What do my genetic testing results mean?

To understand what your Genetic Testing results mean, we have to first review a few concepts.

Genes

Genes are little pieces of DNA that contain the code, or “recipe,” for producing receptors, enzymes, and other important proteins in our bodies.

How an individual responds to a medication will depend primarily on two factors

  1. The quantity and/or “quality” of receptors – this is called pharmacodynamics
  2. How efficiently (or not efficiently) the drug is metabolized (or broken down) and eliminated from the body – this is called pharmacokinetics

Pharmacokinetic Genes code for enzymes that metabolize (or break down) and eliminate medications from the body

After swallowing a medication, it travels to the stomach and intestines where it interacts with enzymes called CYP 450 enzymes. Don’t worry about the names.

CYP 450 enzymes are like Pac-Man swimming around gobbling up medications. There are many different types of CYP450 enzymes, and they all metabolize different medications. These “Pac-Man”-like CYP 450 Enzymes have names such as “CYP3A4” or “CYP3A5”. There are many different types such as CYP2D6, CYP2B6, CYP2C8, CYP2C9, CYP1A2, CYP2C19, CYP2A6, CYP2E1…you get the point.

Most psychotropic medications are metabolized by CYP3A4 and CYP2D6. Some of us have a lot of these enzymes and some of us don’t. Genetics determines how much we have and how well they function. This is why two different people will have two different responses to the same medication.

“Slow” or “intermediate” metabolizers have reduced amounts or reduced activity of specific CYP enzymes and therefore metabolize certain medications slowly.

“Ultrarapid” metabolizers have increased amounts or increased activity of specific CYP enzymes and therefore metabolize certain medications quickly. 

Usually (but not always) the more rapidly you metabolize a medication, the higher the dose will need to be to produce a therapeutic response. The slower you metabolize a medication, the lower the dose will need to be and the greater the probability of developing side effects.

The chart that comes with most genetic testing reports lists which medications are metabolized by which CYP enzymes. To learn more about interpreting these charts in your report, click here.

Pharmacodynamic genes refer to genes that encode the receptors that medications target. 

Most medications work by binding to receptors. Genetics play a major role in the quantity and quality of receptors. 

ADRA2A (ALPHA-2A RECEPTOR) GENE: ADRA2A encodes the alpha-2A adrenergic receptor, which is a norepinephrine (adrenergic) receptor. Alpha-2A receptors are highly concentrated in an area of the brain called the prefrontal cortex (PFC). These receptors help regulate norepinephrine and other important neurotransmitters involved in “higher” brain functions such as focus, concentration, and working memory. Changes in the gene for this receptor have been associated with an altered response to certain ADHD medications. Some ADHD medications directly stimulate the alpha-2A adrenergic receptor, while others indirectly impact the activity of this receptor. For more information on ADRA2A Gene, click here.

HLA-A*3101 & HLA-B*1502: The human leukocyte antigen (HLA) proteins are important in our immune responses. Presence of the HLA-A*3101 and HLA-B*1502 genes increase the risk for serious hypersensitivity reactions, systemic symptoms, and skin reactions to medications known to cause such reactions. Lamictal, Depakote, Tegretol, and Trileptal are examples of medications that may cause serious reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), maculopapular eruptions, and Drug Reaction with Eosinophilia. Remember, this isn’t definitive, and it doesn’t mean you will FOR SURE develop a reaction to these medications if you possess these alleles. For more information on HLA-A3101 and HLA-B*1502, click here.

5HTR2A (SEROTONIN 2A RECEPTOR) GENE:
The 5HTR2A gene codes for the 5HT2A receptor. The 5HT2A receptor is a type of serotonin receptor and important regulator of serotonin signaling. It is also involved in regulating dopamine signaling. The 5HT2A receptor is an important target for many antidepressants and antipsychotics. Variations in this gene have been associated with adverse effects to selective serotonin reuptake inhibitors (SSRIs). For more information on 5HTR2A gene, click here.

