New tool: Genotyping makes prescribing safer, more effective
2D6 enzyme variations identify patients at risk for an unexpected response
| Category | Patient characteristics | % of Caucasian population |
|---|---|---|
| Ultrarapid | Metabolize 2D6 medications rapidly resulting in poor response | 1 to 2 |
| Extensive | Metabolize 2D6 medications at a normal rate | 73 to 82 |
| Intermediate | Metabolize 2D6 medications at a slower-than-normal rate | 10 to 15 |
| Poor | Metabolize 2D6 medications very slowly with increased risk of side effects | 7 to 10 |
When treating ultrarapid metabolizers one strategy is to increase the dosage to obtain a therapeutic effect Because some substrates have complex metabolic pathways, however, high concentrations of secondary or tertiary metabolites can accumulate. Thus, when a substance’s metabolic pathway is not well-documented, a more cautious approach is to choose a medication metabolized by another pathway.
Figure 1 Genotypes and metabolizer categories of 4 illustrative patients
Extensive metabolizer: The ‘norm’
George, a 31-year-old Ethiopian architect, is Abdul’s second cousin. He developed acute depression with intense suicidal ideation and sought psychiatric consultation. He had no history of atypical drug reactions, but—because of his ethnic background—his psychiatrist was concerned that George might be a rapid metabolizer.
2D6 genotyping showed that George’s genotype was *1/*1, which meant he had two functional 2D6 copies (Figure 1). This genotype suggests that he could tolerate many antidepressants. The psychiatrist concluded—with some confidence—that George would not experience adverse effects or low serum levels when prescribed fluoxetine at usual dosages.
Extensive metabolizers have two normal 2D6 gene copies and can produce adequate active 2D6 enzyme Patients with this genotype—common in Caucasians—are generally said to have “normal” 2D6 metabolism. This means they metabolize 2D6 substrate medications at a rate within the recommended dosage ranges determined from North American or European pharmacokinetic studies.
Intermediate metabolizer: Mixed message
Katrina, 27, represents the government of her native Sweden in trade agreements. When she developed depressive symptoms (insomnia, sense of hopelessness), Katrina saw her psychiatrist. She reported that her family has a history of adverse reactions to multiple medications, but she had tolerated most medications. In fact, she had twice been successfully treated with relatively high doses of codeine.
Her psychiatrist suspected she was an intermediate 2D6 metabolizer and ordered testing. Her genotype was *1/*4, with one normal copy and one that produced no functional 2D6 enzyme (Figure 1).
Based on her clinical history and this genotypic information, the psychiatrist prescribed sertraline—metabolized by both 2D6 and 3A4 enzymes— at 50 mg/d. Because Katrina metabolized sertraline at a slower-than-usual rate, she developed a therapeutic blood level and responded well to this low dosage.
Intermediate metabolizers have a chromosome with one functional 2D6 gene copy. The other chromosome has either a copy with a defective functional polymorphism or a deletion of the gene. These patients usually tolerate 2D6 substrate drugs in low dosages.
Poor metabolizer: ‘medication-sensitive’
Olga, Katrina’s mother, has always lived in northern Sweden. She has no psychiatric history except for one psychotic episode that required hospitalization.
Her psychotic illness began on the summer solstice, during an all-night celebration. In addition to using unspecified recreational drugs, she took three 20-mg capsules of fluoxetine that her friend told her would make her feel high. She instead developed acute mania and dramatic paranoid delusions.
Figure 2 Possible genotypes of Brad, son of Abdul and Katrina
Olga was hospitalized and treated with moderate doses of haloperidol that precipitated an acute dystonic reaction. She was subsequently given ben-ztropine, and her extrapyramidal symptoms resolved. After discharge, she was treated with haloperidol and benztropine for 2 years, after which she spontaneously discontinued these drugs against medical advice. Her psychotic illness has not recurred.
Knowing her own genotype, Katrina understood that her mother had a 50% probability of having one copy of the 2D6 *4 allele. Given her mother’s history of medication intolerance, Katrina believed that her mother’s psychiatric illness might have been related to a drug reaction. She persuaded her mother to send a blood sample to a laboratory in Stockholm.
Olga’s genotype was *4/*4, indicating that she would be unlikely to tolerate even moderate doses of 2D6 substrate medications (Figure 1). Given her complete recovery and continued good health without medication, the most probable retrospective diagnosis was drug-induced psychosis. Her 2-year neuroleptic treatment probably was unnecessary.
Figure 3 Genogram for Brad, son of Abdul and Katrina
Poor metabolizers without a functional 2D6 gene copy have low tolerance for many medications and often become labeled as “medication sensitive.” When genotyping reveals that an individual is a poor metabolizer, prescribing medications that do not require 2D6 metabolism is usually prudent.
In rare cases, poor metabolizers have died from normal doses of 2D6 substrate medications.7 Far more commonly, however, they spontaneously discontinue taking these drugs because of adverse side effects.
