Donna Lisi, PharmD.
Contributing writer to the Carlat Psychiatry Report newsletters.
Chris Aiken, MD.
Editor-in-Chief of The Carlat Psychiatry Report. Practicing psychiatrist, Winston-Salem, NC.
Drs. Lisi and Aiken have disclosed that they have no relevant financial or other interests in any commercial companies pertaining to this educational activity.
From cultural expectations to genetic variations, ethnicity has a strong effect on medication response. In this article, we’ll review five areas where ethnic groups can differ in their biological response to psychiatric medications.
Drug metabolism Most medications are metabolized in the liver, and patients’ liver metabolism varies. Slow metabolism causes medications to back up, resulting in higher serum levels, more side effects, and unexpected efficacy in the lower dose range. Ultra-rapid metabolism has the opposite effect—drugs are shuttled through so quickly that patients may need high doses to reach therapeutic levels.
Genes play a major role in the rate of metabolism, and those genes vary by ethnicity. In commercially available pharmacogenetic tests, slow metabolizers are called “intermediate,” normal are “extensive,” and fast metabolizers are “ultra-rapid.” There’s also a fourth category, “poor metabolizers,” whose enzymes are practically blocked, causing very high medication levels and significant adverse effects.
Poor metabolism is 2–3 times more common among Caucasians (7%–10%) at the pathway that most psychiatric medications pass through: CYP2D6. However, non-Caucasians have much higher rates of slow metabolism at this pathway, particularly East Asians. East Asians from China, Korea, and Japan have high rates (20%–40%) of slow metabolism at several pathways that are important in psychiatry: CYP2D6, CYP3A4, or CYP2C19.
Hispanics and African Americans have higher numbers of both slow and ultra-rapid metabolizers, depending on the country of origin. For example, a third of all African Americans are slow metabolizers at CYP2D6, but among the subset from Ethiopia, a third are ultra-rapid metabolizers at this pathway (Henderson DC et al, Ch 11 in Clinical Manual of Cultural Psychiatry, editor Lim RF, 2015). Variations in CYP2D6 metabolism have caused enough problems that in the 1990s, pharmaceutical companies began screening out drugs that pass through this enzyme (de Leon J et al, J Am Acad Child Adolesc Psychiatry 2015;54:532–534).
In practice, slow metabolism is a greater problem than ultra-rapid metabolism, as the side effects it creates can be dangerous or lead patients to drop out of treatment. One solution is to titrate slowly and aim for a low dose, but just how low? Exact figures aren’t known, and they depend on many other factors including age, diet, and drug interactions. Among Asians, most studies arrive at doses that are 30%–50% lower than those used for Caucasians, but that’s the average; the actual dose may be normal for some and significantly lower for those who are slow metabolizers (Henderson DC et al, Ch 11 in Cultural Psychiatry, editor Lim RF, 2015).
Pharmacogenetic testing and the SERT gene Genetic testing can clarify whether a patient is an ultra-rapid or slow metabolizer, but its value continues to be debated. A recent task force weighed in against the routine use of these tests, but also concluded that the metabolic portion of the test is the most useful, particularly for CYP2D6 (Zeier Z et al, Am J Psychiatry 2018; appiajp201817111282). The pharmacodynamic section of these tests, which includes genes that are involved in the brain’s response to medications, is considerably less reliable, and its interpretation may depend on ethnicity.
The serotonin transporter (SERT) gene is the most widely studied of these genes. It comes in two alleles, a short-arm (S) and long-arm (L), and the short-arm is associated with a poor response to serotonergic antidepressants—or at least that’s what the commercial tests report. In actuality, that finding has only held up among Caucasian men. Studies in Asian populations show the opposite trend, with the short-arm predicting a more favorable response to serotonergic antidepressants (Bousman CA et al, J Clin Psychopharmacol 2014;34(5):645–648). The frequency of this short allele also varies by ethnicity: 50% in Caucasians, 30% in Africans, and 70% in Asians (Gelernter J et al, Hum Genet 1997;101:243–246). The exact role of this allele probably depends on factors beyond the reach of a single-gene test, including ethnicity, environment, and interactions with other genes.
Adverse effects Some adverse effects occur more frequently in certain ethnic groups even at normal drug levels. Two to watch for with antipsychotics are hyperprolactinemia in Asians, and metabolic and cardiac problems in African Americans (Kim KM, J Clin Psychopharmacol 1988,8(3):195–201). In fact, nearly half of the published case reports of new-onset diabetes on atypical antipsychotics have occurred in African Americans (Jin H et al, Ann Clin Psychiatry 2002;14(1):59–64).
Carbamazepine hypersensitivity in Asians Several anticonvulsants carry a risk of severe rashes like Stevens-Johnson syndrome, including carbamazepine, lamotrigine, oxcarbazepine, phenytoin, and zonisamide. In the case of carbamazepine, these rashes are 10 times more common among Asians, and a genetic test can identify Asian patients who have an elevated risk. FDA labeling recommends testing for this gene (HLA-B*1502) before prescribing carbamazepine in Asian patients, and the drug is relatively contraindicated if the test is positive. The test is not recommended among non-Asians, where the HLA-B*1502 gene is almost absent.
What about oxcarbazepine? A recent meta-analysis found that Asians with HLA-B*1502 were 30 times more likely to have Stevens-Johnson syndrome on oxcarbazepine (Tangamornsuksan W et al, J Pharm Pharm Sci 2018;21(1):1–18). However, more data is needed to prove this association, and HLA-B*1502 testing is not yet recommended by the FDA in Asians on this relative of carbamazepine.
Other baseline labs (blood count, platelets, liver function, basic chemistry, and thyroid) are recommended before starting carbamazepine, and this test can be added to that list as “HLA-B*1502, carbamazepine sensitivity” (a cheek swab is also available). The test is positive if 1 or 2 alleles are present.
Clozapine and benign neutropenia in African Americans Certain ethnic groups have lower than average absolute neutrophil counts (ANC). This condition, benign ethnic neutropenia (BEN), is a normal finding and not a reason to avoid or discontinue clozapine therapy. BEN is most common in persons of African descent (25%–50%), some Middle Eastern ethnic groups (Yemenite Jews, Jordanians), and other non-Caucasian ethnic groups with darker skin (Rajagopal S, Postgrad Med 2005;81(59);545–546). A hematology consultation can clarify if a patient’s low ANC is due to BEN, and the clozapine guidelines have separate standards for this condition (for more information, see: www.clozapinerems.com).
While BEN is more common in male African Americans, genuine clozapine-induced agranulocytosis occurs more often in women and those of Asian or Ashkenazi Jewish descent (Rajagopal S, Postgrad Med 2005;81;545–546).
TCPR Verdict: With Asian patients, start low and go slow, particularly with meds metabolized by CYP2D6, CYP3A4, and CYP2C19. Hispanics and African Americans may also need modified dosing. Pharmacogenetic testing can clarify some of these problems, but other reasons beyond drug metabolism can make ethnic minorities more prone to side effects. A low white blood count is normal in some populations, particularly African Americans with BEN, and clozapine can still be used in these patients. Before starting carbamazepine, the FDA requires a HLA-B*1502 test in Asians to prevent a potentially life-threatening rash.