Do effects of methylphenidate decline after long-term use? A double-blind, placebo-controlled cross-over study of effects of methylphenidate on cognitive functioning and real world behavior in treatment naïve children compared to effects after 9 months of treatment in clinical practice

Many children and adolescents with attention-deficit hyperactivity disorder
(ADHD) use methylphenidate for extended periods of time, despite the lack of
data on its long-term effectiveness. There is an ongoing debate whether
individuals may develop tolerance towards methylphenidate over the longer term.
It has been suggested that the acute short-term effects of methylphenidate
diminish after prolonged use, but current evidence is lacking.

In addition to the characteristic pattern of symptoms of inattention,
hyperactivity, and impulsivity, ADHD is also associated with cognitive
functioning impairments, which may improve by using methylphenidate. However,
it is currently unclear whether long-term methylphenidate use leads to changes
in underlying brain functioning as expressed by effects on behavior (in the
classroom) and neurocognitive measures (neuropsychological tasks,
electroencephalography), and how this relates to each other.

The main objective of this study is to compare the acute effects of
methylphenidate on behavioral and cognitive functioning in 6 to 12 year old
treatment naïve children compared to the effects after nine months of treatment
with methylphenidate in general clinical practice. We also aim to investigate
if there is an association between the performance on the cognitive tasks, EEG
measures, and classroom behavior.

This study will consist of two series of double-blind, placebo-controlled
cross-over trials: an initial trial to assess the effects of methylphenidate on
behavioral and neurocognitive functioning prior to the start of treatment
with methylphenidate in methylphenidate naïve children. The participants will
also perform a test battery of cognitive tasks and an EEG-recording will be
made, again once on a placebo and once on methylphenidate, one week apart.
Participants will be observed in the classroom, once on a placebo and once on
methylphenidate, one week apart. . After nine months of treatment the trial
will be repeated.

Four day use of methylphenidate in a regular dose and four days use of placebo

The burden for the participating families will include four visits to the
clinical center. Each visit takes around 180 minutes. During each visit the
participant will receive one tablet of study medication. During the first
visit, an IQ screener will be taken right after taking the study medication
(approximately 20 - 30 min). Then an EEG recording (approximately 1 hour,
including 30 min of recordings and 30 min of preparation time) will be made.
The EEG recording will consist of two resting state periods (each 5 minutes,
one at the start and one at the end of the recording) and a recording during a
Stop Signal Task (20 min). Thereafter, participant will complete the test
battery of cognitive tasks (approximately 5045 m inutes per test battery). One
parent will complete two questionnaires (30 min) while they wait for the
participant to finish the assessment. and The following day two investigators
will observe the participant in the classroom (approximately 30 minutes).The
risks of participating in this study are negligible and the possible physical
and psychological discomfort mild. Participation in this study will benefit the
individuals as the effectiveness of methylphenidate will be assessed at
multiple levels (i.e. classroom behavior, cognitive functioning, brain
activity). As ADHD is particularly prevalent during young age and the aim of
the study is to compare the acute effect in drug naïve participants when they
start treatment with methylphenidate and after they have been using it for nine
months, this study requires a population of children and adolescents.