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Clinical and Research News
Gene-Coding Variants Can Affect Treatment Success
Psychiatric News
Volume 40 Number 10 page 33-55

So there it is, that psychotropic drug you prescribed for your patient. It has made its way through that "first pass"—the army of enzymes in the liver that metabolize drugs—without any distortion in its therapeutic potential or the unleashing of unwanted side effects.

It is now crossing the blood-brain barrier into the brain, ready to" do its thing." But wait! Just as variations in genes that code for certain liver drug-metabolizing enzymes can alter psychotropic medication outcome (see related article above), so can variations in genes that code for certain brain receptors and transporters.

In 1999 James Kennedy, M.D., head of neurogenetics at the Center for Addiction and Mental Health of the University of Toronto, along with Mario Masellis, M.D., and Vincenzo Basile, M.D., postdoctoral fellows in psychiatry and neurology at the university, reported that a variation in the gene that codes for a particular dopamine receptor in the brain—the D3 receptor—is strongly linked with tardive dyskinesia in patients treated with typical antipsychotics. This finding has been replicated by numerous groups throughout the world.

Furthermore, Kennedy and Masellis have found that a variant in the gene that codes for the brain's serotonin 2A receptor influences whether patients respond favorably to the antipsychotic drug clozapine. This finding was replicated by scientists in England.

Deviations in the MDR-1 gene that codes for a protein that helps ferry drugs across the blood-brain barrier have likewise been implicated in adverse responses to some psychotropic drugs.

Still other versions of genes that code for brain receptors or transporters have been found to influence psychotropic drug response, while still others will probably be discovered in the near future, Masellis indicated in an interview with Psychiatric News.

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In some cases, variants in genes that code for brain receptors and transporters may be even more crucial to psychotropic drug outcome than are variants in genes that code for drug-metabolizing enzymes in the liver.

Several years ago, for instance, Greer Murphy Jr., M.D., Ph.D., a professor of clinical psychiatry at UCLA, and colleagues gave 246 elderly depressed subjects one of two widely prescribed antidepressants—either the SSRI paroxetine or the non-SSRI mirtazapine. All of the subjects were assessed for variations in the gene that codes for the liver drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6) and for variations in the gene that codes for the serotonin 2A receptor. The CYP2D6 enzyme is known to be involved in determining the metabolism of many psychiatric drugs, and the serotonin 2A receptor in the outcome of some others.

Subjects were followed for eight weeks to see whether they experienced side effects from the antidepressant they were given. Murphy and his coworkers then assessed whether there was a link between such side effects and possession of any of the variants in the gene coding for the serotonin 2A receptor or between side effects and variants in the gene coding for the CYP2D6 enzyme.

No link was found to side effects from mirtazapine; they were not linked with any of the variants in the gene coding for the serotonin 2A receptor or with any of the variants in the gene coding for the CYP2D6 enzyme.

As for side effects from paroxetine, however, a link did appear. A variant in the gene coding for the serotonin 2A receptor was very strongly linked with paroxetine's side effects, whereas none of the variants in the gene coding for the CYP2D6 enzyme were.

So it looks as if, in this study population, a particular version of the gene that codes for the serotonin 2A receptor was implicated in paroxetine side effects, Murphy and his team concluded in the October 2003 American Journal of Psychiatry. Even more noteworthy, it looks as if in this population, the serotonin receptor gene variant of interest had more influence on paroxetine's destiny than did variants of the gene coding for the CYP2D6 enzyme.

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Not surprisingly, this highly specialized domain of molecular genetics is fraught with challenges.

For one, psychotropic drugs are complicated drugs working on multiple neurotransmitter systems. And if identifying the neurotransmitter receptors or transporters involved in drug-treatment outcome isn't difficult enough, linking variants in genes that code for those receptors or transporters to particular drug outcomes is even tougher.

"Still another big problem for us in our area of research," Masellis pointed out, "is how to define `drug response.' It is easier to define `side effects' because if someone gets nauseated, you can document that. Does drug response mean that the patient feels subjectively better? Or do you have to observe improvement in terms of the patients' behavior and how they are interacting with other people and society? And if the latter is the case, behaviors are very difficult to measure...."

Besides, "all of these studies are preliminary, and many are contradictory," James McGough, M.D., cautioned. McGough, a professor of clinical psychiatry at UCLA, is studying variations in genes that code for brain receptors and transporters that are implicated in responses to medications for attention-deficit/hyperactivity disorder.

Thus, it will probably be five to 10 years, Masellis predicted, before tests for variants in genes coding for brain receptors and transporters involved in psychiatric-drug responses might help physicians decide what drug or what drug dose to use. McGough is even less optimistic: "It will be many years before physicians treating attention-deficit/hyperactivity disorder patients will be able to develop individualized therapies based on pharmacogenetics."

But when such findings finally come together, McGough anticipates, tests for variants in genes that code for pertinent brain receptors and transporters could help individualize psychotropic drug treatment.

"If physicians are better able to match patients with individualized medications," he said, "it is possible that patients will remain on effective treatments for longer periods." ▪

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