HLA-B*1502 screening in carbamazepine and lamotrigine candidates of Asian background

To the Editor

The aromatic mood stabilisers carbamazepine and lamotrigine are routinely used in the management of bipolar affective disorder. One wonders to what extent pharmacogenetic findings over the past decade have influenced the prescription of these agents within the psychiatric community, specifically with regard to pre-prescription screening for the human leukocyte antigen (HLA) allele-B*1502 (HLA-B*1502) in patients of Asian background.

There is compelling evidence for the association of HLA-B*1502 with carbamazepine-induced Stevens– Johnson syndrome (SJS) to the extent that it was reported in Nature as the strongest ever association described between an HLA genotype and a disease (Chung et al., 2004). In the studied Han Chinese population, 100% of 44 patients with carbamazepine-induced SJS tested positive for HLA-B*1502 while only 3% of 101 carbamazepine-tolerant patients were HLA-B*1502-positive. When the strength of this association is considered in conjunction with the high mortality rates associated with SJS and its more severe form, toxic epidermal necrolysis (TEN) – reported as about 10% and 50% respectively (Mockenhaupt and Norgauer, 2002) – it is understandable that carbamazepine should be avoided in individuals of this genotype unless this risk is outweighed by expected benefit. The United States Food and Drug Administration issued an alert to this effect in 2007 (U.S. Food and Drug Administration, 2007).

Notably, the HLA-B*1502 allele is present almost exclusively in individuals of East and Southeast Asian ethnicity including South Asian Indians (U.S. Food and Drug Administration, 2007). Genetic testing for this allele is readily available for routine clinical practice and has been associated with a positive predictive value of up to 7.7% for carbamazepine-induced SJS/TEN in the Han Chinese population (Hung et al., 2005). In the recent 3-year prospective study published in the New England Journal of Medicine (Chen et al., 2011), out of 4120 patients of Han Chinese background who tested negative for HLA-B*1502 and subsequently received carbamazepine, none developed SJS/TEN. Based on historical control data, a Taiwanese population of similar size who had not been tested for the HLA-B*1502 allele would have been expected to develop 10 cases of carbamazepine-induced SJS/TEN. The authors concluded that genotyping for carbamazepine candidates in this population showed a strong association with reduced incidence of SJS/TEN.

With regard to patients considered for lamotrigine, there has not yet been a sufficiently large study to adequately characterize the possible association of this genotype with the risk of SJS/TEN. However, based on the similar aromatic structure to carbamazepine and evidence that the HLA-B*1502 is a common risk allele for both agents in inducing SJS/TEN (Hung et al., 2010), caution is advisable at this stage in lamotrigine candidates of Asian background. In conclusion, given the evidence to date, it appears prudent to consider baseline testing for the HLA-B*1502 allele in carbamazepine and lamotrigine candidates of Asian background as part of routine practice.