New Genetic Link May Identify Mechanism Behind Clozapine Agranulocytosis

Agranulocytosis is a rare but potentially fatal problem in which the levels of white blood cells in the blood drop rapidly. Unfortunately, agranulocytosis is one of the potential side effects of taking clozapine, which has limited the use of the antipsychotic despite its proven benefits.

Two years ago, an analysis of the genetic data from over 160 people who experienced clozapine-induced agranulocytosis (CIAG) by an international research consortium revealed two genes associated with an increased risk of this adverse effect—a finding that could one day help to develop a predictive screen for the disorder (Psychiatric News, October 3, 2014).

Researchers in the United Kingdom recently analyzed the genomes of nearly 5,500 schizophrenia patients taking clozapine, which included 66 patients whose blood cell counts dropped below normal levels. This analysis also identified several potential genetic variants linked with an increased risk of white blood cell loss following clozapine use, including one near HLA-DBQ—a critical immune-related gene that was identified in the 2014 study. The findings were published July 12 in Molecular Psychiatry.

Fred Jarskog, M.D., a professor of psychiatry at the University of North Carolina School of Medicine and one of the members of the consortium behind the 2014 study, told Psychiatric News that these latest findings validate the association between HLA-DBQ and CIAG. “In some ways, though, the more exciting news emerged after the U.K. group reached out to our team [led by Patrick Sullivan, M.D., the director of UNC’s Psychiatric Genetics program] to discuss pooling our respective data,” Jarskog said.

When all 239 cases were compared with controls, a new variant associated with clozapine-associated white blood cell loss emerged, in between a pair of genes called SLCO1B1 and SLCO1B3. Both these genes encode transport proteins that help the liver absorb a wide variety of compounds, including drugs, for subsequent metabolism.

While neither of these genes has previously been linked with clozapine responses, they both have strong connections to adverse events brought on by other medications; SLCO1B1 variants are associated with the risk of muscle problems in statin users, while SLCO1B3 variants are interestingly linked to the loss of white blood cells in patients taking the chemotherapy drug docetaxel.

“In the case of docetaxel, the evidence points to a dose-related phenomenon, where higher drug concentrations in the blood lead to worse cell loss,” Jarskog told Psychiatric News. Jarskog said it would be worthwhile to see whether a similar dose-dependent profile exists for CIAG, thus confirming some metabolic influence on this disorder. However, he noted that determining whether such a relationship exists could prove challenging given the rarity of CIAG compared with docetaxel-induced white blood cell loss.

“For our samples, we have the information on the clozapine dosage for each patient, but not how the drug was being metabolized in the body,” he said.

“It took a major international effort to reach the point of having data for over 200 cases of this disorder,” he continued. “For the time being we have to work with what we got.”

The fact that clozapine-associated white blood cell loss is relatively rare also means that even with this new genetic information, it will likely be some time before researchers achieve the ultimate clinical goal of developing a screen that can identify patients who are susceptible to this side effect of the medication.

The authors of the Molecular Psychiatry report calculated that a genomic test incorporating the HLA and SLCO1B variants would be about only 10 percent accurate at detecting whether a person might develop significant white blood cell loss while taking clozapine, as a majority of people who develop this side effect do not carry any of the currently identified risk alleles.

This study was funded by grants from the Medical Research Council. ■

“Genome-Wide Common and Rare Variant Analysis Provides Novel Insights Into Clozapine-Associated Neutropenia” can be accessed here.