Effects 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 MPH does this by blocking the DA transporter (DAT) thus increasing
extracellular 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 raise serious concerns and call for further
investigation of possible effects on brain structure and function.

Primary objective of the study:
1. To report on the effectmodification 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 effectmodification 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 effects of MPH on restless legs syndrome (RLS) symptoms and
insomnia.

A pharmacological MRI (phMRI) study for assessment of dopaminergic function and
connectivity in an 18-week multicenter randomized, double-blind,
placebo-controlled trial with methylphenidate in 100 children-, and adult male
ADHD patients in which the effect of age is investigated before and after
treatment. Patients will be stratified into two age groups: adolescents (10-12
years of age) and adults (23-40 years of age) and randomly assigned to receive
a flexible dose of either MPH or placebo, resulting in four groups consisting
of 25 subjects each.

- Random assignment to a flexible dose of methylphenidate or placebo drug
treatment for a period of 16 weeks with a 1 week washout period.
- 3.0 Tesla MRI scan. Total duration 2 x 30 minutes (with a 90 minute break in
between scans) including a pharmacological phMRI (phMRI), diffusion tensor
imaging (DTI), functional connectivity (rs-fMRI) and task-related fMRI scans
before and after a DA challenge with oral MPH (0.5 mg/kg). Before, during and
after trial end. The MRI scan during the trial will last 30 minutes, without a
DA challenge.
- Assessment of a neuropsychological (NPO) test battery and questionnaires
(duration approximately 1 hour), Before, during and after trial end. The NPO
during the trial will last 30 minutes.
- Assessment of sleep architecture using a questionnaire, actigraph and a sleep
log during 3 x 5 days: Before, during and after trial end.

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:
• Ingestion of study medication (tablets) during 16 weeks daily
(methylphenidate or placebo, doubleblind).
• Screeningvisit and exit-interview during which confronting or uneasy
questions can be asked.
• Three times 5 days of actigraphy (wearing a bracelet), and completing a
sleeplog and short questionnaire.
• Two times assessment of neuropsychological tests and questionnaires
(approximately 1 hour), and once for 30 minutes only.
• Three times MRI scan:
-Twice one hour (2 x 30 minutes) with in between an orale challenge with
methylphenidate (0.5 mg/kg) followed by a 90 minutes break between scans.
-Once 30 minutes preceded, without oral challenge


Risks and burden: The risks and burden of study participation are related to
1) Pharmacotherapy: there is no added risk because the pharmacotherapy is part
of normal clinical practice treatment. There may only be a negligible delay in
start of the treatment in the placebo group. There is a small but negligible
added burden in the placebo group, because after the trial end they can/must
start active treatment. However, the placebo group receives the
studymedication in the period that they would normally be on a waiting list for
treatment. Ths they don*t experience any disadvantage of study participation,
rather a potential benefit. All patients, including the placebo group will
receive adequate care and monitoring and they can switch after trial end to an
active treatment.
2) 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 do in the scanner. In our
experience children experience the tasks in the MRI scanner often amusing,
rather than boring.
3) 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.
4) Actigraphy, neuropsychological examination and questionnaires: no added
risk, minimal burden because these are non-invasive examinations that children
in general find quite amusing.

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