Genetic Testing for ADHD Medication Series—Part 7

Welcome to the final post in this series on genetic testing for ADHD Medication. My husband, Dr. Goat, and I greatly appreciate your enthusiastic response.

We based this series on testing that is is no longer available. But the currently existing tests are very similar.

The overriding message is this: Be careful about physicians misinterpreting these genetic testing results. Your or your child’s appropriate treatment relies upon being a smart consumer.

Moreover, you needn’t be interested in this testing at all to learn a great deal from this series!

ADHD Gene Testing Series in Seven Parts: 

Here is a summary of the previous posts (click on the blue number to link to the article).

1    Provides an overview of genetic testing as it relates to ADHD medication-response.

2   Shares testing results for my husband and me, along with my husband’s personal reactions to our disparate genes.

3   Defines what is meant by the term genotyping test. Briefly,  it’s a test that informs you of your genetic particulars. Specifically for our purposes in this blog series, it refers to tests that identify which variants of the drug-response genes known to be associated with ADHD medications that you have.

4   Explains how, when, and why this data might prove helpful, delving more deeply into the topics of pharmacokinetics (what your body does to the medication) and pharmacodynamics (what the medication does to the body).

5  Reminds us that genotyping data provides only one piece of the puzzle. There are many other factors that can affect how well a medication works for you, including overall health factors and co-existing conditions.

6  Looks at the specifics of Gina’s testing results, the same way this 7th (and final) post looks at Dr. Goat’s results.

Highlighting My Test Results,  By Dr. Goat

ADHD Gene TestingAs I wrote in my previous post:

There I was, confronted with these unsavory results. After years of pontificating professionally, in the abstract, regarding how pharmacogenetics data should be used, I was now faced with getting off my academic high horse and acting on my own “data.”

Acting on this data proved challenging for one reason in particular: Contrary to the intent of this test—which is primarily intended to guide first-time users of a medication—I had already tried several of those medications over the years, finally coalescing on a “combo” that is probably close to optimal for me.

And guess what? Turns out that my combo disagrees fairly strongly from the test’s recommendations. Does that mean that the test is wrong? Not at all.

 

First Point: Strattera (atomoxetine)

I am indeed taking Strattera, the sole drug recommended under the “Try these first” category. But I’m taking it at a much lower-than-average dose.

As for the drugs in the “Try these last,” column, the test may well be right indicating that they are not optimal for me. But … I was already taking one of these. In short, I have no way to tell without experimenting, and that’s something I don’t want to do unless I have strong reasons to do so. Experimentations can be very disruptive personally and professionally, so I am reluctant to mess around with what seems to be working.

Gina would like to pipe in for a second:

Note that the third (try these last) column includes the first-line treatments for ADHD: the stimulants!  It also includes some down-the-line medications sometimes used for ADHD but often with stimulants.
This is an excellent example of how the testing in no way takes into account which medications are most likely to be effective for the condition being treated.
The list of disclaimers includes:

  • The prescribing physician should review the prescribing information for the drugs being considered and make treatment decisions based on the patient’s individual needs and the characteristics of the drug prescribed.
  •  This test looks only at the patient’s genotype and its relationship to these drugs.

 

Second Point: Wellbutrin (bupropion)

Second, I was prescribed Wellbutrin early on (listed in the second column), but only after I had started taking a stimulant. Plus, my physician at the time prescribed 300 mg right off the bat. The result had me flat on my back on the sofa, for two days—a prime example of the importance of slowly increasing dosage.

That was the last time I didn’t “start low, titrate slow,” no matter what the prescribing doc said. Gina had enough of physician recklessness by that episode, and she stood firm. It took me a while to join Gina in questioning my MDs, to realize that having a medical degree—and, further, being a board-certified psychiatrist—did not necessarily mean that the prescriber would be all that, well, smart. Or even careful.

Guidance Notes

Here are the guidance notes for this particular “menu”:

1 Patients with this genotype are less likely to respond to alpha-2 adrenergic receptor agonists [e.g. clonidine, risperidone]

2 Patients with this genotype are less likely to respond to the amphetamines. Consider using medications from another class to achieve desired therapeutic outcomes.

