Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics of CNS Disorder Treatments
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Tardive dyskinesia (TD), typically experienced not only by those who receive
first- generation antipsychotics but also by those who receive second generation
antipsychotics, can cause potentially permanent abnormal motor movements. It has
been associated with genes in the dopamine system, including dopamine 2 (D2) and
dopamine 3 (D3) receptors and the catechol-O-methyltransferase (COMT) enzyme.
Several studies have demonstrated that the minor T allele of the taq 1A polymorphism,
rs1800497, appears to be protective against TD, while the rs6280 SNP of
the DRD3 receptor has shown inconsistent results. 30–32 Additionally, a functional
polymorphism that codes for a substitution of methionine (met) for valine (val) at
codon 158 has been reported to have an association with TD. 33 Other pathways that
have been investigated with varying results include the following: accumulation of
free radicals or oxidative stress, 5-HT2A, and CYP2D6. 34–36
Key Points: Antipsychotic-associated weight gain is a serious consequence for
morbidity and mortality for patients. Pharmacogenomic approaches have allowed
for detection of more than 300 possible candidate genes for this adverse effect.
Given the variable histories of prior drug exposure and medication adherence of
patients treated with these drugs, it has confounded attempts to identify genetic
effects on this complex phenotype. Clinicians should monitor body mass index,
total fat mass, blood glucose, and insulin levels in patients for the development
of obesity. 37
Patient Case
TH, a 45-year-old male who was resistant to schizophrenia treatment, is currently
being treated with haloperidol 10 mg twice daily. He has been treated with several
different antipsychotics in the past with no efficacy. His physician explains the risk
of TD to his family and what to watch for as TH starts on the haloperidol.
Question: Are there any pharmacogenomic tests that can be completed to determine
if TH is at risk for developing TD? If there are, do clinicians have an ethical obligation
to complete the testing prior to prescribing antipsychotics?
Answer: TD is a long-term, potentially irreversible muscular side effect associated
with the use of antipsychotics. It is characterized by random movements in
the tongue, lips, or jaw as well as facial grimacing, movements of arms, lips, fingers,
and toes. It can also be characterized by swaying movements of the trunk or
hips. Extensive research has been conducted to determine if genetics plays a role
in determining who is at risk for developing TD when prescribed antipsychotics.
Currently, the DRD2 polymorphism has mixed results, although a meta- analysis
demonstrates that DRD2 taq A2/A2 genotype increases the risk of TD. 38 The
serine-9-glycine polymorphism in the DRD3 receptor has been studied with mixed
results. 39 There have been consistent results with the G-protein signaling 2 (RGS 2)
gene in identifying those at risk for TD. 39 The evidence currently states that there
is a major role of dopamine and serotonin receptors and the broader dopamine and