A multicentre randomized double-blind placebo controlled discontinuation trial of methylphenidate.

Over the past decade, we have witnessed a rapid and tremendous increase in the
diagnosis of attention-deficit/hyperactivity disorder (ADHD) and in the use of
medication treatments for ADHD, in particular methylphenidate. This development
has received much and almost exclusively negative coverage by media,
politicians and government due to concerns about overdiagnosis and
overtreatment with psychostimulants.
The increased and longer use of methylphenidate contrasts heavily with the lack
of data on its long-term effectiveness. In fact, Dutch multidisciplinary
guidelines state that there is currently only evidence for the long-term
effectiveness of methylphenidate for a treatment duration between three months
and two years.
We will test the hypothesis that ongoing use of methylphenidate is superior to
placebo with regard to ADHD symptom severity in children and adolescents who
have used methylphenidate for two years or longer. In our study we will be able
to establish whether or not long-term use of methylphenidate is still effective
beyond two years of treatment.

Primary objective: To investigate the effectiveness of ongoing treatment with
methylphenidate as prescribed in clinical practice beyond two years in children
and adolescents.

Secondary objectives:
(1) to investigate the effects of discontinuation of methylphenidate on a
number of secondary outcome measurements (e.g. clinical improvement, withdrawal
effects, sleeping behaviour, quality of life, neuropsychological task
performance and biomarkers (ferritin, zinc and cholesterol).
(2) to identify predictors of treatment discontinuation and long-term outcome
six months later. This includes treatment duration and compliance, child
factors (i.e., presence of comorbid psychiatric problems, genetic
polymorphisms, stress regulation and underaroused temperament) as well as
parent factors (socio-economic status, presence of psychiatric problems,
parental stress and other family factors).

A double-blinded randomized placebo-controlled multicentre discontinuation
trial. The centres together will recruit 120 children or adolescents.

The participating subjects will be randomized (ratio 1:1) to either continued
use of methylphenidate or to placebo during seven weeks. Withdrawal will be
gradually over a period of three weeks, followed by four weeks of complete
placebo. There will be three visits, baseline, after four weeks and after seven
weeks. After six months there will be a follow up by telephone.

Children who will participate in the study have all been using methylphenidate
for over two years and as such study participation is not associated with any
particular risks. Extra burden for the participating families is limited to
three visits to the clinical centre (respectively +/- 120, 60 and 120 min), an
interview by telephone with the parent (+/- 45 min), two blood draws by
venepuncture (30ml each), a single collection of hair strands from the child
and neuropsychological tests during two visits (+/- 60 min, this time is
included in the overall time estimation as mentioned above). Besides that, the
parents, the child and the teacher of the child have to complete a number of
questionnaires (parents: +/- 80 min at baseline, +/- 35 min at follow-ups;
child +/- 45-60 min at baseline, +/- 25-15 min at follow-ups; teacher +/- 20
min at each visit). Risks will be negligible and physical discomfort mild. The
research protocol includes the participation of minors as methylphenidate is
primarily indicated for treatment of attention and hyperactivity problems in
children.