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Page 156 Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11

Genetic polymorphisms in other dopamine-related genes were also investigated, such as genetic variance in
[151]
the enzyme, Catechol-O-methyltransferase (COMT), which metabolizes dopamine , and the dopamine
transporter/reuptake pump gene (i.e., SLC6A3). For example, the first study with COMT Val108/158Met
polymorphism (rs4680) found a more significant improvement in attention and verbal fluency domains in
patients with hetero- or homozygosity for the Met allele than the Val/Val group after clozapine
[70]
[152]
treatment . These findings were also supported by a meta-analysis , which showed that patients with met
homozygosity were more likely to respond to antipsychotic treatment. A couple of other studies have also
correlated genetic variance in COMT with antipsychotic efficacy [153,154] .
The study investigating the dopamine transporter gene (SLC6A3) reported that the 71T allele of rs2975226
(T-71A) occurred more frequently in the clozapine responders than the nonresponders after 8-weeks of
[155]
clozapine treatment . However, another study failed to replicate this finding with SLC6A3 .
[71]
Serotonin-associated genes
Several studies have examined clozapine response to genetic variance in serotonin receptors, such as the
serotonin receptor 2A (HTR2A), the serotonin receptor 2C (HTR2C), and the serotonin receptor 6
(HTR6 . However, the HTR2A gene is one of the most investigated genes concerning clozapine response,
[156]
and several studies have produced positive findings [149,150] . Two of these studies replicated better clozapine
response with the HT2RA T102C variant [75,86] . The HTR2A 102-T/C variance was confirmed by a meta-
analysis . In addition, a review reported correlations between HTR2A variants 102-C, -1438-G, and
[157]
[134]
Tyr452 and clozapine response . Another study reported reduced antipsychotic response with the HRT2A
102-C/C genotype in Caucasian patients . This finding is consistent with a more frequent occurrence of
[158]
homozygosity for the C102 allele in clozapine nonresponders compared to the responders . At the same
[75]
time, another meta-analysis reported a better clozapine response in patients with the C allele hetero- or
homozygosity than the T allele or TT genotype . This finding is consistent with a higher N100 amplitude
[144]
in Chinese patients with 102C/C genotypes that reduced significantly after clozapine treatment suggesting
improved sensory processing . One reviewed study was primarily designed for a combinatorial analysis to
[86]
[81]
examine the interaction between HRT2A and other serotonin-associated genes, HRT2C and SCL6A4 .
The next study reported a more frequent occurrence of the Tyr452 (rs6314) allele of the HTR2A gene in
clozapine nonresponders than in responders . This result with Tyr452 (rs6314) allele was reproduced in
[72]
subjects who received at least 6-month treatment with clozapine . The following study reported a positive
[74]
association between CLZ response and the G-1438/A-1438 genotype and G-1438/A allele of the HTR2A
gene and a negative association with homozygosity for the G-1438A (rs6311) allele . However, a meta-
[159]
analysis did not find an association between the G-1438A polymorphism and clozapine efficacy . While
[144]
other studies associated the HTR2A 1438-A/A genotype with treatment resistance for negative symptoms in
a French study and 5-HT2A -1438-G allele with psychotic relapse in an Algerian study . The
[161]
[160]
combination of potent 5H2A and D4 effects is one of the mechanisms for unique clozapine’s efficacy [156,162] .

Variance in HTR2C receptors has been documented in multiple studies [149,150] . However, the first two
observed a positive association between the 5HTR2C Cys23Ser and clozapine efficacy after > three months
[144]
[80]
of clozapine treatment . But a meta-analysis did not support this finding in a Caucasian sample . The
second study replicating earlier results was designed to primarily investigate gene-gene interactions between
three polymorphisms, Ser allele of Cys23Ser (rs6318) in the HTR2C, HRT2A, and SLC6A4 gene to predict
clozapine response .
[81]

Genetic polymorphisms in the HTR3A gene have also been researched in multiple studies [149,150] , but only
two studies produced significant findings [76,77] . The first study demonstrated that the T allele of HTR3A