Nutritional deficiencies in children with Attention Deficit/Hyperactivity Disorder:
A focus on amino acids

ADHD is a childhood psychiatric disorder that is characterized by the early
onset of age-inappropriate and persistent hyperactivity, impulsiveness and
inattentiveness. Despite the field*s scientific progress over the past decades,
there is limited insight into the aetiology of ADHD. A dysfunction of the
frontostriatal, orbitofronto-striatal, and fronto-cerebellar circuits in the
brain has been implicated in ADHD. The serotonergic neurotransmitter system and
the dopaminergic neurotransmitter system primarily modulate activity in the
frontostriatal, orbitofronto-striatal, and fronto-cerebellar circuits. Recent
studies provide evidence for separate contributions of altered functioning of
serotonin and dopamine in ADHD. However, the underlying causes of this
phenomenon are not clear. The serotonergic system is partly dependent on the
availability of the precursor aromatic amino acid (AAA) tryptophan. Studies
investigated the tryptophan levels in children with ADHD and suggested that a
deficiency of this AAA might play a role in ADHD, yet more research is
required. Therefore, in this study we will investigate the availability of the
AAA tryptophan in the body of children with ADHD. Besides, we will investigate
the levels of the AAA*s that serve as precursors for dopamine (tyrosine and
phenylalanine) and the level of another amino acid (homocysteine) that is
related to neurocognitive functioning. Deficiencies in the AAA*s tryptophan,
tyrosine and phenylalanine might explain the decreased functioning of serotonin
and dopamine in children with ADHD and therefore their deviant behavioural
functioning. Meanwhile, large amounts of homocysteine might provide additional
predictive value in explaining neurocognitive dysfunctions in ADHD.
Investigating the levels of the four amino acids of interest serves three
purposes; I) to gain more insight into the aetiology of ADHD, II) to contribute
to a more objective assessment of ADHD and III) to provide foundations for
investigating alternative treatments for ADHD.

The primary goal of this project is to study whether children with ADHD differ
from the normal population on the urinary and plasma levels of the AAA*s
(tryptophan, tyrosine and phenylalanine) that are related to the functioning of
serotonin and dopamine and the amino acid homocysteine. The secondary goal is
to study whether the levels of the four amino acids of interest are related to
behavioural symptoms of ADHD (ADHD core symptoms and comorbid symptoms),
neurocognitive, social-emotional and academic functioning and anthropometric
measures.

In this study the urinary and plasma levels of tryptophan, tyrosine and
phenylalanine and the plasma level of homocysteine will be analyzed in a
reference group (N=117) and in a clinical group (children with ADHD) (N=94), by
means of a 24-hour urine sample and a blood spot. Furthermore, the behavioural
symptoms of ADHD, the neurocognitive, social-emotional and academic functioning
and anthropometric measures will be investigated in both groups, in order to
investigate the associations between the amino acids and the (behavioural)
functioning of children.

Children are treated with both (1) six weeks of nicotinamide supplementation
(an oral dose of 30 mg/kg/day, divided in six equally sized dosages), and (2)
six weeks of placebo (an oral dose of 30 mg/kg/day, divided in six equally
sized dosages).

There are no known risks associated with participation to this study. In order
to analyze the plasma levels of the amino acids we will collect a blood spot in
each child. The finger prick to collect a blood spot is considered safe in
children and no side effects will be expected. In order to analyze the urinary
levels of the AAA*s we will ask children to collect a 24-hour urine sample.
Investigating the behavioural symptoms of ADHD (ADHD core symptoms and comorbid
symptoms), neurocognitive, social-emotional and academic functioning and
anthropometric measures will require time investment of the children (maximum
two hours), parents and teachers (maximum fifteen minutes). An important
advantage of participation in this study is the possibility for parents to gain
insight in possible amino acid abnormalities that may cause increases in
behavioural symptoms of ADHD (ADHD core symptoms and comorbid symptoms) and/or
deficiencies in neurocognitive, social-emotional and academic functioning and
anthropometric measures in their child. Parents will receive a brief report of
the results for their child. It will be especially helpful for the families in
the clinical group to gain insight into the strengths and weaknesses of their
participating child, as ADHD might affect his/her behaviour and performance in
several domains. All children will receive a small present. The families in the
reference group will receive a sum of fifteen euro for each child that
participates, for the insight into the behavioural functioning of the
participating child might be of less interest, as few children within the
reference group are expected to show deficiencies. This study should be
conducted on children rather than adults to be able to study the effect of the
amino acid levels on behavioural symptoms of ADHD (ADHD core symptoms and
comorbid symptoms), neurocognitive, social-emotional and academic functioning
and anthropometric measures, as ADHD is mainly a childhood diagnosed disorder
and ADHD has a substantial influence on children, for they are still developing
numerous abilities (e.g. social skills and academic abilities). Impairments in
the development of these abilities are likely to have an adverse effect on
future performance. It is important to get more insight into the underlying
causal mechanisms in order to start with early interventions. Furthermore,
there is uncertainty about defining features of ADHD in adulthood, which makes
it difficult to conduct research within an adult population.