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Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11 Page 157

[76]
rs1062613 was associated with clozapine response after > 6 months of treatment . The second study
reported an association between the T allele of HTR3A rs106263 and the G allele of HTR3A rs2276302 with
[77]
the clozapine response after patients were stable on clozapine dose for at least three months . A meta-
analysis has also reported a correlation between the T allele of rs1062613 and an improved clozapine
efficacy . However, not all studies have reported a significant relationship between clozapine response and
[144]
genetic variance in HTR3B and 5HTR5 [76,81,163,164] .

With regards to 5HTR1A, one study, primarily designed to examine the interaction between COMT and
HTR1A genes, reported a significant association between 5HTR1A 1019C/G (rs6295) polymorphism and
clozapine response for 8 and 16 weeks of treatment with a more significant improvement in subjects with
[83]
the G homozygosity as compared to the C homozygosity . However, HTR1A polymorphism, 5-HT1A-
1019 G, was associated with lower efficacy with other second-generation antipsychotic medications in
various ethnic groups [165-167] .

Some studies have also examined the correlation between clozapine response and the HTR6 gene [58,79,168] ;
however, only one of these studies found any significant correlation between a genetic variance in HRT6
and clozapine efficacy . This study demonstrated that the C267T polymorphism in the HTR6 gene was
[79]
more frequent in clozapine responders than in nonresponders after at least two months of clozapine
treatment. One of the negative studies with the effects of the HRT6 variant also reported no effects of HTR7
pro279leu polymorphism on the clozapine response .
[168]

Another pharmacodynamic genetic factor studied in the serotonin system is the SLC6A4, which is the gene
for the serotonin transporter protein [78,81,169,170] . One of these studies reported a significant relationship
between the short allele of HTTLPR/rs25531) in the promoter area of the SLC6A4 and the clozapine
[78]
response in a Caucasian sample . However, while examining gene-gene interactions, another study
reported only a trend between a genetic variance in SLC6A4 and clozapine efficacy in a larger sample than
[171]
the earlier study . In addition, a few studies have also produced negative findings [172,173] .

Although multiple other reports have also documented a relationship between specific PD genetic markers
and antipsychotic efficacy, most findings are generally without replication raising questions about the
clinical utility. In addition, a few studies have also produced negative results for various serotonin
targets [149,150] . Nevertheless, the overall data support the critical role of the serotonin system in clozapine’s
efficacy, which requires replication in future large-sample genetic studies.

Combinatorial genetic assays examining the interplay between multiple candidate genes have also assessed
clozapine efficacy. Four studies with significant findings were reviewed in the paper [81-84] . The first study
reported a combinatorial analysis of different polymorphisms, offering one of the most robust predictors of
clozapine response . In this study, six different polymorphisms showing the strongest association with
[81]
clozapine efficacy included 5-HT2A 102-T/C, 5HT2A His452Tyr, 5-HT2C 330-GT/244-CT, 5HT2C
Cys23Ser, 5-HTTLPR H2-1018-G/A. This combinatorial analysis provided a positive predictability of 76%
and a negative predictability of 82%, along with a sensitivity of about 96% and a specificity of 38%. However,
another study did not replicate these findings . The second study reported the most substantial effect of
[169]
gene-gene drug interactions between DRD1 rs686 and DRD3 Ser9Gly on clozapine efficacy for a minimum
of six months in Caucasian subjects . The third combinatorial study demonstrated an additive effect of
[82]
COMT Val158Met and HTR1A-1019 C/G on the clozapine treatment response when taken for 8 and 16
weeks . Similarly, the final study documented a significant effect of a gene interaction between DRD4
[83]
[84]
120-bp duplication and COMT Val158Met on clozapine efficacy when taken for not less than three