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

Pharmacogenomics of CNS Disorder Treatments
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of these additional platforms for clinical practice has been slow to enter all areas
of clinical practice due to the high cost and long turnaround time, although this
is changing as more pharmacogenomic testing is being covered by US insurance
companies.
TARGET GENES INVOLVED IN NEUROLOGY AND PSYCHIATRY
There are a large number of genes involved in both the efficacy and safety of medications
used for the treatment of neurologic and psychiatric medical conditions. The
following sections contain detailed information on many genes that are currently
being researched.
Depression–Serotonin Transporter Gene and Serotonin Receptor Gene
One of the most extensively studied genes affecting the treatment of depression is
the serotonin transporter gene (SLC6A4), which is located at 17q. 20,21 SLC6A4 is a
protein structure made up of 12 transmembrane helices with an extracellular loop
between helices 3 and 4. This transporter is responsible for the reuptake of serotonin
(5HT) into the presynaptic neuron. Variations in SLC6A4 allele frequencies occur
across ancestral populations.
The most widely studied variant of SLC6A4 is the indel promoter polymorphism,
which is frequently referred to as 5-HTTLPR. The polymorphism consists of a variant
that is either 43 or 44 bp in size. There are many variations of both the long and
short alleles of the polymorphism. Additionally, there has been some evidence that
there is an interaction between the SNP (irs25531) located immediately upstream of
the indel polymorphism and the activity of the long allele of the transporter protein. 22
Extensive research, including several meta-analyses, has focused on the pharmacogenomic
variability of SLC6A4 on antidepressant response to SSRIs. One metaanalysis
of 15 studies concluded that patients who are homozygous for the long allele
and are of European ancestry has a more consistent therapeutic response to SSRI
treatment, while an additional meta-analysis (n = 28 various ethnicities) concluded
that there is no significant effect of the transporter promoter length polymorphism
on the rates of antidepressant response. The authors stated that there was substantial
unexplained heterogeneity of effect sizes across the studies, eluding additional interacting
factors that could contribute to an association in some cases. 23,24
Key Points: SSRIs have a broad therapeutic index, and the use of genetic testing
for dose-related outcomes is controversial. Despite the optimism in using
pharmacogenomic testing in determining SSRI response, challenges still exist in
determining the specific genetic components of SSRI response to testing.
Polymorphisms in the genes that code for various serotonin receptors have also
been studied in regard to their roles in altering the efficacy of various antidepressants.
The 5-HT1A and 5-HT2A receptors have also been studied with varying
results. Additional areas of interest, which have been studied to a lesser extent,