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Page 158 Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11

[84]
months . Combinatorial analysis of two candidate genes, COMT rs6269 and HTR2C rs3813929, in a large
[174]
sample of 995 subjects also predicted antipsychotic response, including clozapine .
Finally, few GWAS have found a relationship between specific polymorphisms and antipsychotic efficacy,
such as sharing genetic variance linked to antipsychotic response and risk for schizophrenia in two
GWAS [88,175] . One GWAS consortium study in Caucasians observed an association between homozygosity
for the minor A-allele of rs2535629 in the inter-alpha-trypsin inhibitor heavy chain H3 gene and
improvement in negative symptoms of schizophrenia but not in the total BPRS scores after 6 month
treatment with clozapine . Another genome-wide consortium study found a significant correlation
[87]
between DRD2 SNP rs2514218 and clinical response to clozapine after six months of clozapine therapy .
[62]
Overall, significantly more research is warranted before pharmacogenetics can be cost-effective in
psychiatric patients. Nevertheless, available commercial genetic assays may still help improve patient
outcomes in treatment-refractory populations to decrease healthcare costs and enhance medication
adherence . In addition, pharmacogenetic testing with psychotropic medications is becoming less
[176]
expensive and increasingly covered by major insurance companies. This could explain a steady increase in
genetic testing, particularly in the treatment-refractory population [177,178] .

In conclusion, Adding genetic screening for CIA to clozapine response has a greater potential than either of
the two to identify the most appropriate patients for clozapine treatment without exposing potential
clozapine nonresponders to bone marrow toxicity. Despite growing evidence for the genetic basis of CIA
and clozapine response, genetic testing is not ready for prime time. More research is warranted on large
samples of diverse populations to develop more sensitive and precise genetic predictors of CIA and
clozapine response. However, most research in this area has focused on a candidate gene approach in small
ethnic groups not powered to detect relatively rare genetic predictors across various ethnic groups.
Although a few studies have attempted to employ combinatorial analyses to add more significance to the
findings from candidate gene studies, there is a need to continue the paradigm shift from the candidate
genes to the genome-wide approach. Genome-wide studies provide the first logical step to generate novel
hypotheses that can be later confirmed in a more targeted candidate gene approach to improving the
predictability of genetic biomarkers for CIA and clozapine response.

DECLARATIONS
Authors’ contributions
The author contributed solely to the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The author declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.