QUT find may lead to schizophrenia prescription revamp

Queensland researchers have made a discovery that could transform the way psychiatrists prescribe anti-psychotic drugs for schizophrenia -- and possibly, for other neuropsychiatric disorders, including depression.

Prof Ross Young, of Queensland University of Technology, and Prof Bruce Lawford of the Royal Brisbane Hospital have shown that schizophrenia patients differ markedly in their response to anti-psychotic drugs, depending on which variants of the DRD2 dopamine-receptor gene they carry.

The 30 to 40 per cent of patients who carry the DRD2-A1 allele of the gene are far more sensitive to clozapine, the most effective drug currently used to treat schizophrenia -- but which also causes severe side-effects in some people.

Young and Lawford tested 150 schizophrenia patients with 40 different anti-psychotic drugs, and found the same results in each case: the number of DRD2 dopamine receptors in the brain is the major determinant of how the individual responds to medication, irrespective of the drug used.

Lawford said the brains of DRD2-A1 carriers have only 30 to 40 per cent fewer DRD2 receptors than individuals carrying the more common DRD2-A2 variant of the gene.

With fewer receptors, these patients are more sensitive to clozapine and other antipsychotic drugs, and their symptoms may improve at only a third of the maximum dose prescribed for schizophrenia.

But Lawford said that, in the absence of this dose-response information, it is standard practice for manufacturers to recommend that psychiatrists start newly diagnosed patients on a median dose of 600mg of clozapine, then increase it to 900mg if there is no improvement.

If there is no benefit at the highest dose, which induces serious side-effects in some patients, the person may be classified diagnosed as resistant and taken off clozapine.

But DRD2-A2 carriers are not resistant. They are actually more sensitive to clozapine, and would benefit from the minimum recommended dose 300mg -- a third of the maximum.

Lawford said the discovery should lead to the development of a gene-chip test that would determine, within 20 minutes, which variants of the DRD2 receptor gene their patients were carrying, and to select the optimum dosage.

At the highest dose, DRD2-A1 carriers are likely to be most susceptible to serious side effects including fits, tremors and, in female patients, osteoporosis, because clozapine up-regulates expression of the hormone prolactin, which mobilises bone calcium.

"Clozapine is the best drug we have, but because of its side-effects, it's reserved for patients who show a positive response," Lawford said. "We're keen to avoid exposing [sensitive] patients to high doses.

Lawford said the first edict of the Hippocratic oath was 'Do no harm'. A rapid gene-chip test to determine which alleles of the DRD2 receptor patients carry would not only avoid overdosing, it could benefit sensitive patients who might formerly have been classified as resistant and placed on other drugs.

Some 30 to 40 per cent of the population are A1/A2 heterozygotes, and about 70 per cent are A2/A2 homozygotes. A1/A1 heterozygotes, who are quite rare, are super-sensitive to antipsychotic drugs, and would require only a sixth of the maximum dose, Lawford said.

Lawford said the A1 and A2 alleles produce identical proteins; the particular polymorphism that makes DRD2-A1 carriers more sensitive to antipsychotic drugs lies in a non-coding region at the 5' region of the gene.

Although they have no plans to investigate the mechanism, Lawford said a post-translational modification that shortens the half-life of the gene's messenger RNA, may reduce expression of DRD2 receptors in A1-carrying individuals.