3 Patients with this genotype at ADRA2A are less likely to respond to methylphenidate. Patients with this COMT genotype are less likely to respond to methylphenidate.

4 Use with monitoring. Patients with this genotype may benefit from higher total daily dose (TDD) of bupropion, ranging from 320mg-420mg/day if suboptimal response at lower dosing.

5 Extensive metabolizers may show appropriate response to atomoxetine at the higher end of the recommended dose range.

Taking The Results One By One

Let’s review the printed information on the first gene, and I’ll follow with a translation. (To see a larger version, click the image below.)

 

Dr. Goat’s ADRA2A Gene

Genotype: CC

Prevalence: 48% of patients

Phenotype: Reduced Response (CC): This genotype is associated with the reduced response phenotype. This patient is homozygous for the C allele of the 1291G>C polymorphism in the adrenergic alpha-2A receptor gene, which decreases binding affinity at the alpha-2A receptors. Patients with this phenotype may show a reduced response to methylphenidate and the alpha-2 adrenergic receptor agonists.

Translation: Aargh, this means I’m walking around with a semi-crappy ADRA2A genotype.

Remember post 4, about pharmacodynamics? This genotype means the functionality of the protein produced by the ADRA2A gene, namely, the adrenergic alpha-2A receptor, is a bit wonky.

As such, it reduces the effectiveness of this receptor’s interactions with a number of stimulant drugs as well as the alpha-2 adrenergic receptor agonists (e.g. clonidine and guanfacine).

 

ADRA2A Gene

In other words, and in keeping with the analogy I used in that post, the “Big Gulp” of these medications is only loosely fitting in my cup holder (receptors), such that I might want to consider a higher dosage of the drug. And remember: this is only as far as this particular gene is concerned (there are many other factors beyond this one gene!)

ADHD Gene Testing

I would also have to take into account any other drug I might be taking. Why? Because all drugs are metabolized to be ultimately removed from the body.

Think of the sausage-maker stuffing meat the sausage machine. It’s possible to over-feed that machine, at which point bad things can happen. That’s why your physician and pharmacist should always be consulted before making such changes.

Genetic Testing for ADHD Medication

My semi-crappy receptor is not completely trivial. But obvious strategies exist for dealing with it (e.g. higher dosage).

As I said before, we all have semi-crappy genes. I sure Gina has some unsavory genetic variants in her genome … somewhere.

Dr. Goat’s CYP2D6 Gene

Genotype: *1/*1; CNV=2

Prevalence: 77% – 92% of patients

Phenotype: EM: This genotype is associated with the extensive metabolizer phenotype. When considering half-life and area under the curve (AUC) of atomoxetine in CYP2D6 extensive metabolizers, patients with this phenotype are likely to respond to atomoxetine, but may require doses at the higher end of the recommended range.

Translation:

Yeah! A decent genotype for once! This is the most common form of this gene (that’s what the “*1/*1” means), such that the protein is very effective at metabolizing drugs (“extensive metabolizers” – see previous post).

As with Gina, I might benefit from increasing the dosage of atomoxetine (Strattera) somewhat. So I guess this fits with my benefiting from Strattera, which appears to be the case.

Just for fun, let’s look at one more of my genes:

Dr. Goat’s CYP2B6 Gene

Genotype: *1/*6

Prevalence: 48% African Americans, 25% Asians, 38% of Caucasians

Phenotype: IM: This genotype is associated with the intermediate metabolizer phenotype. Based on ability to metabolize bupropion to hydroxybupropion (HB), patients with this phenotype, who show a 20% decrease in HB levels, are likely to benefit from a higher total daily dose of bupropion.

Translation:

Boo, another semi-crappy genotype. Oh well.

The interesting thing is that bupropion (Wellbutrin) might be a useful medication for me after all. As I previously mentioned, I did try it years ago, but only after I was already taking a stimulant—and starting at too high a dose. Perhaps that’s why it wasn’t beneficial at the time. In other words, this medication never got a fair shake. It’s  useful to know that I might benefit from this drug.

