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Progress Report - August 2008

Participant recruitment

The study recently commenced contacting the clients of one health service who are confirmed cases or controls about giving a blood or saliva sample.  From the blood or saliva we will extract the individual’s DNA for identification of a genetic marker for myocarditis.

We now have 10 samples – 2 saliva and 8 blood.  Recruitment is proceeding.

Case analysis – publication pending

We plan to submit for publication very soon an analysis of the first 30 cases of myocarditis.  The article reports the study case definition and trends observed in the clinical history of these patients.  A strength of the analysis is that we have been able to compare signs and symptoms in cases with those observed in 47 controls who took clozapine for at least 6 months without developing manifest cardiac disease.

Indications of likely success for genetic analysis

Clozapine-associated myocarditis is a hypersensitivity reaction as indicated by cardiac histology.  Researchers have identified genetic markers for three other drug hypersensitivity reactions:

  • HLA-B*1502 for Stevens Johnson syndrome with carbamazepine in Asians1
  • HLA-B*5701 for hypersensitivity to abacavir2
  • HLA-B*5801 for severe cutaneous reactions with allopurinol3

For each of these, 100% of those with the hypersensitivity reaction have had the genetic marker, but it has also been present in small percentages of those without the adverse reaction.

In December 2007, the US FDA recommended that all those of Asian descent be tested for the genetic marker before commencing carbamazepine.1

In February 2008, the first randomised controlled trial involving a genetic marker was published.2  Patients received either prospective or retrospective screening for the genetic marker for hypersensitivity to abacavir.  Those testing positive in the prospective group were not given abacavir, and none of the remaining patients in the group developed the hypersensitivity reaction.  Of those testing positive retrospectively, 48% had developed abacavir hypersensitivity.

These events indicate that identifying a genetic marker for myocarditis with clozapine is not only cutting edge research, but it is also likely to yield a clinically relevant result.

  1. US FDA, Centre for Drug Evaluation and Research. Carbamazepine.  FDA Alert 12/12/2007.  Internet: http://www.fda.gov/cder/drug/InfoSheets/HCP/carbamazepineHCP.htm (Accessed 16 Feb 2008).
  2. Mallal S, Phillips E, Carosi G, Molina J-M, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 2008;358(6):568-579.
  3. Hung S-I, Chung W-H, Liou L-B, Chu C-C, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc. Natl. Acad. Sci. U. S. A. 2005;102(11):4134-9.