New tool: Genotyping makes prescribing safer, more effective

Genotyping for cytochrome P-450 2D6 gene variations is emerging as a valuable clinical tool to help psychiatrists identify patients who:

• will not benefit from a medication
• could be at risk for an adverse response.^1-4

Genetic variation has long been known to influence how individuals metabolize drugs, but only recently could we apply this information.⁵ Many academic medical centers and the two largest U.S. reference laboratories offer 2D6 testing at costs of $200 to $500.

Before long, psychiatrists may adopt routine genotyping before prescribing 2D6 substrate medications. This article and four vignettes illustrate the clinical benefits of psychiatric pharmacogenomics and suggest when prospective genotyping could help you select and dose medications.

Table 1

Drugs metabolized by the 2D6 enzyme*

Why test for the 2D6 gene?

The 2D6 gene codes for the 2D6 enzyme, the primary enzyme required to metabolize many psychotropics Table 1.

Genetic variations. A common variation in a gene is frequently called an allele. More than 100 2D6 gene variations have been described. Consequently, the 2D6 gene’s enzyme activity also varies widely. Most mutations decrease the enzyme’s activity, but some polymorphisms change the gene’s promoter region, which can lead to upregulation and increased enzyme production.

Each 2D6 gene variation has been labeled with a standardized abbreviation (Table 2):

• *1 refers to the “normal” gene
• *2 stands for several variants with different activity levels.
• *3, *4, *6, *7, *8, *9, *10, *11, *12, *14, and *17 code for proteins with little or no activity.
• *5 indicates that the gene is deleted, and no enzyme can be produced.

Multiple copies. Another characteristic of the 2D6 gene is its unusually high propensity to accumulate in multiple copies on the 22nd chromosome. As many as 13 copies of the 2D6 gene have been shown on a single chromosome. Given that each gene can code for the 2D6 enzyme, patients with multiple copies can metabolize 2D6 substrate medications very rapidly.

Nonpsychiatric drugs. The 2D6 enzyme is also involved in metabolizing many nonpsychiatric drugs. To produce analgesia, for example, the 2D6 enzyme must metabolize the prodrug codeine to morphine. Thus, individuals with no 2D6 enzyme activity experience no analgesia with codeine. Approximately 7% of Caucasians metabolize codeine poorly. Conversely, individuals with multiple 2D6 gene copies metabolize codeine to morphine very rapidly, with potential for acute mental status changes, including psychosis.

4 metabolizer types. Based on variation in individual 2D6 genotype, a patient is usually categorized as being an ultrarapid, extensive, intermediate, or poor metabolizer (Table 3). The following case vignettes of patients in each category illustrate the clinical benefits of 2D6 genotyping.

Ultrarapid metabolizer: Extra 2D6 copies

Abdul, 49, is an Ethiopian businessman engaged in international commerce. While in the United States, he underwent a routine wisdom-tooth extraction and was treated with acetaminophen and codeine. Despite having no psychiatric history, he began to experience extreme discomfort and flashing visual hallucinations within 24 hours of taking two codeine doses. The oral surgeon instructed him to discontinue codeine, and his symptoms resolved within 24 hours.

Because of this experience, Abdul underwent genotyping for the 2D6 gene. He was found to have five active copies on one 22nd chromosome and no copies on the other (Figure 1). This genotype is unusual in western European populations but common in North Africa. Abdul then received alternate analgesics; psychiatric symptoms did not recur.

A patient such as Abdul, with multiple copies of a functional 2D6 gene, is an ultrarapid metabolizer. The 22nd chromosome—where the 2D6 gene is located—is short and contains areas of high homology. As a result, uneven crossover events occur more frequently during meiosis than is typical of larger chromosomes. Uneven crossover results in one gamete with two copies of the 2D6 gene and the other gamete with none.

2D6 enzyme activity is not essential for survival, which raises fascinating questions about this gene’s evolutionary importance. In certain geographic regions, many individuals have multiple copies of the gene. In Ethiopia—the country with the highest documented number of ultrarapid metabolizers—more than 25% of the population has one chromosome with multiple copies of the 2D6 gene.⁶ Because these copies produce an increased amount of 2D6 active enzyme, normal doses of 2D6 substrate medications do not benefit these individuals.

Table 2

How common 2D6 gene variations (alleles) affect 2D6 enzyme activity

Table 3

Four ways patients respond to 2D6 substrate drugs