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

212 Applying Pharmacogenomics in Therapeutics
serotonin systems in the development of TD and extrapyramidal symptoms during
antipsychotic treatment.
One area of concern with pharmacogenomic testing and TD is the uncertainty that
comes with the results. The sensitivity, specificity, and predictive value of testing
have not been established to date. Another challenge we face as clinicians is consent
to perform the pharmacogenomic test. Given the nature of the illness we are treating,
this can be quite challenging. Additionally, explaining the future applications of
genetic information is controversial in this field. All of these areas must be considered
prior to deciding whether pharmacogenomic testing will be appropriate to the
patient population you are treating. 39
BIPOLAR DISORDER
Lithium-responsive bipolar disorder is linked to several unique characteristics, including
euphoric manias, positive family history, few comorbidities, and symptom-free
intervals between episodes. 40,41 Pharmacogenetic association studies have focused on
selected genes. Studies that have investigated the mechanism of action of lithium and
predication via SNP pharmacogenomic testing have only modest success, with few
replications. 40,41 GWASs may prove to be a better design in determining the combination
of genetic variations, which may detect lithium response. 40,41
ALZHEIMER DISEASE
Numerous studies have been conducted to determine the influence of the apoE
genotype on drug response in Alzheimer disease (AD). In the monogenic-related
studies, the apoE-4/4 carriers are the poorest responders to medication. 42–45
In trigenic-related studies, the apoE-4/4, presenilin 1 and 2, the best responders
are those patients carrying the 331222-, 341222-, and 441112-genomic profiles. The
worst responders in all genomic clusters were those patients with the 441122+ genotypes.
42–45 These results demonstrate the deleterious effect of the apoE-4/4 genotype
on AD, in sporadic and familial late-onset AD, therapeutics in combination with the
other AD-related genes. 42–45
The current treatments for AD, the cholinesterase inhibitors, are metabolized via
the CYP450 pathway. Poor metabolizers and ultrarapid metabolizers are the poorest
responders to drug treatment, while the extensive and intermediate metabolizers are
the best responders. 42–45 In light of the emerging data, it seems very plausible that
the determination of response to drug treatment of AD could depend on the interaction
of genes involved in the drug metabolism and those genes associated with
AD pathogenesis. 42–45
Additionally, the gene encoding for choline transferase, which encodes the major
catalytic enzyme of the cholinergic pathway, is associated with response to acetylcholinesterase
(AChE) inhibitors (AChEIs). A SNP in the promoter region of choline
O-acetyltransferase (CHAT), rs733722, accounts for 6% of the variance in response
to AChEIs. 46