SEROTONIN TRANSPORTER PROMOTER GENE (SLC6A4 L/S): The serotonin transporter or “serotonin reuptake pump” is what we block with medications like Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs include medications like Paxil, Prozac, Zoloft, Celexa, Luvox, and Lexapro. To produce this important receptor, we have genes called “promoter” genes that essentially “promote” the production of the serotonin transporter. This “promoter” gene, called the SLC6A4 promoter gene has two lengths – Long and Short. The short length has been associated with decreased production of this important Serotonin Transporter which may reduce responsiveness to certain medications such as SSRIs. Essentially, if you possess the “S” allele, it means you may be less likely to respond robustly to classic SSRI antidepressants, may need higher than normal doses to feel a response, and/or may experience more side effects. But it doesn’t mean you won’t respond at all or that using medications like SSRIs will be harmful in any way. Interestingly, a 1996 article stated that the short (S) allele for the promoter gene can partly account for anxiety-related personality traits. For more information on SLC6A4, click here.

Other Genes Tested

CATECHOL-O-METHYL TRANSFERASE (COMT)

The COMT gene encodes catechol-O-methyltransferase, an enzyme that breaks down dopamine (DA) and norepinephrine (NE). Certain variations in the COMT gene have been associated with different levels of COMT activity.

Reduced COMT activity results in less break down of dopamine and norepinephrine and therefore increased levels of these brain chemicals. Note that this gene has not been a reliable marker of medication outcomes is only provided for information purposes. For more information on COMT, click here.

METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) GENE VARIANT:

Folate, also called vitamin B-9 or folic acid, is a B vitamin found mainly in dark green leafy vegetables, beans, peas, nuts, oranges, lemons, bananas, melons and strawberries. Folate has many important roles in red blood cell formation, cell growth, and cell functioning.

L-methylfolate, the active form of folate, is very important in the production of brain chemicals that regulate mood such as dopamine, norepinephrine, and serotonin. The methylenetetrahydrofolate reductase (MTHFR) enzyme (the chef in the figure below) converts folic acid (folate) into L-methylfolate.

Some individuals carry a mutation (or change in the gene) which results in reduced activity of MTHFR. If activity of MTHFR is reduced, then there is also a reduced capacity to create L-methylfolate.

Without enough L-methylfolate, the body may not be able to produce enough serotonin, dopamine, or norepinephrine and this may explain why certain medications that rely on adequate levels of these brain/mood chemicals don’t work that well in some people.

In those individuals with reduced capacity to convert folate to L-methylfolate, supplementation with L-methylfolate may increase production of those important brain/mood chemicals and hypothetically improve the responsiveness to antidepressants and other medications that rely upon the presence of those brain/mood chemicals to work properly. 

For more information on MTHFR, Click Here.

Genetic testing has limitations…

Current genetic testing allows us to take a sample of DNA and look at various genes that may explain why individuals respond uniquely to medications. While genetic testing doesn’t replace clinical decision-making, it can help guide clinicians and patients. However, remember that genetic testing doesn’t tell us if or how you will respond to specific medications. This is because genetic testing results are based upon associations, not causations. Certain genetic factors are more or less associated with, but do not explain, responses to medications. So, we have to be careful how we interpret genetic testing results.

For more information about psychotropics and genetic testing, visit the GeneSight DNA Test for Psychiatric & Depression Medication.

References

  1. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  2. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  3. Stahl, S. M. (2021). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (5th ed.). New York, NY, US: Cambridge University Press.
  4. Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
  5. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  6. Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th
  7. Benjamin J. Sadock, Virginia A. Sadock. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. Philadelphia :Lippincott Williams & Wilkins, 2000.
  8. Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.
  9. Meyer, Jerrold, and Quenzer, Linda. Psychopharmacology: Drugs, the Brain, and Behavior. Sinauer Associates. 2018.

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