Effects of methylphenidate on the developing brain.

Background of the study:

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:

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.



Study design:

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.



Study population:

50 adolescent (10-12 years of age) and 50 adult (23-40 years of age) male outpatients diagnosed with combined type ADHD (combined type) as defined in the DSM-IV, and in need of pharmacotherapy according to existing guidelines.



Intervention:

1. Random assignment to a flexible dose of methylphenidate or placebo drug treatment for a period of 16 weeks with a 1 week washout period;

2. 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;

3. 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;

4. Assessment of sleep architecture using a questionnaire, actigraph and a sleep log during 3 x 5 days: Before, during and after trial end.

Administration of MPH during brain development, but not in adulthood, results in an altered outgrowth of the dopaminergic system. This long-lasting disturbance of the dopaminergic system may result in behavioral abnormalities, such as anxiety and depression.

1. Screening;

2. Baseline: Week 0;

3. Midtreatment: Week 8;

4. Washout: Week 16;

5. Post-treatment: Week 17.

1. Random assignment to a flexible dose of methylphenidate or placebo drug treatment for 16 weeks, followed by a medication-free wash-out period of one week;

2. 3.0 Tesla MR imaging including diffusion tensor imaging (DTI), task-related functional MRI (fMRI) and pharmacological MRI (phMRI) following dopaminergic challenge with oral methylphenidate (0.5 mg/kg);

3. Assessment of a neuropsychological test battery and short questionnaires;

4. Assessment of sleep with actigraphy.