Welcome to Part 4 of the ADHD Roller Coaster’s six-part series: Gene Testing to Inform ADHD Drug Therapy. We could call it, “Goldilocks finds that sweet spot between too high a dose of medication and too low a dose to find the just right dose”
My husband (“Dr. Goat”) and I put our neurons together to bring you this series. The goal: accurate information geared for the layperson with little background in molecular biology or genetics. (I’m the litmus test and editor in that regard!)
I must tell you: Ten years ago, no one could have imagined Dr. Goat and I working together so harmoniously on such a project. Instead, picture miscommunications galore, tempers raising the roof, and no doubt a few epithets thrown around before we both said, “You’re impossible!”
Thank goodness, we are past those days. Working together is fun and productive. Teaming up to produce information that we hope will elevate the lives of our readers is extremely rewarding. Who knows, we might come up with a few more topics. Stay tuned!
Part 1 provides an overview to the topic of genetic testing as it relates to ADHD medication-response.
Part 2 shares testing results for my husband and me, along with my husband’s personal reactions to our disparate genes.
Part 3 defined 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, tests that identify which variants of the drug-response genes known to be associated with ADHD medications that you have.
Here in part 4, below, you’ll discover how, when, and why this data might prove helpful.
Note: This post is a little longer than the previous ones, but we thought it best not to break up the concepts. So, settle back, take it slowly, and enjoy!
Why and When To Pursue Genotype Testing
By Dr. Goat
Too low a dose? You don’t get a therapeutic benefit (nothing happens).
Too high? You might start encountering unacceptable side effects.
So, just like Goldilocks, it is crucial to reach a “sweet spot” of dosage. In that sweet spot, you will get the full benefit of the drug with minimal side effects. [Gina does an excellent job of explaining this vis a vis ADHD medications in her first book, Is It You, Me, or Adult A.D.D.?]
Introducing: Gene Variants
One factor to consider when aiming for that sweet spot of medication effectiveness: your specific gene variants that affect drug response. That’s where genotyping tests come in: They identify these gene variants. In turn, this information helps you to:
- Determine what dosage you should start with, and
- Decide the order in which medications should be evaluated.
This information is especially valuable if you are
- Beginning drug treatment for ADHD,
- Considering changing to a different drug, or
- Introducing an additional drug to your regimen.
Note: Information from these tests will not be a “silver bullet.” It is simply a starting point. The last post in this series will examine how I might use my personal results.
Pharmacokinetics (PK) and Pharmacodynamics (PD)
To understand why this information is important, let’s further explore the two key aspects of pharmacogenetics—briefly defined, this is the study of genetic variations in drug metabolic pathways that can influence individual responses to drugs.
You learned a bit about these two key aspects in a previous post: pharmacokinetics and pharmacodynamics. We take one at a time.
1. Pharmacokinetics (PK): “What the Body Does to the Medication”
We’ve all seen those TV commercials for laundry stain-removers with “enzymes.” These various types of enzymes find their targeted stains, latch on, and break down the stain.
We also have enzymes in our bodies. We need them not to break down stains, but to break down certain substances and convert them into other substances. For example, stomach enzymes break down the food you ingest into tiny bits that can be converted into energy. Among their many functions, enzymes convert inactive drugs into the active form.
Once that conversion happens—and only after it happens—we can actually benefit from the medicine. (We’ll explain examples of an active and inactive ADHD medication below.)
Enzymes are produced by—you guessed it!—our genes. Genes, as the “instruction manuals of life,” specify how to make proteins; and that includes enzymes and various other molecules. (To learn more, visit “How Genes Work.”)
The small variations in the instructions coded in our genes (the “gene variants” discussed in post 3) end up influencing how enzymes are produced and how they operate. In turn, some of these enzymes (and other types of proteins) affect your body’s response to a medication.
Tiny differences in your genes—and thus your enzymes and other proteins—can affect how your body can metabolize (convert) a drug. This also can affect how long the drug stays your body.
In other words, these genetic variants affect pharmacokinetics (PK).
Deconstructing this word’s Greek roots, we have pharmaco (medication) and kinetics (moving, putting in motion). Think of pharmacokinetics as the physiological mechanisms by which the body absorbs, distributes, metabolizes, and removes a drug from the body.
A Major Player Among Drug-Response Genes: CYP2D6
There are lots of enzymes in humans, but here’s a particularly significant one when it comes to drug-response: Cytochrome P450 2D6, an enzyme encoded by the CYP2D6 gene. It breaks down about a quarter of all drugs, including:
- Antidepressants such as Prozac
- Breast Cancer (Tamoxifen)
- Antipsychotics (e.g. Risperdal, Abilify,)
- Pain Killers (e.g. Codeine)
One Size Does Not Fit All
You’ve probably heard people say, “I’m very sensitive to medication.”
What these people typically mean is, anything larger than a very small dose knocks them for a loop. Conversely, there are the “nothing phases me” types, and of course plenty of people in between. This in part due to the drug-response gene variants that people have.
For example, there are generally three categories that describe the rate at which humans metabolize drugs, based on the enzymes produced by their gene variants:
- Slow, or poor, metabolizers: These folks don’t break down medications well at all. Their genetic differences make them slower than average at converting the drug.
- Extensive, or normal, metabolizers: These folks metabolize drugs normally. This is the most common class, representing the type of people for which most drugs are designed.
- Rapid metabolizers: This is the opposite extreme to slow metabolizers. These people may require a higher-than-average dose of a medication.
Sometimes these categories are further broken down into smaller gradients, such as ultra-rapid metabolizers and intermediate metabolizers.
