Antidepressant Response Testing

Is Testing Right for Me? I Have My Test Results

Antidepressant Response Testing

CYP2D6, CYP2C19 and Antidepressants

There are many different classes of antidepressants. Each class works a little differently on the brain chemicals. Two of the first kinds of antidepressants developed were tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). A newer class, called selective serotonin reuptake inhibitors (SSRIs), has become a common first choice for treating depression because SSRIs tend to cause fewer side effects. There are also other classes of antidepressants that include drugs like Wellbutrin, Effexor, and Cymbalta.

Signs of Abnormal Antidepressant Metabolism
Testing for Antidepressant Response

All antidepressants don't work equally well for everyone. It is difficult to predict which antidepressant may be best for a specific person. So, doctors usually take a trial and error approach – they use what they know about a patient's symptoms and medical history to choose a drug and then adjust the drug and dosage based on how the person responds. Only about 50% to 60% of people who take an SSRI get relief from their symptoms. Up to 15% of people stop taking an SSRI because they can't tolerate the side effects.

Drug response is influenced by many different factors – including how that drug is metabolized. Genetic variations in the CYP2D6 and CYP2C19 drug metabolism enzymes may a play a role in how people respond to several different antidepressants – especially SSRIs or TCAs. These enzymes don't metabolize all antidepressants. For some antidepressants that are metabolized by CYP2D6 or CYP2C19, enzyme variants don't seem to play an important role in how they work in practice.

SSRIs and SNRIs

Generic NameBrand Name(s)Major Metabolizing Enzyme
citalopramCelexa, Ran-CitaloCYP2C19
escitalopramLexapro, CipralexCYP2C19
fluoxetineProzac, Sarafem, FXTCYP2D6
fluvoxamineLuvox, Riva-FluvoxCYP2D6
paroxetinePaxil, PexevaCYP2D6
sertralineZoloftCYP2C19
venlafaxineEffexorCYP2D6
duloxetineCymbaltaCYP2D6

TCAs

Generic NameBrand NameMajor Metabolizing Enzyme
amitriptylineElavil, Endep, Enovil, Etrafon, Levate CYP2C19 and CYP2D6
clomipramineAnafranil, Novo-ClopamineCYP2C19 and CYP2D6
desipramineNorpramin, PertofraneCYP2D6
doxepinAdapin, Sinequan, Prudoxin, Silenor, Zonalon, TriadapinCYP2D6
imipramineTofranil, Impril, Novo-pramineCYP2D6
nortriptylinePamelor, Aventyl, NorventylCYP2D6

 

Signs of Abnormal Antidepressant Metabolism

A CYP2C19 Poor Metabolizer

  • May have intolerable side effects from average doses of the SSRIs: citalopram, escitalopram, and sertraline.
  • Is more likely to have side effects from certain TCAs (notably amitriptyline and clomipramine).

A CYP219 Ultrarapid Metabolizer

  • May need higher doses than usual of some TCAs (amitryptyline and clomipramine) and other antidepressants that are metabolized by CYP2C19 (citalopram, escitalopram and sertraline) to get symptom relief, but this isn't certain.

A CYP2D6 Poor Metabolizer

  • Is more likely to have intolerable side effects from usual doses of most TCAs.
  • May be at increased risk for side effects from SSRIs metabolized by 2D6 (fluoxetine, fluvoxamine, and paroxetine).
  • May also be at risk for side effects from certain other antidepressants that are metabolized by CYP2D6 — like duloxetine and venlafaxine.

A CYP2D6 Ultrarapid Metabolizer

  • May need higher doses than usual of most of the TCAs to get symptom relief.
  • Could, in theory, need higher doses of other antidepressants that are metabolized by CYP2D6 – but this isn't certain.

Testing for Antidepressant Response

CYP2D6 and CYP2C19 testing isn't recommended for everyone taking (or planning to take) an antidepressant. A group of experts supported by the Centers for Disease Control and Prevention (CDC) recently looked at all of the available research about how these variants relate to prescribing SSRIs specifically. Although these enzymes are clearly involved in metabolizing many SSRIs, these experts found that there was very little research to show that doctors could prescribe SSRIs more safely or effectively when they know your metabolizer status. They discouraged doctors from ordering genetic testing before they prescribe SSRIs until more information is available.

This group of experts specifically looked at whether CYP2D6 and CYP2C19 testing is useful for everyone starting SSRI treatment. They didn't look at whether testing might be valuable for patients who have had problems with SSRIs, TCAs, or other drugs that are metabolized by these enzymes. No other professional organizations have made clear recommendations either. As a result, it is up to your doctor to review your history and decide if testing might be useful for you given your specific medical history.

