Page 48 - Read Online

Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11 Page 143

biomarkers for CIA and clozapine’s response to propose a genetic screening for both a safe and efficacious
use of clozapine. However, the discussion of other clinically serious AEs is beyond the scope of this paper,
primarily due to inadequate genetic data and/or lower clinical significance than CIA. Similarly, the reviewed
studies investigating clozapine response include those with significant results. However, negative studies are
presented in the "DISCUSSION" Section.

METHODS
Literature search
A comprehensive literature search was performed for all currently available eligible studies until December
[37]
2022 using PRISMA guidelines . Separate searches were conducted on 18th January 2023 for CIA and
clozapine response using the key words: “clozapine” AND “agranulocytosis,” and “clozapine” AND
(“response” OR efficacy “outcome”) AND “schizophrenia”. Only peer-reviewed articles on human subjects
published in English were eligible. These searches were limited to the titles and abstracts of the papers,
which were reviewed against study eligibility criteria, which included studies that compared the frequency
of genetic polymorphism(s) associated with CIA from those that did not. Genetic studies investigating the
polymorphisms associated with the antipsychotic response to clozapine were also included. Lack of
information on clozapine dosing and treatment duration was not an exclusion criterion for efficacy studies
since some studies did not report this information. Case reports, case series, conference proceedings,
narratives, abstracts, systematic reviews, and meta-analyses were not included. Only studies with significant
positive findings were reviewed with or without Bonferroni corrections. Replicated findings were discussed
in more detail. The negative and the genome-wide association studies (GWAS) were not included in the
study tables for brevity and clarity but were reviewed under the "DISCUSSION" Section.

Data extraction process
Data items collected included the subjects’ ethnicity, the genetic variant(s) investigated, study subjects with
at least one genetic variant, and the cases and controls with no genetic variant(s). For CIA, these data
included ethnicity, haplotype, CIA with haplotype, CIA without haplotype, controls with haplotype, and
controls without haplotype, specificity, and sensitivity of the findings, odd ratio, and P-values. For the
clozapine response, the data included the genetic predictors, sample size, ethnicity, the clozapine dose and
treatment duration, assessment measures, and the significance of the results.

RESULTS
Clozapine-induced agranulocytosis
Out of 572 studies of CIA, 494 were excluded following the studies screened for titles and abstracts; out of
the remaining 57 studies, 21 met the selection criteria after removing duplicates, and studies with
insignificant findings left 12 studies for inclusion in the final review. The results of the literature search are
shown in the PRISMA flowchart [Figure 1].

All 12 studies reviewed were completed in various ethnic groups, including the Jewish population, non-
[38]
Jewish Europeans, and other populations , which can be seen in Table 1 below.
The first study investigating the CIA primarily focused onthe Jewish population . However, four studies
[39]
had Jewish as well as non-Jewish populations [40-43] . One study included participants with non-schizophrenia
diagnoses . Three GWAS studies were not included in the 12 formally reviewed studies but have been
[41]
discussed in the "DISCUSSION" Section [51-53] . However, these studies are briefly discussed in the
"DISCUSSION" Section.