By Sherman, Carl
Clinical Psychiatry News , Vol. 33, No. 8
The biologic aspects of ethnopharmacology are complex. Ethnicity cannot be reduced to genetically distinct categories, but an awareness of characteristic distributions of genotypes and phenotypes that affect pharmacokinetics can inform decisions about drug choice and dosage.
The area deserves more attention than it has received. Although research into pharmacogenetics, ongoing for decades, has intensified in recent years, "it's never made it into the mainstream journals or texts that people train on," said David C. Henderson, M.D., of the department of psychiatry at Harvard Medical School, Boston.
In particular, findings about the cytochrome P450 enzymes that metabolize many psychotropics have important clinical implications. More than one-third of African Americans and Asians, for example, produce reduced amounts of CYP2D6 and are therefore slow metabolizers of drugs--including certain atypical antipsychotics, selective serotonin reuptake inhibitors, and tricyclics--that are substrates for that enzyme.
By starting patients of these groups at a dosage that is lower than the recommended one and then titrating up slowly, physicians may avoid adverse events while achieving a therapeutic response, Dr. Henderson said. With drugs like tricyclics, which have a narrow therapeutic range, failure to appreciate metabolic variations can be particularly dangerous.
On the other hand, individuals who inherit multiple copies of the gene for CYP2D6 will fail to respond to high doses and will show negligible blood levels of substrate medications. "They're often labeled treatment resistant or noncompliant," said Michael Smith, M.D., director of the research center on the psychobiology of ethnicity at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. "The lab doesn't lie, so it must be the patient."
Only 3%-5% of whites in the United States are "superfast metabolizers," but 10% of those of Mediterranean ancestry, 20% of Saudi Arabians, and 30% of ethnic Ethiopians have that genetic endowment, Dr. Smith said.
In such cases, greatly increased doses of the substrate medication--or an agent metabolized by a different route--may be indicated, he said.
A genotyping test, the AmpliChip (Roche), which was approved by the Food and Drug Administration several months ago and is now available at many laboratories, subjects DNA from blood samples to microarray analysis to identify the polymorphisms associated with both slow and superfast CYP2D6 metabolizers. It can augment clinical impressions when treatment results are unexpected, Dr. Smith said.
As for anxiolytics, 20%-25% of Asians lack the gene for CYP2C19, which is the primary metabolic pathway for diazepam (Valium). These individuals, in whom the half-life of the drug is twice the norm, may do well on a lower dosage of the medication or on another agent of the same class. (This genotype can also be identified with the AmpliChip, Dr. Smith said.)
Metabolism of benzodiazepines in general, via the CYP3A4 pathway, tends to be slower in Asians, so smaller initial doses are indicated, he said.
Lithium blood levels are apt to be misleading in African American patients, said William B. Lawson, M.D., professor and chair of psychiatry at Howard University in Washington. The red blood cell to plasma ratio appears to be different from that found in whites, so that "the usual blood levels are associated with increased side effects," Conversely, "there are numerous case reports where patients, at what seem to be grossly subtherapeutic lithium levels, show marked improvement with tolerable side effects," he said. …