For more information about antidepressants, see National Institute of Mental Health: Antidepressant Medications.

Next: CYP2D6 and Antipsychotics

Which of the following drugs are you interested in? (Check only one at a time.)

One of these selective serotonin reuptake inhibitor (SSRIs) antidepressants: citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine, sertraline, venlafaxine, and duloxetine

One of these tricyclic antidepressants (TCAs): amitriptyline, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine

One of these antipsychotic drugs: haloperidol, thioridazine, aripiprazole, risperidone, perphenazine, and chlorpromazine

Atomoxetine

None of these

Why are you considering testing? (Check only one.)

I may start treatment with this drug.

I am taking this drug – or have in the past – without any unusual reaction.

I have had an unusual reaction (includes side effects or not responding) to this drug.

The CYP2D6 and CYP2C19 enzymes metabolize several selective serotonin reuptake inhibitor (SSRIs) antidepressants. Changes in the CYP2D6 or CYP2C19 genes can cause people to process these drugs slower or faster than usual.

Even though we know the enzymes that process these drugs and the gene changes that speed up or slow down metabolism, we don't know that doctors can actually prescribe these drugs better if they know your genetic makeup. These are some of the reasons your genetic makeup may not predict your drug response:

  • Many other things affect how you react to a drug — like other drugs, age, gender, and health problems.
  • Other enzymes can process most drugs when there is a problem with the main metabolizing enzyme.
  • Drugs are usually prescribed in a way that maximizes safety. Doctors often start at a lower dose than most people need. They raise the dose as people show they can tolerate it and need more to control their symptoms.
  • Many drugs are safe even if the amount of drug in the body is higher or lower than expected.

Experts don't recommend CYP2D6 or CYP2C19 testing for everyone starting SSRIs. You reportedly might start taking an SSRI. One expert group reviewed the research in 2007. They didn't find enough evidence that genetic testing made SSRI treatment safer or more effective to recommend all people be tested. However, testing may be more useful if you have had problems with other drugs that suggest you may metabolize some drugs abnormally. The decision about testing is up to you and your doctor. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

Genetic testing is unlikely to be useful if you are having no problems with your SSRI. You reportedly have taken an SSRI without any problems. Experts don't recommend CYP2D6 or CYP2C19 testing for everyone taking SSRIs. If you are taking an SSRI that is working for you without significant side effects, genetic testing isn't likely to help you.

The decision about testing is always up to you and your doctor. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

Genetic testing may help explain an unusual drug reaction and avoid others. You reportedly have had an unusual reaction to an SSRI. Certain reactions are more likely to point to CYP2D6 or CYP2C19 gene changes (see the table below). If you have had one of these reactions, you could have a metabolism gene change. Genetic testing can look for a group of the most common gene changes in CYP2D6 and CYP2C19.

CYP2C19 Slow Metabolizers CYP2D6 Slow Metabolizers CYP2D6 Fast Metabolizers
Serious side effects from usual doses of citalopram, escitalopram, and sertraline Serious side effects from usual doses of paroxetine, fluvoxamine, or fluoxetine — especially early in treatment May need higher doses than usual of paroxetine, fluvoxamine, fluoxetine, duloxetine and venlafaxine — but this isn't proven

See CYP2D6, CYP2C19, and Antidepressants for more information.

The CYP2D6 enzyme metabolizes most tricyclic antidepressants (TCAs). The CYP2C19 enzyme plays an important role in metabolizing two TCAs — amitriptyline and clomipramine. Changes in the CYP2D6 or CYP2C19 genes can cause people to process these drugs slower or faster than usual.

Even though we know the enzymes that process these drugs and the gene changes that speed up or slow down metabolism, we don't know that doctors can actually prescribe these drugs better if they know your genetic makeup. These are some of the reasons your genetic makeup may not predict your drug response:

  • Many other things affect how you react to a drug — like other drugs, age, gender, and health problems.
  • Other enzymes can process most drugs when there is a problem with the main metabolizing enzyme.
  • Drugs are usually prescribed in a way that maximizes safety. Doctors often start at a lower dose than most people need. They raise the dose as people show they can tolerate it and need more to control their symptoms.
  • Many drugs are safe even if the amount of drug in the body is higher or lower than expected.

