How Genetic Testing Is Improving Treatment for Depression

September 17, 2019

For those struggling with major depressive disorder (MDD), antidepressants can often be a solid first-line treatment. They help to increase the availability of certain chemicals in the brain, such as serotonin, that control mood and stress.

But these medications aren’t a one-size-fits-all solution.

Only one-third of those with MDD achieve remission with their first antidepressant, and up to 33% don’t show any improvement despite trying multiple antidepressants.

For individuals who are considered to be treatment-resistant, the prognosis can be dangerous. Without help, symptoms remain and can worsen, reducing the person’s quality of life and increasing thoughts of (and attempts at) self-harm or suicide.

That’s where pharmacogenetics can help.

Pharmacogenetic testing assesses an individual’s genetic makeup to identify mutations and variations that can interfere with the way medications are processed and also how the body processes certain medications. Pharmacogenetics combines the science behind how certain drugs react in your body (pharmacology) with information about how your genes, in turn impact that  medication.

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What that means for patients: more informed treatments, cost-savings, and a more personalized approach to medicine.

 

Trial and Error Is a Dangerous Prescription 

When managing MDD, it can take months or years of trial and error to find the right treatment or combination of treatments. When more treatment steps are needed to relieve depression, it often results in lower short-term remission rates, greater treatment resistance, and higher rates of relapse.

“With each subsequent treatment, you have less of a likelihood of having adequate treatment response and remission,” explains Jay Fawver, M.D., a psychiatrist with Parkview Physicians Group Mind-Body Medicine in Fort Wayne, Ind. “So you have more failures the longer you try one, then another, then another.”

It takes up to 12 weeks for antidepressants to achieve their full effect, says Roy H. Perlis, M.D., M.Sc., a Genomind advisory board member and professor of psychiatry at Harvard Medical School.

Side effects, however, can begin with the first dose, which can include nausea, weight gain, diarrhea, sleepiness, and sexual problems. All antidepressants contain  boxed warnings, as thoughts of self-harm or suicide can be one of the most serious side effects of these drugs.

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“If you can imagine someone where the first medicine doesn’t work, and perhaps the second medicine doesn’t work, that’s up to six months of trial and error. And, of course, during that time depression is impacting their functioning and quality of life,” says Dr. Perlis.

 

The Right Medication at the Right Dosage 

Pharmacogenetic testing can help doctors arrive at a safe and effective medication treatment plan more efficiently and with fewer side effects. “When we introduce genetic testing to people, we tell them we want you on the right medication at the right dosage,” says Dr. Fawver.

The U.S. Food and Drug Administration Table of Pharmacogenetic Biomarkers in Drug Labeling currently lists 27 psychiatric medications with genetic variations used to treat mood and anxiety disorders. Genomind Professional PGx Express tests for 24 genes that have been associated with psychiatric treatments and published in peer-reviewed journals.

Genomind Professional PGx Express analyzes both pharmacokinetic genes, which determine how quickly your body absorbs or metabolizes drugs, and pharmacodyamic genes, which determine how effective a particular medication may be, or its chances of causing side effects.

Pharmacokinetic genes help doctors choose a dosage that’s individualized  for the patient’s specific metabolism. For any medication, not just psychiatric drugs, the main benefit of pharmacogenetic testing is in determining how people metabolize drugs, says Dr. Fawver. Genomind analyzes eight genetic enzymes responsible for how your body breaks down over 90% of all medications.

“If a person is a fast metabolizer, they tend to have fewer side effects, but the medication doesn’t work well,” explains Dr. Fawver. “If they’re slow metabolizers, that’s when you’re going to have more side effects because the blood levels will go higher than expected.”

According to Bruce Alan Kehr, M.D., president of Potomac Psychiatry in Rockville, Md., which offers Genomind testing through its National Genetic Testing Consultation Program, identifying these genetic biomarkers plays a key role in overcoming treatment resistance.

“We only analyze those genetic variations where we can do something about them to restore better health,” says Dr. Kehr. “Where we can turn the genes on or turn them off, upregulate or downregulate them, or work around them, to begin to help you feel better and function more effectively.”

