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Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11 Page 155

Dopamine-associated genes
Dopamine is the primary neurotransmitter system mediating the antipsychotic efficacy of all antipsychotic
medications. Therefore, several studies have replicated findings from studies that examined the relationship
between clozapine efficacy and genetic variance in various dopamine receptors genes, such as DRD1 [68,69] ,
DRD2 [62-65] , and DRD3 [59-61] , and DRD4 [66,142] .

The first study investigating DRD1 found a positive clozapine response in individuals with rs4532 2/2 and a
diminished response in those with rs4532 1/2 after five weeks of clozapine treatment . The second study
[69]
reported novel findings showing clozapine nonresponse with SNP, rs265976 A/C and haplotype T-G-A
(rs265981, rs4532, rs686) in African Americans but a better response with haplotype T-G-G haplotype in
[68]
Caucasians after at least six months of clozapine treatment . However, the findings from the later study
[68]
may carry more weight due to the larger sample size of 232 and more extended clozapine treatment than the
first study [Table 2].

The first study investigating the DRD2 genes reported a significant correlation between 141C Ins/Del and a
10-week clozapine efficacy with a fivefold improvement in psychosis in Del- carriers as compared to Del+
[65]
carriers . The second study reported 3 DRD2 SNPs (Taq1A, Taq1B, and rs1125394) as predictors of
clozapine response after at least six months of clozapine treatment in African Americans . The same group
[64]
replicated findings with 2 SNPs (Taq1B and rs1125394) in a smaller sample of African American patients .
[63]
A comprehensive metanalysis has supported the relationship between the allelic variance in D2 -141C Del
[143]
and TaqIA2 and response from antipsychotics, including clozapine . But a recent meta-analysis reported a
[144]
lack of relationship between 141C Ins/Del and clozapine response . Allelic variants, D2 -141C Del and
TaqIA2, have also been correlated with inadequate clozapine response with other antipsychotic medications
across various ethnic groups [145-148] . Thus, various genetic polymorphisms in DRD2 have been the most
replicated findings with the clozapine response in the dopamine system. At the same time, some studies
have also found genetic variance in the promotor areas of DRD2, DRD3, and DRD4 associated with
antipsychotic efficacy [149,150] .

Regarding the DRD3 gene, the first study found a higher frequency of the genotype Ser-9/Ser-9 (rs6280) in
patients who responded to at least three months of clozapine treatment versus those who did not . The
[59]
[60]
second study in the Pakistani sample replicated these findings in a smaller sample . However, a meta-
[144]
analysis failed to find any relationship between clozapine efficacy and Ser-9-Gly . In the second study ,
[61]
at least six months of clozapine treatment was significantly associated with clozapine response to the
positive symptoms with the DRD3 polymorphism in A allele (i.e., rs2134655) in Caucasians (N = 183) and
the clozapine response to the negative symptoms with the DRD3 polymorphism in T allele (i.e., rs1394016)
[61]
in African Americans (N = 49) .

Although multiple studies have examined the DRD4 gene [149,150] , only two reported variances in DRD4
associated with clozapine efficacy [66,142] . The first study reported that the frequencies of 5 alleles and 5/5
genotype in the variant number tandem repeat of the DRD4 48 bp were higher among the clozapine
nonresponders than the responders after two weeks of clozapine treatment . The second study in African
[142]
Americans documented a significant correlation between 120-bp and intron I 142/140 bp genotype and lack
of clozapine efficacy after six months of clozapine treatment and a significant positive relationship between
48 bp repeat and clozapine efficacy in a Caucasian sample (N = 183) . However, genetic variance in DRD5
[66]
was not correlated with clozapine efficacy .
[66]