______________________

And there you have it, folks: Mostly everything you need to know about interpreting gene tests to inform ADHD medication choices.  Does genetic testing for ADHD Medication provide vital information? Maybe, if you have some unusual mutations or you are a very rapid/slow metabolizer. That is useful information.  But this the best way to identify optimal medication? No. Absolutely not.

Remember: Only One Piece of the Puzzle

There are other puzzle pieces, including the huge number of published studies examining the overall efficacy of ADHD’s first-line medications: namely, the stimulants and Strattera.

There is no “silver bullet” in finding the best medication(s), at the best dose for you. But there is a relatively straightforward “trial and error” method, as described in my book, “Is It You, Me, or Adult A.D.D.?”

In the coming year, I will be offering Adult ADHD-related webinars for therapists and the public. They will cover medication and more. To be notified when they are ready, please be sure to subscribe to my blog.

 

—Gina Pera

54 thoughts on “Genetic Testing for ADHD Medication Series—Part 7”

  1. Hello! Thank you for this article!
    Recently, I was diagnosed with ADHD, and I was prescribed different stimulants that would not do anything except cause some side effects, even at high dosages.
    My doctor ordered me a genetic test that indicated that I carry ADRA2A C/C and SLC6A4 S/S (short serotonin transporter). Now I see why I did not react to the stimulants, and I had no “green” ADHD take-as-prescribed medication on the list at all.
    What do you think? Is there a way to normalize the work of the brain somehow? Are there any supplements that would be helpful? My doctor is not against taking supplements, but she cannot recommend me anything since there’s little to no research done on the ADRA2A C/C people.
    I asked my doctor, and she agreed we must continue looking for the proper medication and dosage. But I am tired.
    Thank you,
    Agness

    1. Hi Agness,

      I can only imagine how tired you are. Sometimes I wish we could fast-forward 50 years or so, and hope for better, clearer ways to select medications.

      Here’s the thing, though: When someone tells me they were “prescribed different stimulants”, it really tells me nothing. Because I’d want to know sleep status, diet, generic vs. brand, delivery system, stimulant class, and a lot more.

      Things that many prescribers don’t even know to ask about. Which is why some overly rely on these tests — and don’t know how to interpret them!

      I cannot possibly have an opinion in your case. I’m just saying, this is the realm of possibility. These are all issues to consider before “going into the weeds” of genetic-testing.

      If you read about my husband’s test results, he had only one Rx in the “green” category: Wellbutrin. Does that mean Wellbutrin would address his ADHD symptoms? No, it does not.

      I know this series is a lot to take in. But I encourage you to read it start to finish, a bit at a time, taking note of the bits that resonate for you.

      It might be that stimulants — the first-line Rx for ADHD — might work well for you with a more informed approach.

      I am completing right now Course 2 in my online training, solely on sleep and medication. Stay tuned!

      Gina

  2. Hi Gina,
    I appreciate you and your husband devoting so much efforts to better understanding and coping with ADHD. I was wondering if you may help me understand whether, in your opinion, you think trying an alternative medication (I am thinking Strattera?) would be beneficial.

    I have been taking immediate release generic adderall for nearly 10 years (20mg 3x/day) but no longer feel like it is effective. At first I thought it was due to the pharmacy switching generics on me, (there is a stark difference in generics efficacy when I get Teva vs the other one), but I don’t think its that, more so – my current treatment isn’t working and I am scheduled to see the doctor next week. I had a severe adverse reaction to wellbutrin which prompted a genetic testing (my nearly 8th failure at an antidepressant and/or anxiety med) where like your husband I did not win the genetic lottery!

    In terms of ADHD genotypes you mention, my results indicated I am a poor metabolizer of CYP2D6 *4/*5 but extensive normal CYP2B6 *1/*1. While the test is not be all say all, it explained ALOT about why I would get violently ill from codeine, why so many antidepressant treatments failed for severe AEs etc.
    That aside, I don’t know what medication to attempt (as there are so many) and hoping you or your husband may provide your two cents on the matter.