Why Does Metabolizer-Type Matter?
Why is it important to know what type of metabolizer you are? If your body metabolizes a drug too quickly, it can decrease the drug’s efficacy. At the other extreme, if your body metabolizes the drug too slowly, unacceptable side effects may result.
Typically, a drug is taken in its active form; it goes to work “as is.” Think of it as the protein equivalent of “ready to wear”. Other drugs, however, enter the body in an inactive form and require some additional … alterations. These drugs rely on bodily organs such as the liver for conversion to the active form in order to take effect.
An Inactive Form of ADHD Medication: Vyvanse
Consider the ADHD medication Vyvanse. It starts out in an inactive state.
For this reason, it has been marketed as being less easily abused than other medications in the amphetamine class of stimulants (e.g., Adderall, Dexedrine). The medication in the Vyvanse capsule becomes active only when it reaches a certain point in the gut. That’s because, at that point, specific gut enzymes convert it into the active form of the drug (lisdexamfetamine). Inactive medications are also called “pro-drugs.”
An Active Type of ADHD Medication: Strattera
We talked about an ADHD medication that starts out in the inactive form: Vyvanse. For an example of an ADHD drug in its active form, consider Strattera. This non-stimulant was the first drug to receive an FDA-certified indication for adult ADHD.
Below is an excerpt from the drug label for Strattera regarding genes that affect its metabolism. By the way, this is FDA-controlled text, which means it is carefully validated and evidence-backed.)
Note in the text the aforementioned CYP2D6, a gene that influences the metabolism of many drugs in addition to Strattera and is known to have many variants:
CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 [-metabolized drugs] have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of STRATTERA compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. (…) The higher blood levels in PMs lead to a higher rate of some adverse effects of STRATTERA (see ADVERSE REACTIONS).
Here’s the Layperson’s Translation:
Poor metabolizers of Strattera reach a much higher peak blood concentration (5 times higher) than extensive metabolizers. Therefore, they are more likely to manifest “adverse reactions” (side effects), ranging from constipation to dizziness, as stated elsewhere in the drug label.
If you are Caucasian, your chances of having the poor metabolizer form of CYP2D6 are pretty high (7%). The drug label says nothing about other racial groups, but that doesn’t mean these groups don’t have poor metabolizers. It may simply mean there is no data available for them, or the data are simply not listed here.
As you can see, it is very useful to know which variant of a gene you have, whatever the type of drug (active or inactive). This is especially true for CYP2D6 because it metabolizes a huge number of drugs. Conversely, some drugs are metabolized by only a very few genes. So in practice, drug-response genotyping typically involves several genes so as to get the whole picture. (In Part 2, we list the four genes involved in the genotyping tests we took for ADHD medications: CYP2B6, CYP2D6, ADRA2A, and COMT.)
Consider First the Slow, or Poor Metabolizer
If you are a poor metabolizer, there are two very different scenarios to consider. Each scenario rests on whether the drug in the bottle is 1) active (ready to go) or 2) inactive (the body must metabolize it into an active form):
1. If the drug is taken in its active form, the poor metabolizer might require a lower-than-average dosage.
If you are a poor metabolizer, you are slower at removing the drug from the bloodstream than the average person. As a result, you could reach a blood concentration that is too high if given an “average” dose, thereby potentially triggering side effects.
The outstanding question then becomes: how much lower of a dose should you take? Unfortunately, there is no ready answer to that question (more below).
2. If the drug is taken in its inactive form—that is, the drug must be metabolized to become active—a standard dose might not be enough.
What?! How can that be? I just said poor metabolizers risk having too much medication in their system, even with an average dose. How is it that poor metabolizers now suddenly do not get enough from an average dose?
Here’s why: If you’re a poor metabolizer, you are slow at converting the inactive drug into its active form. Therefore, you are failing to reach the dose necessary for beneficial effects, and the drug gets cleared from your system before having had a chance to be converted.
To recap, the slow metabolizer risks two primary effects:
- An over-concentration of active medication
- An under-concentration of inactive medication
2. Pharmacodynamics: “What the Medication Does to the Body”
Again, pharmacodynamics refers to the manner in which the drug affects a cell. Pharmacodynamics is all about how the drug does its work.
For example, consider the “lock and key” nature of the way a drug typically works with a cell. The “lock” is the receptor, a structure on the cell’s surface that selectively receives and binds a specific substance. (Like enzymes, receptors are proteins made according to genetic instructions.) In this illustration, Substance A fits the receptor perfectly. Substance B doesn’t come close. Substance A can bind to the receptor and an action results.
A stimulant such as Adderall or Ritalin interacts with certain receptors with great specificity (that is, it interacts only with those receptors). This lock-and-key” interaction is imperative for the drug to do its job. By interaction, I mean that Adderall molecules literally slot into those specific receptors in the same way as, well….as your Big Gulp fits snugly in your car’s cup holder.
The snugness of the stimulant with its receptor, however, can vary. Much depends on—yes, that’s right— the variant of the gene that produces this receptor. Some forms of the gene will produce a receptor with good snugness, thereby requiring less stimulant to reach a given effect. Other variants may produce a receptor form with more … looseness; therefore requiring more drug (higher dosage) to be piled into the “cup holder” to reach the same snug-fitting effect.
Are you with us so far? Are you gaining a better idea of how these genotyping tests might inform the medication choices for you or your loved one?
Coming up next Wednesday: Post 5, The Limits of Genotyping and the Takeaway Message. The Wednesday after that: Post 6, the final post.
—Gina Pera and Dr. Goat