapunture on each of the main assessment timepoints (T0,T1,T4) has already
been approved for the TRACEstudy
in order to determine concentration of nutrients. Thus, there is no additional
venapuncture needed for blood collection for the TRACE-BIOME
study* an additional volume of 20 ml (at T0) or 10 ml (at T1 and T4) maximally
will be collected in this study. All participants in TRACE-BIOME
will be asked to provide saliva and stool samples. Participants will be allowed
to participate in parts of the TRACE-BIOME study instead of the complete
protocol. In summary, because the risk is negligible and the burden associated
with participation (additional to the approved TRACE study) can be considered
negligible, we do not expect (serious) adverse events during this study