    Side note: I thought to try Strattera as I found some helpful information on dosing for CYP2D6 poor metabolizers –
    https://www.ncbi.nlm.nih.gov/books/NBK315951/

    Looking forward to your response, thank you kindly
    Alex

    1. Hi Alexandra,

      Thank you for the kind words. It was a lot of work. 🙂

      Just to be clear: My husband and I worked on this together, to explain pharmacodynamics, etc.. But I’m still the ADHD expert in the house. He’s involved in other scientific pursuits, like cancer. 🙂

      There is an expression in the medical diagnosis field: Think horses, not zebras. In other words, instead of jumping to a complicated and rare diagnosis, start with the basics.

      The basics in your case might be less in realm of genes, snips, and enzymes and more in…..the basic protocol for treating ADHD.

      For example, maybe you’ve tried a methylphenidate stimulant and just didn’t mention it. But anyone starting ADHD medication should be given a trial in each class. Unfortunately, many are given an amphetamine (more often than not, Adderall), and that’s it. Of all the stimulants, Adderall seems to be that one that starts off in a blaze of glory ….. and then peters out over time. Often more quickly than 10 years, though.

      I wonder if antidepressants have failed you so many times because it wasn’t depression at all. It was ADHD-related fallout that appeared as depression to the untrained clinical eye. It happens ALL the time. Especially with women.

      At least you might have an answer about codeine, though!

      I would also wonder:

      —Have your habits changed around eating, sleeping, exercising?

      —Is it possible that you are entering peri-menopause or menopause?

      These issues can affect how well a stimulant works.

      Also: Has your life started demanding more of you in the way of Executive Functions? Sometimes Adderall works well for a person, in terms of sort of propelling them through the day. But when life gets more complicated, and they haven’t steadily been developing supportive habits, Adderall taps out.

      As for Strattera, it’s worth a trial. The last I heard regarding the research, Strattera tends to work well for about 30% of people with ADHD. That’s much lower than the stimulants. Will you respond well to it? It’s impossible to know until you try. No genetic test can tell you that, unfortunately.

      We’ve known for a long time about the CYP2D6 enzyme issue with Strattera/Atomoxetine. Another good reason to follow the “start low, increase slow” rule that applies to all psychiatric medications.

      I hope this helps! Good luck!
      g

  3. Hi Gina,
    I see that Adderall XR is metabolized bu CYP2D6 and that Vyvanse is not metabolized by the P450 system. So, if dextroamphetamine=Adderall XR and Vyvanse breaks lisdexamfetamine into dextroamphetamine, wouldn’t it also need to be broken down by the 2d6 enzyme at that point? I’m confused as to whether the Vyvanse does, in actuality, use that enzyme. Very long story but trying to find a stimulant for my 17-year-old daughter. She is a low partial metabolizer for 2d6 and didn’t do well on the Adderall. I told her doctor I didn’t want that med, but my insurance wouldn’t pay for the Vyvanse and that’s what she got. So I guess I’m asking if you think that she would have the same issues on Vyvanse or would it be worth a shot? She tried Concerta as well up to 36mg and it did nothing. I still think she may have made it a higher dose . I am having very hard time with her doctors . I was very interested to see your series on this topic as many doctors and psychiatrists still are not educated in drug metabolism. Thank you for any help!
    Sue
    Sue

    1. Hi Sue,

      I’m not sure I understand the question. Mainly because you wrote: “dextroamphetamine=Adderall XR”.

      Do you mean that the two are the same? Because that’s one thing I can tell you: they’re not.

      That means, perhaps she will do better on Vyvanse than Adderall. It just depends on her genetics, not just the metabolizing genes but all the rest. About 40% of people with ADHD do clearly better on one class of stimulants than the other (MPH vs AMP). They should be given trials of each.

      Many people do poorly on Adderall, for a host of reasons, and do better on Vyvanse. But some don’t do well on any amphetamine—or any methylphenidate.

