These 2 Tests Will Help Your Doctor Personalize Your Therapy for Depression

As many as 50% of people with major depressive disorder don’t respond well to the first medication prescribed.  Antidepressant medicines can make you feel terrible if the wrong one is prescribed and feel great if the right one is chosen.  But choosing the right one can often take a lot of trial and error for a person experiencing depression.  You may be told it will be 2 weeks or more before a new medicine works.  You wait and wait.  The challenge can begin to feel insurmountable.  If it feels like there’s no easily measurable test for these medicines, that’s wrong.  Here’s why. 

A pharmacogenetic test could provide some key information.  Pharmacogenetic testing measures and reports which copies you have of genes that affect the medicines you take. Your genes decide how your body responds to a medicine or how your body breaks down a medicine. For example, knowing about your genes can tell your doctor: Which medicine is likely to work best for your illness, or how likely you are to have a side effect from a medicine. Testing to learn how genes work with certain medicines is called pharmacogenetic testing.  The test results can help your doctor and pharmacist choose the best medicine and dose for you. Pharmacogenetic testing can be done in several ways: one gene at a time, which may be done when the doctor knows you will need a certain medicine; or many genes at a time, which tests for several genes that can affect medicines. This may be done before your doctor has chosen a medicine to treat your illness.

These tests measure the 2 versions of a gene you inherited from your mother and your father.  But there’s a catch.  A pharmacogenetic test is only helpful if it can be interpreted by someone into a recommendation for dosing a medication of interest.  This is where evidence-based medicine comes in. Evidence for the usefulness of a pharmacogenetic test can be established through peer-reviewed literature in medical journals and demonstrated by clinical practice guidelines.

There are several societies or consortia which have helped to make sense of which pharmacogenetic tests are useful.  The first one is CPIC, or the Clinical Pharmacogenetics Implementation Consortium.  This is a group of researchers and clinicians who work in the area of pharmacogenetics.  These experts form author groups and publish clinical practice guidelines designed to help doctors understand how to use available pharmacogenetic test results to optimize drug therapy (www.cpicpgx.org).  Likewise, the Dutch Pharmacogenetic Working Group (https://upgx.eu/guidelines/) has published evidence-based guidelines on how pharmacogenetic test results can be used.

An available resource that is specific to psychiatry is the International Society of Pyschiatric Genetics, which is a group of experts who have published a genetic testing statement recognizing the growing attention given to clinical genetic testing and the questions raised about the value of such testing in psychiatry.  In this blog I’ll summarize what they found.

Pharmacogenetic-based guidelines are available for many antidepressants, such as the selective serotonin reductase inhibitors (SSRIs) citalopram (brand name Celexa®), escitalopram (brand name Lexapro®), fluvoxamine (brand name Luvox®), and paroxetine (brand name Paxil®), and for the tricyclic antidepressants amitriptyline (brand name Elavil®), and nortriptyline (brand name Pamelor®).

Of all the pharmacogenetic tests offered by commercial labs, these independent experts agree that 2 tests with the strongest evidence are for the 2 cytochrome P450 genes CYP2C19 and CYP2D6.  The experts agree that genetic information for CYP2C19 and CYP2D6 are the most helpful gene tests for choosing antidepressant therapy.  CYP2C19 and CYP2D6 are both enzymes that break down some antidepressant medicines in your body.  Your genetic test results for CYP2C19 and CYP2D6 could tell you if you are a poor metabolizer, an intermediate metabolizer, a normal metabolizer, a rapid metabolizer (for CYP2C19) or an ultra-rapid metabolizer.  The testing report that you get back should clearly classify your results for either of these genes into one of these categories. Because every medicine is broken down by a unique pathway in your body, knowing how these enzymes work in your body can help narrow down which antidepressants to avoid or to use.  Let me explain.