The usefulness of genetic testing isn't clear for people starting TCAs. You reportedly might start taking a TCA. No expert groups have recommended testing for all people starting TCAs. The U.S. Food and Drug Administration (FDA) approves the information included with drugs (called the package insert). While some TCA package inserts talks about the risks in people with slower CYP2D6 metabolism, the FDA doesn't specifically recommend genetic testing.

Without clear expert guidance, the decision about testing is up to you and your doctor. Testing may be more useful if you have had problems with other drugs that suggest you may metabolize some drugs abnormally. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

Genetic testing is unlikely to be useful if you are having no problems with your TCA. You reportedly have taken a TCA without any problems. Experts don't recommend CYP2D6 or CYP2C19 testing for everyone taking TCAs. If you are taking a TCA that is working for you without significant side effects, genetic testing isn't likely to help you.

The decision about testing is always up to you and your doctor. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

Genetic testing may help explain an unusual drug reaction and avoid others. You reportedly have had an unusual reaction to a TCA. Certain reactions are more likely to point to CYP2D6 and CYP2C19 gene changes (see the table below). If you have had one of these reactions, you could have a metabolism gene change. Genetic testing can look for a group of the most common gene changes in CYP2D6 and CYP2C19.

CYP2C19 Slow Metabolizers CYP2D6 Slow Metabolizers CYP2D6 Fast Metabolizers
Serious side effects from usual doses of some TCAs (especially amitriptyline and clomipramine) Serious side effects from usual doses of most TCAs (including amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline) Lack of response to usual doses of most TCAs, but especially desipramine and nortriptyline

See CYP2D6, CYP2C19, and Antidepressants for more information.

The CYP2D6 enzyme metabolizes most of the older antipsychotic drugs, like haloperidol and thioridazine, and newer ones, including aripiprazole and risperidone. Changes in the CYP2D6 gene can cause people to process these drugs slower or faster than usual. Serious side effects such as movement disorders can happen in people that are CYP2D6 slow metabolizers, particularly when taking the older antipsychotics such as haloperidol and thioridazine.

See CYP2D6 and Antipsychotics for more information.

The usefulness of genetic testing isn't clear for people taking or starting antipsychotics.

Even though we know the enzymes that process these drugs and the gene changes that speed up or slow down metabolism, we don't know that doctors can actually prescribe these drugs better if they know your genetic makeup. Studies are being done now to try to prove that patients will have fewer side effects and better response to antipsychotic drugs if they have CYP2D6 genetic testing. Until more proof is available, experts haven't recommended genetic testing for all people starting or taking antipsychotics.

Without clear expert guidance, the decision about testing is up to you and your doctor. Testing may be more useful if you have had problems with other drugs that suggest you may metabolize some drugs abnormally. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

CYP2D6 is the main enzyme that metabolizes atomoxetine (brand name Strattera®) — an attention deficit with hyperactivity drug. Changes in the CYP2D6 gene can cause people to process this drug slower or faster than usual.

People who process atomoxetine slower tend to have higher amounts of the drug in their bodies. Studies found that slow metabolizers got more relief from their symptoms and tended to stay on the drug. Higher drug levels were linked to mostly minor side effects like mildly higher heart rate and blood pressure, tremors, and poor appetite.

See CYP2D6 and Atomoxetine for more information.

The usefulness of genetic testing isn't clear for people taking or starting atomoxetine.

Even though we know CYP2D6 processes atomoxetine and gene changes speed up or slow down metabolism, we don't know that doctors can actually prescribe the drug better if they know your genetic makeup.

The U.S. Food and Drug Administration (FDA) approves the information included with drugs (called the package insert). The Strattera package insert gives drug-dosing instructions for people with CYP2D6 enzyme that metabolizes slowly, but they don't specifically recommend genetic testing for all people starting the drug. Some studies found that doctors could choose a safe and effective dose well enough without knowing a patient's CYP2D6 gene results.

Until more proof is available, experts haven't said whether people taking or starting atomoxetine should have genetic testing. Without clear expert guidance, the decision about testing is up to you and your doctor. Testing may be more useful if you have had problems with atomoxetine or other drugs that suggest you may metabolize some drugs abnormally. Be aware that an insurance company may not pay for testing if they decide it isn't medically necessary.

This tool only discusses how CYP2D6 and CYP2C19 results relate to antidepressants, antipsychotics, and atomoxetine. If you are interested in CYP2D6 or CYP2C19 variant testing for another reason, you should talk with your doctor or a genetic counselor about how testing might help you. You may also be interested in reading CYP2D6, CYP2C19 and Other Drugs.