Genomics helps to find right antidepression drug
Assurex Health, a precision medicine startup based in Ohio, uses genomic scans to identify which anti-depressant medication patients will most likely respond to. This approach is known as pharmacogenomics, and analyses the individual's ability to metabolise antidepression and antipsychotic medicines. The approach can also be used to find the best medicine to treat arthritis, heart disease, infectious disease, lung disease, cancer and many other conditions.
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DNA testing already has been employed against cancer, but now it's being used to determine which drugs might work best for other conditions. (KEVIN CURTIS / Science Photo Library)

Since childhood, Mandy E. has struggled with feelings of hopelessness and inadequacy. She seemed incapable of having fun. She experienced what she described as "constant discontent."

Her parents felt it was a matter of the will to fix the problem; they didn't accept the possibility of mental illness.

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Finally, a year ago, Mandy, 24, a marketer for a Boston e-commerce startup (she asked that her full name be withheld) sought psychiatric help. "I needed to do something because I wanted to move my life in a certain direction, and I felt I wasn't going to do that if I didn't get help," she said.

She saw Dr. Mindy Rosenbloom, a psychiatrist in Barrington, R.I., who practices near Mandy's hometown.

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Rosenbloom, a clinical assistant professor at Brown University, diagnosed Mandy with dysthymia, a mild but persistent form of depression. The psychiatrist, who specializes in hard-to-treat cases, said finding the right antidepression drug is a complicated process that can take months, even years. In Mandy's case, Rosenbloom simplified the trial-and-error process with a genomic test.

The doctor turned to cotton swabs and DNA testing to personalize her recommendations for Mandy. She used the swabs to collect Mandy's cheek cells and sent them for DNA extraction and a genomic scan to Assurex Health, a precision medicine startup based in Mason, Ohio, "to identify the antidepressant medication options Mandy would tolerate best and would most likely respond to."

This approach is an emerging field known as pharmacogenomics, or drug-gene testing.

The U.S. Food and Drug Administration in recent years has recognized the power of pharmacogenomics and lists known genetic factors on package inserts for 137 medications, including several dozen for psychiatric conditions such as depression and anxiety. (For a list of the drugs with warnings, go to www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm.)

Pharmacist/pharmacogenomist Mark Dunnenberger, who runs the Pharmacogenomics Clinic at NorthShore University HealthSystem, one of the first clinics in the U.S. dedicated to interpreting the effects DNA has on drugs, said inroads are being made in the field. The process is to analyze the individual's ability to metabolize antidepression and antipsychotic medicines as well as medicines to treat arthritis, heart disease, infectious disease, lung disease, cancer and many other conditions.

Just as we inherit eye and hair color from our parents, we inherit genes that determine how our bodies respond to medicines, especially genes used to break down drugs in the liver, kidneys and other organs. Genes are the body's manuals that determine how we respond individually to drugs.

Though genomics differ, doctors generally have taken a one-size-fits-all approach to prescribing meds, taking into consideration age, sex and weight while overlooking growing evidence of differences based on genetic inheritance.

The NorthShore clinic, in Evanston, Ill., collects pharmacogenomics data on psychiatric illnesses and other conditions to incorporate the information in the patient's electronic medical record.

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Dunnenberger said genomic testing is not a panacea but it helps reduce guesswork: Drugs that likely won't work can be avoided, and doses can be adjusted based on the individual's genomic makeup.

"We need to help our patients understand pharmacogenomics can be helpful to them when they get certain medications but not every medication," he said. "And we can discuss cost and risk of getting genetic information and wrap that up together."

A handful of personalized companies extract DNA from cheek swabs or saliva samples and compare genes with findings in medical literature of how gene mutations affect the body's ability to metabolize medicines.

Assurex Health, the company that processed Mandy's DNA sample, uses technology licensed by the Mayo Clinic in Rochester, Minn., and by Cincinnati Children's Hospital, with financial backing from Sequoia Capital, the Silicon Valley venture capital firm behind Google, Airbnb and PayPal.

