The GeneSight® Psychotropic test evaluates a person’s DNA to determine how they may metabolize or respond to certain medications.

The GeneSight test may help inform medication selection and dosing. The results of the test show which medications may require dose adjustments, may be less likely to work, or may have an increased risk of side effects based on the patient’s genetic results.

On the GeneSight Psychotropic Test, three color-coded categories are used to assist in report interpretation.

Use as Directed
These medications are not associated with any known genetic issues that would be expected to change patient medication outcomes. However, these medications are not guaranteed to work and may not always be the best options, as there are many other factors that influence medication response and susceptibility to side effects, including drug-drug interactions, diet, environmental factors, age, etc.

Moderate Gene-drug Interaction
These medications may require dose adjustments in order to have the desired effect, may be less likely to work, or may cause side effects.

Significant Gene-drug Interaction
These medications are likely to require dose adjustments in order to have the desired effect, may be less likely to work, or may cause side effects. Genetics are expected to have a greater impact on medications in the significant gene-drug interaction category than those that fall into the moderate gene-drug interaction category.

Interpreting the Clinical Considerations

All medications start in the “Use as Directed” category on the report. Based on an individual’s genetic variation, medications may be moved to the Moderate or Significant Gene-drug Interaction categories, depending on how significantly the variation is expected to impact outcomes with that medication. Medications in the Moderate or Significant Gene-drug interaction categories on the report do not necessarily need to be avoided. The clinical considerations, which are denoted by numbers next to the medications, explain the rationale for a medication’s classification and can be used to help inform treatment decisions.

Clinical Considerations
  1. Serum level may be too high, lower doses may be required.
  2. Serum level may be too low, higher doses may be required.

Clinical Considerations 1 and 2 reflect an issue with how a medication is metabolized, which means the individual has variation in one or more pharmacokinetic genes. This may affect how much medication is in an individual’s system and may require a lower or higher dose. For medications that may require a higher dose, it is not advising to start the individual on a high dose of the medication, but rather to start at a standard dose while being aware that dose increases may be needed to get the desired benefit.

  1. Difficult to predict dose adjustments due to conflicting variations in metabolism.

Clinical Consideration 3 also provides information about a medication’s metabolism. This clinical consideration indicates that there are conflicting variations in the metabolism of that medication, thus making it difficult to predict a dose adjustment. The most common example is when there are two genes that contribute a relatively similar amount to the overall metabolism of the medication, but one has increased activity and the other has decreased activity. If a medication with clinical consideration 3 is chosen, it may be appropriate to consider starting on a lower dose and increasing the dose based upon how the individual is doing.

  1. Genotype may impact drug mechanism of action and result in moderately reduced efficacy.

Clinical Consideration 4 indicates that an individual may have a moderately reduced response to certain medications. This is due to variation in a pharmacodynamic gene, and thus reflects an issue with the drug’s mechanism of action. Since pharmacodynamic genes do not affect metabolism, it is unlikely that adjusting the dose will improve efficacy.

  1. CYP2D6 genotype indicates that this patient may experience increased frequency of side effects but also greater symptom improvement in those who find the treatment tolerable.

Clinical Consideration 5 specifically applies to atomoxetine (Strattera®) when an individual is a CYP2D6 poor metabolizer. This is based on evidence which shows that CYP2D6 poor metabolizers treated with atomoxetine experienced an increased frequency of side effects but also significantly greater improvement in ADHD symptoms compared to extensive (normal) metabolizers.1

  1. Use of this drug may increase risk of side effects.

Clinical Consideration 6 indicates that an individual may have an increased risk for side effects when taking this medication. This can be due to variation in one or more pharmacokinetic genes that may predict slower than normal metabolism of certain medications, which may result in higher levels of medication in the system. It could also be due to an effect caused by one of the pharmacodynamic genes.

  1. Serum level may be too low in smokers.

Clinical Consideration 7 only applies if the individual is a smoker and indicates that smoking may increase the metabolism of that medication. This is because smoking induces CYP1A2 in individuals who already have an increased activity for this enzyme.2-5 The reaction is not caused by the nicotine, but rather by inhaling the burning hydrocarbons.4 When you see clinical consideration 2 coupled with clinical consideration 7, it means that if the individual is a smoker, they are expected to metabolize that medication even more quickly than someone who is an ultra rapid metabolizer and does not smoke.

  1. FDA label identifies a potential gene-drug interaction for this medication.

When medications have Clinical Consideration 8, it means that FDA label contains information that may be relevant for the patient based on their genetic results. This may include information about dosing or more general information to consider.

  1. Per FDA label, this medication is contraindicated for this genotype.

Clinical Consideration 9 indicates that per the FDA label, this medication is contraindicated for an individual with this genotype.

  1. While this medication does not have clinically proven genetic markers that allow it to be categorized, it may be an effective choice based on other clinical factors.

