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.
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
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
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
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." ▪