Long-term effects of psychotropic medication on the developing brain. A cohort study based on medical prescription data

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 long-term effect on brain structure and function.
Studies in animals raise serious concerns
and call for further investigation of possible long-term effects on brain
structure and function.

SSRIs are the second most commonly prescribed psychotropic drugs in children
and adolescents. In the
pediatric population they are mainly prescribed for treatment of major
depressive disorder (MDD) and
anxiety disorders. In 2007 there were 8.500 patients under age 21 prescribed
with SSRIs in the
Netherlands alone. The rate of prescription is increasing over the past years
(Stichting Farmaceutische
Kengetallen), despite the controversy on their efficacy in treating childhood
MDD. Although numerous
trials have shown robust safety of SSRIs in adults, limited data is available
on their effects on the
maturing brain, and their efficacy in children and adolescents even debated
(Hetrick et al., 2007). Animal
studies have demonstrated that peri-adolescent pharmacological manipulations of
extracellular serotonin
(5-HT) concentrations ([5-HT]E) can lead to abnormal outgrowth of the 5-HT
system (Azmitia et al., 1990;
Shemer et al., 1991; Won et al., 2002). SSRIs increase [5-HT]E by blocking 5-HT
transporters (SERT).
Recently, pilot experiments of our group have shown that early chronic
treatment with the SSRI fluoxetine
results in a significant increase in prefrontal and hypothalamic SERT density
in juvenile treated rats, but
not in adult treated rats. These findings are in line with Wegerer et al.
(1999), who has shown that this
effect persists into adulthood, long after discontinuation of treatment with
SSRIs. This raises concern
about the use of SSRIs in children and adolescents and it is therefore vitally
important to evaluate the
long-term effects of SSRIs on the developing human brain.

Primary objective of the study:
1. To report on the age-dependency of the effect(s) of MPH or SSRI treatment
on the outgrowth of the DA and 5-HT systems, respectively, using
state-of-the-art Magnetic Resonance Imaging (MRI) techniques

A pharmacological MRI (phMRI) study for assessment of DA and 5-HT function and
connectivity in the brain of adult subjects that have been previously treated
with SSRIs or MPH during childhood/adolescence or adulthood (exposed group).
Their outcome measures will be compared to a healthy age and gender matched
group (unexposed healthy group) and an age and gender matched group suffering
from ADHD or MDD/anxiety disorders but who have not been treated with these
medications (unexposed, diseased group). The (interaction) effect of age and
treatment is investigated.

Burden of MPH investigation, total 5 hours:
-Neuropsychological test, saliva sampling for DNA, completing questionnaires.
-1 hour MRI scan divided over 2 x 30 minutes; subsequent ingestion of
methylphenidate (0.5 mg/kg) followed by 90 minuten rest and a repeat of the MRI
scan

Burden of fluoxetine investigation, total 5 hours:
-Neuropsychological tests, saliva sampling for DNA, filling out questionnaires.
-Inserting i.v. cannula
-MRI scan, during approximately one hour
-cortisol sampling in saliva through cotton swabs which can be returned to the
investigators via post

Risks
No risks are invloved in the study. MRI scanning, neuropsychological
examination, saliva sampling, and filling out questionnaires have no added
risks. Oral challenge with methylphenidate (0.5 mg/kg) is a probe during the
MRI examination to turn the dopamine system 'on'. The dose is generally well
tolerated (see also page 11 of the study protocol), with minimal (usually
positive) side effects. The intravenous form of citalopram is also well
tolerated (see also pages 10-11 of the study protocol).


Conclusion: we find the risks to be negligable and the burden to be minimal.