Clinical Consideration 10 is associated with medications in the gray “No Proven Genetic Markers” category, meaning that genetic markers have not yet been discovered to reliably predict treatment outcomes with these medications. Due to this lack of evidence, we are not currently able to categorize them or provide actionable recommendations. However, these medications may be effective choices based on other clinical factors. Medications hat fall into the “No Proven Genetic Markers” category and receive a clinical consideration of 10 are the same for all individuals.

Interpreting the Patient Genotypes and Phenotypes

The patient genotypes and phenotypes section of the report provides a list of all the genes tested on the GeneSight® Psychotropic report along with the individual’s specific genetic result (genotype) and the characteristic associated with the genetic result (phenotype). The patient genotypes and phenotypes are broken down into two categories:

Pharmacodynamic genes provide information about how a medication works on the body. Variation in these genes may affect likelihood of response or risk of side effects with certain medications.

ADRA2A encodes the alpha-2A adrenergic receptor, which is a norepinephrine receptor. Individuals with the C/C genotype may have a moderately reduced response to certain stimulants, specifically methylphenidate and dexmethylphenidate. If an individual with this genotype is having a less than optimal response to these medications, increasing the dose may not necessarily improve efficacy.

The human leukocyte antigen (HLA) complex, encoded by the HLA gene family, plays a critical role in immunity. Presence of the T allele (either T/T or A/T genotype) is associated  with a higher risk of serious hypersensitivity reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), when taking certain mood stabilizers, specifically carbamazepine.

Presence of genetic variation in HLA-B*1502 is associated with a higher risk of serious dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), when taking certain mood stabilizers, including carbamazepine, oxcarbazepine, and lamotrigine.

HTR2A encodes for the Serotonin Receptor Type 2A, which is responsible for serotonin signaling. Studies show an increased risk of adverse effects with certain SSRIs, particularly paroxetine, in individuals who have the G/G genotype.

SLC6A4 encodes for the serotonin transporter, which is the main site of action for SSRIs. SLC6A4 has two main versions: the long (L) allele and the short (S) allele. Studies have shown that the short allele results in less serotonin transporters than the long allele. Individuals who have the S allele may be less likely to respond to certain SSRIs based on this genotype. Additionally, due to the lower number of transporters, increasing the dose may not necessarily improve efficacy.

Pharmacokinetic genes provide information about how the body works on the medication. Variation in these genes may affect the metabolism of a medication. The following PK genes are included on the GeneSight test: CES1A1, CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4, UGT1A4, and UGT2B15.

These genes are categorized based on average enzyme activity into one of four metabolizer phenotypes on the GeneSight Psychotropic report.

The GeneSight test uses a combinatorial approach that measures multiple genomic variants for each individual and weighs them in combination in order to categorize the medications on the report and provide clinical considerations when applicable.

The genotype for COMT, or catechol-o-methyltransferase, is provided for informational purposes only. This gene has not been shown to be a reliable marker of medication outcomes, and therefore, it is not used to categorize medications on the report.

Interpreting the Gene-drug Interaction Chart

The gene-drug interaction chart provides supplementary information about which pharmacokinetic genes are involved in the metabolism of each medication.

The pharmacokinetic genes on the GeneSight® report are listed across the top of the chart.
Medications are listed in a column on the left side.
Any dot (either shaded or unshaded) signifies that the enzyme is involved in the metabolism of the associated medication.
A shaded dot means that variation was found in the patient’s genotype that may impact medication metabolism.
An unshaded dot indicates that the gene is associated with medication metabolism, but the predicted patient phenotype is normal.

It is not mandatory to refer to the gene-drug interaction chart when using the GeneSight test to inform patient medication selection. It is simply intended to augment the patient results on the pages where the medications are categorized and the clinical considerations are provided, which serve as the primary resource to help inform treatment decisions.

The format of the gene-drug interaction chart is similar to the earlier pages of the GeneSight report where medications are categorized into the green, yellow, and red categories.

There are situations where an individual may have shaded dots in the green “Use as Directed” category. This means that although the individual has variation in one or more genes, it is unlikely to impact their overall metabolism of that particular medication. This could mean that while an enzyme is involved in the metabolism of the medication, its role is not clinically significant enough to warrant a change in dosing or there may be compensation among the enzymes known to metabolize the medication, which results in the medication not being moved from the green “Use as Directed” category.

Download the full Report Interpretation brochure

The results of the GeneSight test are intended to supplement other clinical factors considered by a healthcare provider during a comprehensive medical assessment to help inform treatment decisions.

Not all patients who receive the GeneSight test will have improved outcomes. The GeneSight test is intended to supplement a clinicians comprehensive medical assessment.

  1. Michelson D, et al. 2007. J Am Acad Child Adolesc Psychiatry.
  2. Dobrinas M, et al. 2011. Clin Pharmacie Ther.
  3. Kroon LA. 2007. AM J Heal Pharm.
  4. Zevin S, and Benowitz N. 1999. Clin Pharmacokinet.
  5. Tantcheva-Poôr I, Zaigler M, Rietbrock S, and Fuhr U. 1999. Pharmacogenetics.