Pharmacogenomics question - ADRA2A vs COMT for methylphenidate

[SpongeBob DoctorPants]

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I have seen pharmacogenomic reports showing methylphenidate listed with two separate results: ADRA2A and COMT. For instance, I'm looking at report right now which states the following details for methylphenidate:

Methylphenidate (ADRA2A): ADRA2A(C-1291G): C|C
Typical response is expected; no additional therapeutic recommendations.

and

Methylphenidate (COMT): COMT(Val158Met): Decreased function. Two alleles with decreased activity.
Individuals with the Met variant may be at an increased risk of therapeutic failure.

Anyone familiar with this? What am I to take away from it? I've tried reaching out to the company that runs this test, and they basically said that this medication is multigenetic and conclusive outcomes data for all combinations of both genes together does not yet exist, so the doctor will need to decide the best route of prescribing based on all of the data available.

 

[dl2dp2]

I do research in this area. There's not really RCT on this topic. The bottom line is this result is not actionable. It's useful though sometimes to argue for a higher than usual MPH dose with insurance coverage.

 

[hamstergang]

Methylphenidate (COMT): COMT(Val158Met): Decreased function. Two alleles with decreased activity.
Individuals with the Met variant may be at an increased risk of therapeutic failure.

I believe the theory here is that with underactive COMT, there's more dopamine and norepinephrine floating around the synapses. Giving a stimulant medication then increases the dopaminergic and noradrenergic tone by relatively less than if COMT were at full strength. Therefore, less chance of response to psychostimulant.

Whether there's data to back this up or not I do not know.

 

[clausewitz2]

I believe the theory here is that with underactive COMT, there's more dopamine and norepinephrine floating around the synapses. Giving a stimulant medication then increases the dopaminergic and noradrenergic tone by relatively less than if COMT were at full strength. Therefore, less chance of response to psychostimulant.

Whether there's data to back this up or not I do not know.

Data i think is critical here. The account you outline is fine as far as it goes but if the response function for dopamine and norepi is non linear than even that logic goes out the window.