First, we willdiscuss the polymorphisms affecting the main target of most first line depressiontreatments, SSRIs, working on serotonin transmission by blocking its reuptakeby the serotonin transporter (5-HTT) acutely. However, their durable effectsrely on their adaptive modification caused by the long term reuptake blockade.
(Serretti, et al. 2005).Three major polymorphisms couldaffect the transcription level of this transporter, the first is situated inthe promotor region of 5-HTT and called 5-HT transporter gene linkedpolymorphism region (5-HTTLRP). It’s a repeated sequence allowing the controlof 5-HTT transcription and has two genotypes, the longer version called Lcausing a higher 5-HTT mRNA expression, a higher inhibitor binding and astronger serotonin uptake than the shorter S when both genotypes are expressedin lymphoblasts. (Lesch & Gutkneckt 2005).
In Caucasians, many robustpharmacogenetic studies suggest a strong association between the longer versionof this polymorphism and a shorter symptom relief delay with less adverse drugeffects (Helton & Lohof 2015). However, in Asian patients, results weresomewhat contradictive. In some studies, this polymorphism showed noassociation with differential treatment outcome (Reynolds et al. 2013).
Inother studies, L genotype was even associated with a worst treatment outcome inAsian patients (Kato 2006).To widen the understanding of thiscontroversy, a second polymorphism was studied. This time situated in thesecond intron of 5-HTT gene and called variable number of tandem repeats (STin2VNTR). This polymorphism affects also the expression of 5-HTT. Asian patientswith the genotype containing 12 repeats showed a better response toantidepressant treatment than those with 10 (Popp, et al. 2006). Reynolds, etal.
2013 suggest that these results show this second polymorphism as the moreaffective one in the Asian population since 5-HTTLRP long version is poorlyfound there.One third functional polymorphism isa single nucleotide polymorphism (SNP) affecting the promotor region A>G.One pharmacogenetics study using citalopram showed that having Lg genotype willrender the good responders L non-responders (Hu, et. Al 2007). This shows thecomplexity of this trialellic genotype.Secondly, we will discuss thepolymorphisms that could logically affect the treatment outcome ofantidepressants, serotonin receptors. There are seven types of serotoninergicreceptors.
5-HT-1A is implicated in the negative feedback due to its inhibitingeffect on presynaptic axons (Kushwaha & Albert 2005). The presence of anupstream SNP called rs6295 in the regulatory region of the gene was shown.Rs6295 increases the expression level of this receptor. Results for thisgenotype 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 similarin Caucasian and Asian patients (Reynolds, et al. 2013).
Another 5-HT receptor gene that wasstudied intensively is 5HTR2A. Antagonism of these receptors contributes to theantidepressant effect of second generation antidepressants. In earlypharmacogenetics studies polymorphisms in this gene were considered as animportant indicator for antipsychotic drugs. Nevertheless, recentinvestigations showed that their effects are not decisive (Reynolds, et al. 2013).However, variants such as rs6311, rs6313 and rs6314 were associated with someadverse drug effects such as gastrointestinal side effects and sexualdysfunction (Helton & Lohoff 2015). Moreover, another intronic SNPrs7997012 A>G resides in the sequence of this gene.
In a study performed on alarge sample called STAR*D, results showed that having the A allele gives 18%less chance of not obtaining beneficial treatment results from citalopram. The frequencyof this polymorphism is differential between Blacks and Caucasian, againemphasizing the importance of ethnic differences in pharmacogenetics studies (McMahonet al. 2006).Finaly, 5HT3A codes for another typeof serotonin receptor and is home for another polymorphism 178C>T in theupstream regulatory sequence. Once more in Asian patients with CC genotype respondedmore efficiently to antidepressants (Kato, et al 2006).Based on all the previous data, wecan see that we are far from understanding this complex network ofpolymorphisms governing the expression of 5-HTT and many serotonin receptors. Moreover,environmental differences, which affect the expression of many of theseproteins, and ethnic ones cause the blunting of the effects of polymorphisms,making pharmacogenetics studies in this field arduous.