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.

The table below has examples of SSRI and TCA antidepressants and the enzymes that metabolize them.

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 CYP2D6 Poor Metabolizer

• Is most 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 (Cymbalta) and venlafaxine (Effexor) – but this isn’t clear.

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.