Long-term effect modification by age of methylphenidate on the development of the dopaminergic system in the brain

50-90% of prescribed pediatric drugs have never been tested or licensed in
children, only in adults. Approximately 100 million children in the European
Union are prescribed off-label or unauthorized drugs and in doing so risk
adverse reactions or do not respond to treatment at all. In fact, medication
doses used in children are no more than *guestimates*. Clearly, there are
potential dangers in assuming that children will have the same response to
therapy as adults. Methylphenidate (MPH) is primarily used as treatment for
attention deficit hyperactivity disorder (ADHD), effectively reducing symptoms
of inattention, hyperactivity, and impulsivity in up to 70% of children. It is
assumed that MPH does this by blocking the dopamine transporter (DAT) thus
increasing extracellular dopamine (DA) in the brain. Its efficacy and safety
has been documented in many studies. However, there is still a gap of knowledge
concerning the influence of MPH on brain development and its effect on brain
structure and function. Studies in animals and humans raise serious concerns
and call for further investigation of possible short and long-term effects on
brain structure and function. In a recently conducted RCT on the age-dependency
of the effects of MPH on the DA system (NL34509.000.10) we observed increased
DA reactivity to MPH (presumably reflecting abnormal high levels of DA) in
children, but not adults, 1 week after double blind treatment for 4 months with
MPH or placebo. This urges follow-up assessment to study the long-term effects
of MPH exposure in this sample.

Primary objective of the study:
1. To report on the long-term effect modification by age of MPH treatment on
the outgrowth of the DA system using state-of-the-art Magnetic Resonance
Imaging (MRI) techniques

Secondary objectives:
1. To report on the long-term effect modification by age of MPH on the
outgrowth of the DA system using several functional outcome measures
(functional MRI (fMRI), neuropsychological test battery)
2. To report on the long-term effect modification by age of MPH on restless
legs syndrome (RLS) symptoms and insomnia.

Naturalistic 3-4 year follow up study of patients that participated in the
ePOD-MPH RCT (NL34509.000.10) : a pharmacological MRI (phMRI) study. This
study will consist of a single assessment day with a (pharmacological) MRI
scan, neuropsychological tests and actigraphy.

Since we study the effect of methylophenidate use on outgrowth of the
dopaminergic system in the maturing brain, it is essential to include
individuals in which brain development is still ongoing, thus minors.

Burden:
* One time 5 days of actigraphy (wearing a bracelet), and completing a sleeplog
and short questionnaire.
* One time assessment of neuropsychological tests and questionnaires
(approximately 1 hour).
* One time MRI scan:
-Twice one hour (2 x 50 minutes) with in between an orale challenge with
methylphenidate (0.5 mg/kg) followed by a
90 minutes break between scans.

Risks and burden: The risks and burden of study participation are related to
1) MRI: No added risk. MRI studies in children of 8 years and older have
previously been approved by the METC of the AMC (e.g., MEC 06.053). There are
no risks involved in MRI scanning. It is a non-invasive technique, and we will
do everything in our potential to make the children at ease. The burden is
considered minimal. There will be fun tasks to amusing, rather than boring.
2) Oral challenge during the MRI scan: Negligible added risk. Oral challenge
with methylphenidate (0.5 mg/kg) as a kind of probe during the MRI examination
to turn the dopamine system 'on'. The dose is well tolerated in children of
4-14 year old (see also page 10-11 of the study protocol). They may experience
an inrease in heartbeat and blood pressure, but no significant side effects,
thus a minimal added burden.
3) Actigraphy, neuropsychological examination and questionnaires: no added
risk, minimal burden because these are non-invasive examinations that children
in general find quite amusing.
4) One week prior to the assessment patients are asked to stop with their
current medication. Medication-free periods are common for patiënts with ADHD
(e.g. during a holiday). No added risk.

The added risk of this study is thus negligible and the burden is minimal.