Bottelier, 2014 The effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design.

[Altostrata]

"Long-term effects of drug exposure are delayed and come to expression once the vulnerable system reaches maturation," this proposal for a series of studies suggests. (The results have not yet been published.)

BMC Psychiatry. 2014 Feb 19;14(1):48. doi: 10.1186/1471-244X-14-48.
The effects of Psychotropic drugs On Developing brain (ePOD) study: methods and design.
Bottelier MA, Schouw MLj, Klomp A, Tamminga HG, Schrantee AG, Bouziane C, de Ruiter MB, Boer F, Ruhé HG, Denys D, Rijsman R, Lindauer RJ, Reitsma HB, Geurts HM, Reneman L1.

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/24552282
Free full text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930821/
and http://www.biomedcentral.com/1471-244X/14/48

BACKGROUND:
Animal 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/DESIGN:
Animal 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.

 

DISCUSSION:
The combined results of these approaches will provide new insight into the modulating effect of MPH and FLX on brain development.


From the paper:
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Background
The brain in development is dependent on the emergence of critical developmental processes (i.e. synaptogenesis, [1], and therefore sensitive to pharmacological interventions. Treating children and adolescents with serotonergic (5-HTergic) or dopaminergic (DAergic) drugs like fluoxetine (FLX) and methylphenidate (MPH), is therefore likely to have influence on the maturation of the brain.

For the 5-HTergic system, FLX (a selective serotonin reuptake inhibitor (SSRI), registered for the treatment of depression in children aged 8 years and older, is known to increase extracellular levels of 5-HT by blocking the serotonin transporter (SERT). However, animal studies have demonstrated that periadolescent 5-HT pharmacological manipulations can lead to abnormal outgrowth of the 5-HT system [2,3]. Experiments by our group have shown that chronic treatment with FLX results in a significant increase in prefrontal and hypothalamic 5-HT transporter (SERT; +30%, p < 0.01) in juvenile-treated rats, but not in adult treated rats [4]. These findings are in accordance with Wegerer and Bock who have also shown that this effect persists into adulthood, long after discontinuation of treatment with SSRIs [5,6]. Recently it was confirmed that FLX administration upregulates SERT long-lastingly, also in non-human primates [7]. These preclinical studies suggest that 5-HT manipulations have an impact on the regulation of 5-HT outgrowth which is dependent on the age of exposure.

For the DAergic system, recent animal studies with MPH, a DA reuptake inhibitor and stimulant drug frequently prescribed in the treatment of attention deficit hyperactivity disorder (ADHD), have demonstrated that these effects are also age-dependent. For instance, early treatment with MPH led to a considerable (-50%) reduction of dopamine transport density (DAT) in rat striatum when compared to non-treated animals, whereas no effects were observed in adult animals [8]. These alterations in the DA system have been shown to result in behavioral abnormalities. For example, young rats treated with MPH show more anxiety- and depression-related behavior in adulthood than adult rats treated with MPH [9].

There is some clinical evidence for related findings in humans. For example, after concerns about increased suicide risk among children and adolescents treated with SSRIs, the Food and Drug Administration and European Medicines Agency (EMEA) stated in 2003–2004 that SSRIs were contraindicated for treating depression in children and adolescents. Furthermore, in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) children who received behavioral therapy had a lower rate of diagnoses of anxiety or depression (4.3%) than the children who were treated with MPH (19.1%) thus indicating a (transient) increase in the occurrence of emotional disorders six to eight years after treatment with MPH [10]. Age-related differences have also been found between adolescent and adult patients on fMRI studies, with adolescent patients treated with MPH showing more activity in the prefrontal cortex after treatment than adult patients [11].

Thus, evidence is slowly emerging that the long-term effects of drug exposure are delayed and come to expression once the vulnerable system reaches maturation (i.e., typically during adulthood). This phenomenon is known as ‘neuronal imprinting’ and occurs when the effects of drug exposure outlast the drug itself [12]. Still, very little is known on exposure during later brain development. Most (clinical) studies are hampered by the fact that they are retrospective in design, and therefore the findings could be caused by other factors on which the groups differed. As pointed out by Shaw and colleagues: ‘….the ideal study design for this question would be a randomized trial comparing cortical growth in children on psychostimulants against an unmedicated comparison group—but this would be both logistically and ethically challenging’ [13]. Notwithstanding this challenge, we have set up three studies (the effects of Psychotropic drugs On the Developing brain ‘ePOD’ project): two randomized controlled trials (RCTs) and a retrospective cohort study, investigating the possibility of the existence of neuronal imprinting in children medicated with these drugs while using several modalities to assess neurocognitive development. Here we report on the objectives and methods of these studies.

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[btdt]

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Fluoxetine - Wikipedia, the free encyclopedia

en.wikipedia.org/wiki/Fluoxetine‎

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Fluoxetine (also known by the tradenames Prozac, Sarafem, Ladose and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor ...