Medication Optimization for ADHD: MOVA study. Implementation and evaluation of double-blind placebo-controlled titration in clinical practice

ADHD is one of the most common child psychiatric disorders, with a prevalence
of around 5% (Polanczyk e. a, 2007). It is associated with significant negative
consequences in different functional domains and quality of life (for example
at home, school, work) (Shaw and others, 2012; Dabon e. a; 2010). The outcome
is improved by treatment. Drug treatment is usually involves the use of
stimulants, with as first choice methylphenidate. The treatment of ADHD with
stimulants is effective in about 75% of the cases (Award 1992). The variability
in the response, however, is large and can*t be predict well (Bang et al 1995).
To obtain an optimal drug treatment, it is important to titrate with different
doses, use checklists during medication evaluation, and include proactive and
standardized questioning about possible side effects and using a concept with
room for improvement with a constantly try to optimize the effect of the
medication on the symptoms. (Verhulst and others, 2014). Making decisions about
the treatment is often considered as complicated and time-consuming by
practitioners and research shows that certainly not all practitioners apply
this strategy (Kovshoff and others, 2012).
In addition, there are social concerns about the number of children with ADHD
in Netherlands that are being treated with methylphenidate (see Report Health
Council of the Netherlands, 2014). Data show that in the last ten years the
number of prescriptions for methylphenidate has quadrupled to around 4.5% of
all children and young people. This percentage is almost as high as the
prevalence of ADHD (about 5%), while according to the guidelines not all
children with ADHD should be treated with methylphenidate. Overtreatment with
methylphenidate should be reduced so children would not unnecessarily expose to
negative side effects. The current guidelines recommend to use stepwise
titration for the titration of methylphenidate. In this form of titration the
dosage is gradually raised to the proper dosage. A higher dose will be given
when a lower dose does not have the desired effect. Stepwise titration has,
however, some important weaknesses.
First, it is not possible to objectively determine whether methylphenidate is
sufficiently effective. This is a real problem, because a large-scale study has
shown that treatment with methylphenidate at about ten percent of children with
ADHD is not effective (non-responders) and that an additional 13%
methylphenidate no more effect than placebo (placebo-responders) (Greenhill et
al., 2001; Vitiello et al., 2001). There is substantial evidence that up to a
third of the children treated with methylphenidate in the Netherlands is
treated unjustified, given the above alarming figures about methylphenidate
use. A second weakness is that the method does not double-blind, because
parents and practitioner know that the dosage goes up, which may be an
expectation effect (placebo effect). The optimal dose is not objectively
defined. This is a worrisome, because many children will not get the correct
dosage of methylphenidate (Greenhill et al., 2001) and an incorrect dosage
reduces the effectiveness and safety of drug treatment.

The primary goal of this study is to investigate whether placebo-controlled
double-blind titration leads to optimizing the use of methylphenidate. This by
detecting placebo-and non-responders more efficiently and by treating
responders better so they have better controlled ADHD behaviors and fewer
side effects.
The second objective of this research is to make double-blind titration easier
implementable by means of the application. The satisfaction of parents,
teachers and therapists will be investigated in comparison with the current
stepwise titration.

This project is a RCT (Randomized Controlled Trial) with two arm design: a drug
treatment optimal titrated by the practitioner with support off the application
(N = 70) and a drug treatment, through step-by-step titration, as is commonly
used in the treatment centers (N = 70).

The children in the control arm will have a gradual titration of
methylphenidate, according to the protocol of the participating centers.
The children in the placebo-controlled double-blind titration group will be
treated according to the protocol of the study medication by their own
practitioners. The optimal dose methylphenidate is determined by means of a
double-blind randomized placebo-controlled titration procedure. It starts with
an open lead-in phase where the child gets different doses (5 mg, 10 mg, 15/20
mg) methylphenidate in ascending order. In this phase side effects will
determine whether a child can participate in the titration according to the
study protocol. When the highest dose is not tolerated it will be replaced by
the 2nd highest dose during the titration. If a child does not tolerate
multiple doses the child can*t participate in the titration and will be further
treated by the Centre. During the titration phase the child gets administered
methylphenidate, 3 times a day with a fixed ose for each week with 5 mg, 10 mg,
15/20 mg (depending on the weight, children lighter than 22 kg: 15 mg) or a
placebo in a random order for 4 weeks.The highest dosage will never be given
immediately after the placebo. Parents and teachers register each week the
effects of the medication on the behavior through the application by means of
questionnaires (for inattention, hyperactivity-impulsivity, oppositional
behavior and side effects). After 4 weeks the practitioner chooses the optimal
dose with the application. The child is classified as ' responder ', ' placebo
responder "or" non-responder '. A child is a responder if the ADHD symptoms
reduce significantly during the use of at least one of the dosages
methylphenidate compared to the use of placebo. Low symptom scores and no room
for improvement in all dosages, indicate a placebo responder. If there is room
for improvement at all doses but no significant difference between the
methylphenidate dosages and placebo, the child is classified as non-responder.
The children are 6 months further treated by their own practitioner and after 6
months there is new evaluation. Non-responders are further handled within the
institution, but do still take part in the intervention period for the '
intention to treat analysis. We expect that 70-80% of the children is a
responder and that 20-30% of children either in the placebo responder or
category in the category non-responder falls

There are no known risks associated with participation to this study. There is
an extra time effort to parents and teachers asked to fill out questionnaires
(10-15 min per week) during the titration . More extensive questionnaires (15
min-20 min) have to be completed before the start of the titration, after the
titration and after 6 months.