BackgroundAnimal studies have shown that methylphenidate (MPH) and fluoxetine (FLX) have different effects on dopaminergic and serotonergic system in the developing brain compared to the developed brain. The effects of Psychotropic drugs On the Developing brain (ePOD) study is a combination of different approaches to determine whether there are related findings in humans.Methods/DesignAnimal studies were carried out to investigate age-related effects of psychotropic drugs and to validate new neuroimaging techniques. In addition, we set up two double-blind placebo controlled clinical trials with MPH in 50 boys (10–12 years) and 50 young men (23–40 years) suffering from ADHD (ePOD-MPH) and with FLX in 40 girls (12–14 years) and 40 young women (23–40 years) suffering from depression and anxiety disorders (ePOD-SSRI). Trial registration numbers are: Nederlands Trial Register NTR3103 and NTR2111. A cross-sectional cohort study on age-related effects of these psychotropic medications in patients who have been treated previously with MPH or FLX (ePOD-Pharmo) is also ongoing. The effects of psychotropic drugs on the developing brain are studied using neuroimaging techniques together with neuropsychological and psychiatric assessments of cognition, behavior and emotion. All assessments take place before, during (only in case of MPH) and after chronic treatment.DiscussionThe combined results of these approaches will provide new insight into the modulating effect of MPH and FLX on brain development.

Preclinical studies suggest that dexamphetamine (dAMPH) can lead to monoaminergic neurotoxicity. This exploratory study aimed to investigate effects of recreational dAMPH use on the dopamine (DA) and noradrenaline (NA) systems in humans. To that purpose, eight male abstinent dAMPH (26.0 ± 4.0 years) users and 10 age- and IQ-matched male healthy control subjects (23.0 ± 3.8) underwent neuropsychological testing sensitive to DAergic function and single photon emission computed tomography (SPECT) scanning with [(123)I]FP-CIT to determine striatal DA transporter (DAT) binding. In addition, changes in cerebral blood flow (CBF) induced by the DA/NA reuptake inhibitor methylphenidate (MPH) were measured using pharmacological magnetic resonance imaging (phMRI). Performance of dAMPH users was significantly worse on executive function and verbal memory tasks. Striatal DAT binding ratios were on average lower in dAMPH users (near-significant, p=0.05). In addition, CBF in control subjects decreased significantly in response to MPH in gray matter and basal ganglia, among which the striatum, thalamus and hippocampus by 10% to 29%. However, in dAMPH users the CBF response was blunted in most brain areas studied, only decreasing in the hippocampus and orbitofrontal cortex. When comparing groups, CBF response was found to be significantly different in the thalamus with a decrease for healthy controls and a blunted response in dAMPH users. Collectively, our findings of a blunted hemodynamic response in monoaminergic regions, in combination with indications for lower striatal DAT binding and poorer behavioral measures are likely to represent DAergic dysfunction in dAMPH users, although NAergic dysfunction may also play a role.

The combination of these findings provides further evidence for frontostriatal DAergic dysfunction in recreational dAMPH users and is consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use. The findings of this explorative study could have important implications for humans in need for treatment with dAMPH, such as patients suffering from ADHD and therefore this study needs replication in a larger sample.