Assurex's GeneSight line of tests specializes in psychiatric and neurological disorders. Competitors offer broader pharmacogenetic testing, which includes psychiatric medications.

Tyler Mamiya, director of pharmacy at Seattle-based Genelex Corp., noted that more than 75 percent of the population has genetic variations that determine how their bodies process and use drugs. "This applies not only to prescription medications but also to over-the-counter medicines, herbal and dietary supplements, and recreational drugs such as marijuana," the pharmacist said.

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Mandy had three tests. One was GeneSight Psychotropic, a pharmacogenomic test involving the analysis of 50 markers from six genes and a clinical outcomes-based tool that weighs the influence the markers have on 32 different agents. A second was Genesight ADHD for determining drugs to use for attention deficit hyperactivity disorder. The third, MTHFR, tested her ability to process folate, a B vitamin. If insufficiently metabolized, folate can result in deficiencies of three brain chemicals that antidepressants use.

Rosenbloom received the report in a few days with a traffic signal-style list of medicines, a strategy typically used by testing companies.

Medications listed under green can be used as directed. Those in the yellow category should be used with caution. Those in the red category should be used with increased caution and more frequent monitoring. Additional notes explain whether higher or lower doses are indicated, whether the patient's genes may reduce efficacy of meds or whether a drug simply should be avoided.

Rosenbloom said testing reduces but doesn't eliminate trial and error. She said Mandy "felt tired all day" during the first days on a green-zone medicine and has felt well on a red-zone option, Wellbutrin XL (bupropion), prescribed at the lowest dose to compensate for her much slower than average metabolism of that drug.

Most significantly, testing showed Mandy had a single mutation in the MTHFR enzyme critical in metabolizing folate found in foods or vitamin supplements. Researchers showed in the 1960s that folate deficiency could trigger depression. Genetic testing can reveal enzyme mutations linked to commonly consumed drugs and vitamins.

Rosenbloom gave Mandy a prescription form of processed folate, l-methylfolate, that can cross the blood-brain barrier and switch on enzymes that would help her metabolize antidepression medicines such as Wellbutrin. "The rest is history. Mandy applied for and obtained a full-time job in Boston and has been commuting and doing well," she said.

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The test panels are not cheap. GeneSight Psychotropic, Assurex's most commonly prescribed test, lists for $3,800, which Don Wright, executive vice president and chief operating officer of Assurex Health, said is comparable to that for many other genetic tests.

He added that multiple studies have shown the testing on average saves patients $2,500 per year in prescription costs and reduced number of medical office and emergency room visits. Patient co-insurance responsibility for bills is typically 10 percent to 20 percent for commercial insurance, while Medicare and Medicaid patients have no out-of-pocket expense.

Mandy said her family's Blue Cross plan covered all but $6 of the testing. Insurance coverage varies.

Dr. James Evans, a medical geneticist at the University of North Carolina and editor-in-chief of Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics, is bullish on genomics. He even has a DNA tattoo on his shoulder.

But he has been skeptical about pharmacogenomics, even as President Barack Obama gave the field a boost in his 2015 State of the Union along with the promise of a $215 million investment and a genomic study of more than a million Americans.

He said pharmacogenomics is well-established for cancer but is on shaky ground in many areas, such as testing for the anti-clotting drug Coumadin (warfarin). "The public clamors for astrology too. It's just not a good reason to offer a medical test," he said. "Some of it is snake oil." Evans examined the research Assurex Health has sponsored and was impressed that the researchers are "publishing in peer-reviewed journals and going about collecting evidence in the right way."

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Meanwhile, Rosenbloom said pharmacogenomics is dramatically changing psychiatric practice. She said psychiatric patients traditionally were, in effect, "guinea pigs" as they tried out a variety of medications in a variety of doses.

"There were limited criteria to help us select medications," she said. "Personalizing psychiatric prescriptions based on DNA makes pharmacology safer, better tolerated, improves patient adherence and the likelihood of their response to the medications we prescribe."

Howard Wolinsky is a freelance reporter.