If your doctor is considering a medicine in the SSRI class, we are most concerned with 4 groups of patients who can be identified by either their CYP2C19 or their CYP2D6 test results.  People who are poor metabolizers of either CYP2C19 or CYP2D6 will have reduced enzyme activity which means higher concentrations of some SSRIs.  This could put a person at risk for side effects.  People who are CYP2C19 or CYP2D6 ultra-rapid metabolizers will have increased enzyme function and are at risk of low concentrations of some SSRIs, and therefore these medicines are less likely to work. 

In a CYP2C19 poor metabolizer: avoid citalopram, escitalopram and sertraline or use a lower dose of these medications to avoid side effects. 

In a CYP2C19 ultra-rapid metabolizer: avoid citalopram and escitalopram because there is a risk that the concentrations will be too low and these medicines won’t be effective.

In a CYP2D6 poor metabolizer: avoid paroxetine and fluvoxamine or use a lower dose of these medications to avoid side effects. 

In a CYP2D6 ultra-rapid metabolizer: avoid paroxetine because there is a risk that the concentrations will be too low and the medicine won’t be effective.

If your doctor is considering a medicine in the tricyclic antidepressant class, we are most concerned with 4 groups of patients who can be identified by either their CYP2C19 or their CYP2D6 test results.  The medicine in the tricyclic antidepressant class have very complex pathways as they get broken down and cleared from our bodies.  People who are poor metabolizers of CYP2C19 or CYP2D6 will have reduced enzyme activity which could result in greatly reduced breakdown of these medicines.  People who are CYP2C19 or CYP2D6 ultra-rapid metabolizers will have increased enzyme activity and are at risk of varying response or side effects due to an imbalance of the medicine to its breakdown product inside the body. 

In a CYP2C19 poor metabolizer: avoid amitriptyline, clomipramine, doxepin, imipramine, and trimipramine due to a risk of poor response.

In a CYP2C19 ultra-rapid metabolizer: avoid amitriptyline, clomipramine, doxepin, imipramine, and trimipramine due to a risk of poor response.

In a CYP2D6 poor metabolizer: avoid amitriptyline and nortriptyline to avoid side effects or use a lower dose and check blood concentrations to make sure levels are where they should be. 

In a CYP2D6 ultra-rapid metabolizer: avoid amitriptyline and nortriptyline because there is a risk that the concentrations will be too low and the medicine won’t be effective.  Alternatively, use a higher dose and check blood concentrations to make sure levels are where they should be.

A word of caution about using these test results for fluoxetine (brand name Prozac®) dosing, and for other SSRIs.  CYP2D6 does break down fluoxetine to a metabolite, but in this case the metabolite also adds activity as an antidepressant.  So, while there is a difference in the ratio of parent to metabolite in the body depending on a person’s CYP2D6 metabolizer status, this difference does not change the medicine’s overall effect in treating depression.  Also, no studies have found a difference in side effects to fluoxetine in people with different CYP2D6 metabolizer status. 

The market is saturated with genetic tests which have varying degrees of usefulness for choosing antidepressant therapy.  It’s clear that there are gene tests for medicines which have a weak evidence base and are not clinically actionable, despite being heavily marketed to healthcare providers and to the public. The 2 genes discussed here are two with the strongest level of evidence.  After that, the evidence gets considerably weaker, as determined by the experts who write clinical guidelines.

What’s the bottom line? Pharmacogenetic testing should be viewed as a tool to assist you doctor in personalizing your care.  These tests are a potentially powerful enhancement to getting your care right.  You are strongly encouraged to discuss your individual test results with your pharmacist, doctor, genetic counselor or other health-care provider before making any medical decisions. Genetic test results with the highest level of evidence can be used to supplement your wants, needs, and lifestyle factors to guide treatment decisions for your illness.  The pharmacogenetic tests with the strongest evidence for antidepressants are the CYP2C19 and CYP2D6 gene tests.

Please keep in mind that anyone being treated with antidepressants for any indication should be monitored appropriately and observed closely for worsening symptoms, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times

of dose changes, either increases or decreases.  Please don’t change your therapy without the oversight of your doctor.