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Should psychiatrists be testing their patients for drug response?

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We have just conducted a review of the biomarkers in drug labels to complete the population of the theranostic clinical biomarkers in BiomarkerBase™, and it was not surprising to note how well-represented the cytochrome p450’s are in the labels of approved drugs. Of the 135 biomarker associations in drug labels, 54 of them are CYP’s.

The drugs with CYP’s in the labels are from nine different therapeutic areas, but Psychiatry stands out as significantly the most represented, with 26 of the 54 aforementioned drugs. The next highest category is Cardiovascular, with just 8 drugs.

Table 1. Number of drugs with cytochrome p450 biomarkers in their labels by therapeutic area.

Therapeutic Area

Drugs

Psychiatry

26

Cardiovascular

8

Gastroenterology

5

Neurology

4

Analgesics

3

Antifungals

2

Reproductive & Urologic

2

Antiarrhythmics

1

Dermatology & Dental

1

Musculoskeletal

1

Rheumatology

1

Only four CYP’s are listed as biomarkers in drugs labels, and 2D6 and 2C19 account for the lion’s share of companion diagnostic biomarkers.

Table 2. Number of drugs that include cytochrome p450’s as biomarkers in their drug labels, by cytochrome p450 type.

Target

Drugs

CYP2D6

35

CYP2C19

14

CYP2C9

3

CYP3A4

2

Of the 26 Psychiatry drugs that have CYP’s as companion diagnostic biomarkers, 3 are among the top 100 sellers in 2011, and one, aripiprazole (Abilify®) is the #4 seller overall with over US$5 billion in sales during 2001 (source: Drugs.com). Other commonly prescribed drugs include diazepam (Valium®), fluoxetine (Prozac®), atomoxetine (Strattera®), and paroxetine (Paxil®).

Clearly, antidepressants and other Psychiatry drugs represent a significant chunk of overall drug sales. But how important is CYP testing?

According to Uniprot, 5-10% of Europeans and North Americans have genetic mutations in CYP2D6 that make them “Poor Metabolizers,” and thus most at risk for drug toxicity from drugs metabolized by this protein.

CYP2C19 warrants perhaps even more attention, as Uniprot states that “2-5% of Caucasians, 13-23% of Asian populations, and as many as 38-79% of individuals of some of the islands of Polynesia and Micronesia” are “Poor Metabolizers,” and again are at increased toxicity risk.

It would seem irrefutable that screening for CYP2D6 and CYP2C19 mutations or protein levels will help to reduce the risk of toxicity from antidepressant and other Psychiatry drugs. But how common is such testing?

Anecdotally, psychiatrists are probably among the least likely of all physicians to order lab tests, and psychiatric patients are also probably likely to be among the least engaged in their healthcare decision-making.

A quick search for CYP2D6 and CYP2C19 testing yields several labs that offer tests for multiple mutations of these targets, although this is usually within the context of testing for tamoxifen resistance. Quest Diagnostics offers mutation testing for these two targets, but one has to be searching quite specifically to find them. Quest has a section of their website designed for healthcare providers, and Psychiatry is not among the therapeutic areas included.

Atlantic Health System provides a very informative website (powered by DNAdirect®, and so presumably available via other DNAdirect licensees) about antidepressant response testing. This content is geared toward patients, however. Among the pros and cons listed on this site, the cons include the fact that insurance doesn’t always cover the testing and it can be expensive, neither of which bodes well for regular testing. After an admittedly brief search we were unable to find resources targeting psychiatrists.

A quick search of PubMed yields an appreciable recent literature covering toxicity and brain function related to CYP2D6, CYP2C19 and psychiatry topics. There does not seem to be a lack of scientific information, at least, covering these targets.

To summarize:

– Cytochrome p450s are among the most common biomarker targets

– Psychiatry drugs have significantly the most CYP biomarkers in the drug labels

– There is appreciable variability in CYP genotype which can confer risk of drug toxicity to large populations

– CYP testing does not seem to be very actively marketed to psychiatric professionals

– There is no lack of information available in the scientific literature

– Genetic mutation testing is costly and not consistently reimbursed

Some follow-up questions:

1. How significant is the problem of toxicity from antidepressant and other psychiatry drugs in terms of hospital admissions and other measurable events?

2. How aware are psychiatrists of this issue? Assuming that the problem of toxicity is adequately significant, is there a case for wider promotion of the need for testing, and for more consistent reimbursement?