The selection and dosing of medication in psychiatry is far from scientific – even though a great deal of hard science goes into the preclinical design and clinical development. One reason, among many, has to do with the so-called ‘inverted-U-shaped’ relationship between the dose of a psychoactive compound and an individuals’ performance. Some folks show dramatic improvement with a given dose (their system may be functioning down at the low side of the inverted U mountain and hence, and added boost from medication may send their system up in performance), while others may actually get worse (those who are already at the peak of the inverted U mountaintop). How can a psychiatrist know where the patient is on this curve – will the medication boost raise or topple their patient’s functioning ? Some insight comes in the form of a genetic marker closely linked to the DRD2 gene, that as been shown to predict response to a dopaminergic drug.
Michael Cohen and colleagues, in their European Journal of Neuroscience paper (DOI: 10.1111/j.1460-9568.2007.05947.x) entitled, “Dopamine gene predicts the brain‘s response to dopaminergic drug” began with a polymorphism linked to the DRD2 gene wherein one allele (TaqA1+) is associated with fewer DRD2 receptors in the striatum (these folks should show improvement when given a DRD2 agonist) while folks with the alternate allele (TaqA1-) were predicted to show a falling off of their DRD2 function in response to additional DRD2 stimulation. The research team then asked participants to perform a cognitive task – a learning task where subjects use feedback to choose between a ‘win’ or ‘not win’ stimulus – that is well known to rely on proper functioning of DRD2-rich frontal and striatal brain regions.
Typically, DRD2 agonists impair reversal learning and, as expected, subjects in the low DRD2 level TaqA1+ genetic group actually got “more” impaired – or perseverated longer on rewarding stimuli and required more trials to switch on the go and figure out which stimulus was the “win” stimulus. Similarly, when differences in brain activity between baseline and positive “you win” feedback was measured, subjects in the drug treated, TaqA1+ genetic group showed an increase in activity in the putamen and the medial orbitofrontal cortex while subjects in the TaqA1- showed decreases in brain actiity in these regions. The authors suggest that the TaqA1+ group generally has a somewhat blunted response to positive feedback (sore winners) but that the medication enhanced the frontal-striatal reaction to positive feedback. Functional connectivity analyses showed that connectivity between the frontal cortex and striatum was worsened by the DRD2 agonist in the TaqA1+ genetic group and improved in the TaqA1- group.
Although the interpretations of these data are limited by the complexity of the systems, it seems clear that the TaqA1 genetic marker has provided a sort of index of baseline DRD2 function that can be useful in predicting an individual’s relative location on the theoretical inverted-U-shaped curve.
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Image via Wikipedia Amidst all the genome-wide ‘snp-ing’ going on of late (my 23-and-me data should arrive in a couple of weeks), Walsh and colleagues provide an incredible trove of structural variation (deletions/insertions in the size range of more than 100kbp but less than 100Mbp) that is 3- to 4-fold enriched in patients with adult onset and childhood onset schizophrenia. Their paper, “Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia” (DOI 10.1126/science.1155174) uses a variety of genome hybriziation techniques to map novel variants and finds, amazingly, that many of the hits are within genes that function in common pathways of brain development and synaptic function. The authors admit that it is hard to ascribe a population risk value to any one of these variants, but the biochemical pathways suggest that the genes that were identified by this method deserve a great deal of attention in the basic and clinical genetic research community.![Reblog this post [with Zemanta]](https://i0.wp.com/img.zemanta.com/reblog_e.png)
Genes 2 Brains 2 Mind 2 Me 