First, we will
discuss the polymorphisms affecting the main target of most first line depression
treatments, SSRIs, working on serotonin transmission by blocking its reuptake
by the serotonin transporter (5-HTT) acutely. However, their durable effects
rely on their adaptive modification caused by the long term reuptake blockade.
(Serretti, et al. 2005).
Three major polymorphisms could
affect the transcription level of this transporter, the first is situated in
the promotor region of 5-HTT and called 5-HT transporter gene linked
polymorphism region (5-HTTLRP). It’s a repeated sequence allowing the control
of 5-HTT transcription and has two genotypes, the longer version called L
causing a higher 5-HTT mRNA expression, a higher inhibitor binding and a
stronger serotonin uptake than the shorter S when both genotypes are expressed
in lymphoblasts. (Lesch & Gutkneckt 2005). In Caucasians, many robust
pharmacogenetic studies suggest a strong association between the longer version
of this polymorphism and a shorter symptom relief delay with less adverse drug
effects (Helton & Lohof 2015). However, in Asian patients, results were
somewhat contradictive. In some studies, this polymorphism showed no
association with differential treatment outcome (Reynolds et al. 2013). In
other studies, L genotype was even associated with a worst treatment outcome in
Asian patients (Kato 2006).
To widen the understanding of this
controversy, a second polymorphism was studied. This time situated in the
second intron of 5-HTT gene and called variable number of tandem repeats (STin2
VNTR). This polymorphism affects also the expression of 5-HTT. Asian patients
with the genotype containing 12 repeats showed a better response to
antidepressant treatment than those with 10 (Popp, et al. 2006). Reynolds, et
al. 2013 suggest that these results show this second polymorphism as the more
affective one in the Asian population since 5-HTTLRP long version is poorly
One third functional polymorphism is
a single nucleotide polymorphism (SNP) affecting the promotor region A>G.
One pharmacogenetics study using citalopram showed that having Lg genotype will
render the good responders L non-responders (Hu, et. Al 2007). This shows the
complexity of this trialellic genotype.
Secondly, we will discuss the
polymorphisms that could logically affect the treatment outcome of
antidepressants, serotonin receptors. There are seven types of serotoninergic
receptors. 5-HT-1A is implicated in the negative feedback due to its inhibiting
effect on presynaptic axons (Kushwaha & Albert 2005). The presence of an
upstream SNP called rs6295 in the regulatory region of the gene was shown.
Rs6295 increases the expression level of this receptor. Results for this
genotype showed a greater response to treatment (Helton & Lohof 2015).
However, meta-analysis studies could not prove this effect (Serretti, et al.
2013). However, this is one of the few polymorphisms which effect was similar
in Caucasian and Asian patients (Reynolds, et al. 2013).
Another 5-HT receptor gene that was
studied intensively is 5HTR2A. Antagonism of these receptors contributes to the
antidepressant effect of second generation antidepressants. In early
pharmacogenetics studies polymorphisms in this gene were considered as an
important indicator for antipsychotic drugs. Nevertheless, recent
investigations showed that their effects are not decisive (Reynolds, et al. 2013).
However, variants such as rs6311, rs6313 and rs6314 were associated with some
adverse drug effects such as gastrointestinal side effects and sexual
dysfunction (Helton & Lohoff 2015). Moreover, another intronic SNP
rs7997012 A>G resides in the sequence of this gene. In a study performed on a
large sample called STAR*D, results showed that having the A allele gives 18%
less chance of not obtaining beneficial treatment results from citalopram. The frequency
of this polymorphism is differential between Blacks and Caucasian, again
emphasizing the importance of ethnic differences in pharmacogenetics studies (McMahon
et al. 2006).
Finaly, 5HT3A codes for another type
of serotonin receptor and is home for another polymorphism 178C>T in the
upstream regulatory sequence. Once more in Asian patients with CC genotype responded
more efficiently to antidepressants (Kato, et al 2006).
Based on all the previous data, we
can see that we are far from understanding this complex network of
polymorphisms governing the expression of 5-HTT and many serotonin receptors. Moreover,
environmental differences, which affect the expression of many of these
proteins, and ethnic ones cause the blunting of the effects of polymorphisms,
making pharmacogenetics studies in this field arduous.