      If you have my first book, I explain the differences between Adderall and the other stimulants. Adderall was a problem 20 years ago, and it’s still a problem! Because too many prescribers don’t have the first clue about it—but still believe it is the “best” for adults thanks to aggressively persuasive pharma reps of years ago. It’s a deplorable situation.

      https://amzn.to/37ea04V

      She tried brand/authorized-generic Concerta? Because the Concerta generics don’t work as Concerta goes. Poor approximations (though they might work well for people who well on actual Concerta).

      Did she go up to 54 mg? Might have made a difference.

      You also want to have a clear idea of what “working” will mean. Treatment targets. Also, try to address any sleep deficits before starting the stimulant. It can affect response.

      I hope this helps.
      Gina

  4. I have tried in total 4 types of adhd medications. First, I tried Ritalin modified release but had too much anxiety in general to get to a decent dosage. Then I tried Strattera. Had to stop due to high diastolic blood pressure and little effect. Then I was put on Concerta a year later with 72 mg having no effect except depression and high pulse rate. I am now on Vyvanse, just started taking the max dose (70mg) after 1 month. Still not a good effect, but at least less depressing. I have tried potentiating with antacids without luck. I also respond very little to codeine, and my tolerance goes through the roof after 3 days. This is a recent development. I used to get very CNS depressing effects of codeine when I started using it for severe menstrual pain years ago.
    What does this mean? Rapid metabolism? I haven´t tried any immediate release, just XR.

    1. Hi Birgitte,

      Sorry you’re having such trouble. Yes, it’s possible that you are a rapid metabolizer, but you’d need tests to confirm that. And if you’re at 72 mg Vyvanse with “not a good effect but at least less depressing,” I’m not sure that would be useful. Especially if it’s not covered by insurance and money is tight.

      Assuming the diagnosis is correct, there could be many other reasons why Ritalin, Strattera, and Concerta did not work for you:

      e.g.
      —Generics
      —Sleep deficits
      —Caffeine/nicotine consumption
      —Nutritional deficiencies
      —co-existing anxiety (that is, not as fallout from ADHD but as a genetically co-existing condition; many adults with ADHD do best on two Rx)

      You say you are getting someone more of an effect from Vyvanse. Maybe that means you respond better to the amphetamine class of stimulants.

      Adderall is not my favorite Rx; it gets many people into trouble — and most prescribers haven’t a clue.

      But it might be that it’s extra mechanism of action is what works for you. Might be worth a try.

      I hope this helps.
      g

  5. Since Vyvanse, Risperdal, and Adderall are all metabolized by CYP2D6, would this seem like a reasonable drug regimen for a patient who is a CYP2D6 poor metabolizer? These are the results I received, and doctor is not willing to discuss.

    1. Hi N,

      First, regardless of CYP2D6 metabolizer status, you want to know that those three medications are necessary and represent methodical treatment — not just throwing spaghetti at the wall.

      Maybe that’s the best approach for you. To me, I’d be wondering if the Risperdal was added to address the side effects from perhaps-not-the-best stimulant choices.

      Also: Adderall is not the same stimulant as Vyvanse. Vyvanse contains dexedrine. Adderall contains mixed amphetamine salts.

      But I’m confused. You’re saying that the genetic testing indicated that Vyvanse, Risperdal, and Adderall are the choices for you? And that this prescriber ordered the testing? Or you did it independently?

      Personally, I’d be wary of any prescriber who is “not willing to discuss”. That is, not explain the reasoning.

      Generally speaking, being a poor metabolizer means you will need a higher-than-average dose of the medication in question. It does NOT mean that you should not take the medication.

      I hope this helps.
      g

Leave a Comment

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Stay in Touch!
Ride the ADHD Roller Coaster
Without Getting Whiplash!
Receive Gina Pera's award-winning blog posts and news of webinars and workshops.
P.S. Your time and privacy—Respected.
No e-mail bombardment—Promised.
No Thanks!
close-link