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Page 142 Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11

Keywords: Pharmacogenomic, screening, clozapine, efficacy, agranulocytosis

INTRODUCTION
Schizophrenia is one of the most complex brain disorders that affects 24 million people worldwide . One
[1]
out of every three patients is diagnosed with treatment-resistant schizophrenia (TRS), which is an
inadequate response to two different antipsychotic medications (APMs) despite adequate dose and
[3]
duration . Clozapine is the only APM with evidence-based efficacy in managing patients with TRS .
[2]
Clozapine treatment is cost-effective by reducing rehospitalizations , suicidality , substance use relapse,
[5,6]
[4]
and improving life quality in the treatment-refractory population . Despite these benefits, clozapine is still
[7]
underprescribed [8-11] , with an average delay of 5 years in initiating clozapine in treatment-refractory
patients . There is also a myth that patients do not like using clozapine, resulting in less emphasis on
[8]
inquiring about patients’ experiences with clozapine . However, when asked, patients report more positive
[12]
experiences [13-15] and fewer concerns with clozapine than perceived by clinicians .
[16]
Although underutilization and delayed clozapine use may be due to its serious adverse effects (AEs) of
myocarditis and metabolic syndrome , the most limiting AE has been the clozapine-induced
[17]
[18]
[19]
agranulocytosis (CIA) . Agranulocytosis is an absolute neutrophil count (ANC) that is < 500 cells/mm
with severe and potentially fatal neutropenia with a fatality rate of 0.05% and can be a common cause of a
[20]
lethal outcome, particularly after pneumonia . Historically, clozapine was available in Europe for about 30
[21]
years before its approval in the United States due to several reports of CIA from Europe. However,
clozapine remained available for European psychiatrists if they requested it due to its unique efficacy. Other
barriers to prescribing clozapine include a relative lack of training for the mental healthcare providers to
safely and effectively use clozapine [22,23] and mandatory blood testing to monitor CIA requiring
[24]
registration with the Risk Evaluation and Mitigation Strategy (REMS) [25,26] . However, regular blood testing in
clozapine patients has been challenged for not being cost-effective in the longer run due to the majority of
clozapine patients having CIA between four to five months of clozapine initiation, with the incidence of
CIA decreasing from 1.3% to 0.07% after one year with less than one day increase in quality-adjusted
[27]
survival per patient . This finding was replicated in another study during the first year of clozapine
[28]
[29]
treatment . Additionally, this level of mandatory monitoring may delay the clozapine treatment when
some evidence suggests that the earlier the treatment with clozapine, the better the response [30-32] . Therefore,
researchers have investigated predictive genetic biomarkers for CIA to identify patients less susceptible to
developing CIA, requiring less frequent or no blood monitoring over time. At the same time, those at high
risk for CIA may still undergo the current level of white blood cell monitoring (WBC) or be provided
alternate treatments .
[33]

Although the main current focus is on finding genetic predictors for CIA, it is equally, if not more,
important to discuss the genetic biomarkers for clozapine response. Similar to the AEs, the clozapine
response is also variable and unpredictable, with a short-term response of 32% and a long-term response of
39% in a large number of patients with TRS (40%-70%) remaining treatment-resistant [35,36] . Therefore, a
[34]
patient with a genetic risk for agranulocytosis and clozapine nonresponse may be unnecessarily exposed to a
clozapine trial with potential toxicity. Determination of clozapine response is also warranted as clozapine is
the only APM, as opposed to other APMs, that is selected for its superior efficacy in treatment-refractory
patients. While the research to determine clinical predictors of CIA is underway, many studies have also
investigated genetic biomarkers for clozapine’s efficacy. Once genetic predictors with high sensitivity and
specificity are developed, genetic testing for clozapine response may be utilized as a screening test to assess
if it is worth exposing a high-risk patient to CIA. This review assesses currently available data on genetic