Could pharmacogenetics help you find the right antidepressant?
Patients have many options when it comes to antidepressants. Yet despite the vast number of drugs on the market, it’s surprisingly hard to find one that works.
About half of all patients don’t respond to first-line medication. One in three suffer negative side effects. It can take months of trial and error to find the right prescription – a lengthy process that leaves patients frustrated and exhausted.
Pharmacogenetic testing may offer a solution. Using a patient’s genetic information, physicians could – in theory – determine which antidepressant to prescribe. New commercial tests aim to customize depression treatment for every patient. But has the science caught up with the hype?
Hospitals, government agencies, and private companies are working to expand clinical understanding of gene-drug interactions. While much remains unknown, some intriguing tools have emerged in recent years that could pave the way for genetic testing in psychiatry.
Why genetic testing? Antidepressants and metabolism
Reactions to antidepressants vary widely. A medication that works well for one patient may not work at all for another. The reason is partly genetic, and has to do with a patient’s metabolism.
Like other drugs, antidepressants can only do their job if the body can metabolize them into a useful form. This process begins when the patient takes the medication. Enzymes break down the drug inside the liver. The resulting chemicals travel to the nervous system and produce an effect.
Take selective serotonin reuptake inhibitors (SSRIs) as an example. These common antidepressants work by preventing neuron receptors from absorbing serotonin, a mood-regulating neurotransmitter. Enzymes break down the drug and release the active chemical. That chemical increases serotonin levels in the brain, improving mood.
But what if a patient’s enzymes can’t break down the antidepressant? In that case, the drug would build up in the patient’s system, causing harmful side effects. The patient’s mood won’t improve. A doctor might prescribe a new medication, but there’s no guarantee it would work. This process can repeat over and over before a solution emerges.
Genetic testing removes uncertainty by revealing information about a patient’s metabolic proteins. Since we know the genes that code for those proteins, tests can show whether the patient has the right genes to metabolize an antidepressant. Doctors can use that information to customize patient care.
Which Metabolism Type are You?
When a patient doesn’t respond to treatment, doctors may recommend genetic tests before prescribing a new medication. The cytochrome P450 test is one example. Cytochrome P450 enzymes, or CYP450 for short, process many common antidepressants. These enzymes are linked to the genes CYP2D6 and CYP2C19.
CYP2D6 produces the enzyme 2D6, which processes drugs like fluoxetine (Prozac) and paroxetine (Paxil), plus some tricyclic antidepressants. CYP2C19 codes for the enzyme 2C19, which processes SSRIs like escitalopram (Lexapro) citalopram (Celexa).
Patients who take the CYP450 test fall into one of four categories:
- Poor metabolizers can’t metabolize certain drugs, because they lack the necessary enzymes. They may have a genetic variation that inactivates the relevant gene.
- Intermediate metabolizers can process drugs, but at a reduced rate.
- Normal metabolizers process drugs well and respond at a normal level.
- Ultra-rapid metabolizers metabolize drugs too fast. They have a hyperactive version of the gene that makes their enzymes super-efficient.
Doctors adjust dosage or prescription based on a patient’s metabolism. An intermediate metabolizer usually needs a lower dosage than a normal metabolizer. Ultra-rapid metabolizers need a higher dosage, because they process ordinary amounts too quickly to see any effect. In some cases, a different medication altogether may be required.
CYP450 testing can help prevent adverse reactions. For example, if a patient can’t metabolize a certain drug at all, that drug should probably be avoided.
Challenges in commercial testing
Genetic tests could potentially reveal much more about a patient’s needs – not only metabolism, but variations in nerve receptors and drug transport. Unfortunately, because gene expression so complex, it’s difficult to create tests that reliably predict an outcome.
Part of the problem is that drug effectiveness goes beyond genes. Environment also determines how well an antidepressant will work. Age, diet, and surroundings can all play a role. The question for researchers is, how much of a patient’s response is purely genetic?
So far, opinions vary. According to a 2013 study, only about 1% to 2% of individual genetic variants can be linked to antidepressant response. A different study put the figure as high as 42%. While it appears that genes are significant, it’s clear that more research is needed to determine exactly how those genes are producing certain outcomes.
A growing commercial industry is leading the charge in pharmacogenetic testing. Some companies offer tests that patients can do on their own. While direct-to-consumer tests offer a tempting solution, they also present many challenges. Results can be hard to interpret, and patients may not know how to benefit from them.
Physician-directed tests offer a more reliable option. Mount Sinai, Mayo Clinic, and the Cincinnati Children’s Hospital have established pharmacogenetic research groups that perform testing. The FDA and the Clinical Pharmacogenetics Implementation Consortium (CPIC) offer guidelines for best practices.
A few commercial tests are marketed towards physicians. While some doctors are skeptical about cost and utility, these products may provide an option for patients seeking additional insight along with expert guidance.
A global opportunity?
Depression is a public health issue affecting millions worldwide. In the U.S., antidepressant use went up 65% since 2002. It’s critical for depressed patients to get the right medication at the right time – yet for many, this goal remains elusive.
Genetic testing has the potential to improve psychiatric medicine. With the right information, patients could find treatments that are customized and effective. The question now is whether researchers can develop clinically reliable tools to make this opportunity into a reality.
Pharmacogenetics is still evolving. The link between genetics and antidepressant response is not yet clear, but as commercial products drive demand and research continues to advance, it’s likely just a matter of time before genetic testing brings millions of patients the results they need.