One frequently problematic genetic variation, according to Dr. Kehr, is when a patient is homozygous for two of the so-called “short alleles” of the SLC6A4 serotonin transporter gene. He refers to these patients as “Orchids,” who develop higher rates of depression in response to environmental stressors. Antidepressants that are selective serotonin reuptake inhibitors, or SSRIs, are often well-tolerated medications for many people with MDD. But “Orchid” patients with their SLC6A4 gene variant often can’t tolerate SSRIs: “because you’re blocking a lower than average number of serotonin reuptake pumps that in effect already provide a ‘genetic SSRI,’” Dr. Kehr explains.  

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For these SSRI-intolerant patients, Dr. Kehr prescribes non-SSRI medications such as SNRIs or multimodals. “You’re less likely to have side effects, and more likely to bring about symptom relief and functional improvement, by picking a medication that is respectful of a patient’s genetic variants.”

 

The Financial Benefits of Genetic Testing

In his research using health claims data, Dr. Perlis and his Stanford colleague Guido Imbens found that patients who received genetic testing prior to treatment for mood disorders had lower healthcare-related costs, compared to those who didn’t receive the testing.

Over a six-month period, those who received genetic testing had, on average, 40% fewer all-cause emergency room visits and 58% fewer all-cause hospitalizations. Healthcare costs for the tested group were estimated to be $1,948 lower.

“From the beginning, we expected to see savings beyond psychiatry,” says Dr. Perlis. “The study showed that the test had enough of a reduction in cost to be cost-effective.”

Some of this could be attributed to better outcomes for diseases that can be exacerbated by depression, as it can often travel with conditions such as diabetes, cancer, and heart disease.

“It’s repeatedly been shown that depression makes everything else more expensive and harder to treat,” says Dr. Perlis. “Apart from the fact that we should manage depression for its own sake, we also need to be more efficient in how we manage depression because of all the potential follow-on benefits for the rest of someone’s health.”

As for the concern that genetic testing could lead to using more expensive medications? “We haven’t seen evidence of that. In our study, medication costs were not any greater in people who got the test,” says Perlis.

Most patients with commercial insurance will pay $325 or less.

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Environmental Factors Still Matter, Too

Medical professionals continue to be optimistic about the benefits of pharmacogenetic testing. But it’s also important to note that pharmacogenetic tests aren’t diagnostic, meaning they can’t tell whether you have MDD or related disorders. Doctors still rely on your phenotype—your observable symptoms and health history—to diagnose MDD and other mental health disorders.

“While the genetics can help with the decision-making process for some patients, we’re certainly not at the point where you take the test, and it says this medicine works every time,” says Dr. Perlis. “Testing can help to decrease the trial and error by avoiding medications that are broken down differently and [are] less likely to be effective or more likely to have side effects.”

Other factors Dr. Fawver analyzes in piecing together a mental-wellness puzzle for each patient: environmental stressors, past trauma, medical illness, the use of marijuana and alcohol.

“All sorts of things can turn genes on and off inappropriately and that’s when you will have symptoms of depression. So just looking at someone’s genetics won’t tell you what they need,” Dr. Fawver says. “You have to put the whole spectrum together.”

 

What’s Next for Pharmacogenetics?

Dr. Fawver cites the success of genetic testing in cancer research and treatment as an example of the potential benefits for pharmacogenetics in psychiatry.

“In the 1960s, remission rates for breast cancer were less than 28%. Here we are in the 21st century and remission rates for breast cancer are over 90%,” Dr. Fawver says. “Much of the success is due to having genetic testing for breast cancer. If we can get that precise eventually with treating mood disorders and psychiatric disturbances in general, that would be phenomenal.”

Dr. Kehr encourages other clinicians to embrace pharmacogenetics.

“Why not do everything you can to optimize treatment effectiveness and minimize and eliminate side effects while promoting effectiveness,” he says. And for those patients struggling with mental health concerns, “Whether you’re treatment-resistant or having your first episode of depression, it’s an approach that is personalized and more precise.”

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