Genetic tests for antidepressant effectiveness?

Can genetic tests gauge how well antidepressants will work?By Rebecca Robbins @rebeccadrobbins – September 28, 2018

It can be notoriously difficult for psychiatrists and patients to determine which antidepressant might be most effective, or which might cause side effects.

And so Color Genomics, a company that already sells genetic tests to determine someone’s risk of developing certain cancers, said this week that it will also begin to offer a DNA test to determine how well widely used antidepressants are likely to work for patients.

With the new test2 (part of a $249 product), Color joins several dozen companies probing patients’ DNA in search of insights to help inform decisions about which psychiatry medications patients should take. 

They’re touting applications for

  • depression,
  • bipolar disorder,
  • attention deficit hyperactivity disorder, and
  • post-traumatic stress disorder.

But some top psychiatrists say the evidence doesn’t support the commercial rush.

In a review published this past April, a task force of the American Psychiatric Association’s research council concluded that such genetic testing is not ready for prime time in their field.

Color’s test will initially look at two genes, CYP2D6 and CYP2C19, that the company says impact metabolism of 13 medications for mental health.

Among the antidepressants it will report on are Zoloft, Paxil, and Lexapro.

This makes me wonder why there’s no market for genetic tests that check CYP2D6 for the rate of opioid metabolism in pain patients, requiring some to need far larger doses than “average”. (See Need for High Opioid Dose Linked to CYP450) That’s not a future wish, but rather a very real and well studied phenomenon:

Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes.

The variation in response to pharmacological agents between individuals has been recognized for decades.

However, the underlying genetic basis that provides a rational explanation for the observation that different individuals can display widely different responses to the same pharmacological agent came to light with the sequencing of the human genome, which allowed the identification of thousands of gene polymorphisms, most often single nucleotide polymorphisms (SNPs)

Genetic polymorphisms for many drug targets and enzymes involved in drug metabolism have been identified.

Experts estimate that genetic factors account for 20% to 95% of patient variability in response to individual drugs.

The problem of extreme variability in opioid metabolism has been known for years, yet is completely disregarded in creating more and more guidelines for standardized dosages.

Here are two more articles about the great variety in individuals’ ability to metabolize opioids (and a list of 6 previous posts about this), which leads to great variety in the pain relief they achieve from opioids.

A spokesperson for Color, based in the Bay Area, said the science behind pharmacogenetics for psychiatry “is sound and based on clear evidence and consensus statements.” The information Color provides is based on guidelines from the Food and Drug Administration6 and a consortium dedicated to implementing pharmacogenetics, the Color spokesperson said.

A pharmacogenetics initiative managed at Stanford also rated the two genes Color is analyzing as “very important” in how the body metabolizes and responds to certain drugs.

The psychiatry offerings from Color and other companies are part of a broader effort to try to use genetic testing to help inform medication choices for all sorts of different conditions.

Leading hospitals including Mayo Clinic and Mount Sinai have programs to incorporate pharmacogenetics into clinical care. And the Cincinnati Children’s Hospital has been performing pharmacogenetic testing for neuropsychiatric medications for the last 14 years.

In this case, I wonder why they aren’t they using genetic testing to determine if we are able to properly metabolize opioids, or if higher than average doses will be needed.

But compared with other fields, there’s relatively little evidence supporting pharmacogenetic testing in psychiatry.

Yet there’s a lot of evidence about how opioid metabolism is affected by genetics, even though the CDC asserts we are all “average” metabolizers who are subject to the same dose limits.

A 2013 meta-analysis looked at three studies that collectively gathered data on more than 2,200 patients, analyzing their genes and their response to psychiatric mediation. The result?

“The authors identified no reliable predictors of antidepressant treatment outcome,” they wrote. They also ran an analysis that suggested that genetics may have accounted for between 1 and 2 percent of the differences in how patients responded. (Other research suggests the contribution is higher.)

Critics also say that research supporting the use of pharmacogenetics in psychiatry is flawed.

This could be because they still don’t know how or why SSRIs work on depression.

Another concern: Companies don’t share their secret sauce — how exactly they combine their analyses of different genetic variants to come up with an assessment of whether a drug is likely to work — so the formula can’t be independently reviewed.

Cohen said he understands that psychiatrists and patients are desperate for answers about which drug to try. But even basic questions about a patient’s symptoms, diet, and other medications will yield more insight than a genetic test, he said.

Yes, but that requires a doctor to listen to a patient for more than 90 seconds. This kind of inefficiency is exactly what’s being cut in the modern for-profit healthcare business.

Color’s tests must be ordered by a physician — unlike genetic tests offered by direct-to-consumer companies like 23andMe — and factor genetic counseling into their price.

The company is not accepting insurance for the new product.

Other thoughts?

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