Long-term effects of SSRI treatment during (late) brain development in OCD patients: a retrospective MRI 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. 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, MRI experiments of our group have
shown that early chronic treatment with the SSRI fluoxetine in juvenile rats
leads to an enhanced response to an acute 5-HT challenge in later life while
adult-treated rats show a decreased response to a similar challenge. This
clearly indicates the existence of age-dependent effects of SSRI treatment on
5-HT function (Klomp et al., 2012) and raises further 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.

To report on (the age-dependency of) the long-term effect(s) of chronic SSRI
treatment during adolescence or adulthood on the outgrowth and function of the
5-HT system, using state-of-the-art Magnetic Resonance Imaging (MRI) techniques
and other, more indirect, measures of 5-HT function in a homogeneous group of
OCD patients.

A pharmacological MRI (phMRI) study for assessment of 5-HT function and
connectivity in the brain of adult subjects that have been previously treated
with SSRIs during childhood/adolescence or adulthood (exposed group). Their
outcome measures will be compared among each other and to an age and gender
matched group suffering from OCD as well but who have not been treated with
this type of medication (unexposed group). The (interaction) effect of age (of
treatment) and treatment is investigated.

Burden of research day, total duration 4 hours:

- Neuropsychologic tests, saliva sampling for DNA and cortisol, questionnaires
(about 1.5 hours)

- Insertion of intravenous line, administration of citalopram (7.5 mg) and
twice drawing blood (max. 10ml each time)

- MRI scan (1 hour)

- 5 cortisol samples at home using cotton swabs (5x 2 minutes)

Risks:
Intravenous administration of a low dose of citalopram is generally well
tolerated (See also section 5 of the study protocol) and does not contain any
health risks for the participants. There will be minimal burden, which exists
mainly of the insertion of the i.v. line.
Neuropsychologic tests, saliva sampling, questionnaires and the MRI scan do not
add any risk and are considered to give minimal burden.