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Page 154 Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11

[Table 1]; some replicated polymorphisms may provide reliable genetic predictors for CIA, such as HLA-
B38, HLA-DBQ1, HLA-DRB1, and HLA_DQA1.

Finally, it is worth mentioning that in patients who developed CIA or granulocytopenia, adjunctive therapy
with a single dose of granulocyte stimulating factor (GSF) reduced the risk for blood toxicity during a
clozapine rechallenge [130-132] . This adjunctive strategy may be investigated to see if GSF can be used
prophylactically during the early weeks of clozapine treatment in vulnerable patients with high genetic risk
for bone marrow toxicity. Another option is lithium, which has also been used successfully to induce
[133]
leukocytosis in patients who develop neutropenia with clozapine treatment .
Genetic predictors of clozapine efficacy
Pharmacogenetic studies of clozapine response have focused on pharmacokinetic (PK) genetic factors
primarily involving genetic variance in the CYP enzymes mediating clozapine’s metabolism) and the
pharmacodynamic (PD) genetic factors affecting primary neurotransmitter systems targeted by clozapine,
mainly dopamine and serotonin.

Pharmacokinetic genetic factors for clozapine’s efficacy
Any genetic variance in the CYP (cytochrome-P450) enzymes involved in the metabolism of antipsychotic
medications may affect their efficacy and/or tolerability . In this context, the most observed clinical
[134]
finding is a genetically mediated increase in drug levels resulting in increased adverse effects with no
apparent correlation with efficacy. Therefore, most data on PK genetic biomarkers represent adverse effects
and not effectiveness. The only exception is clozapine due to an evidence-based relationship between
clozapine levels and its efficacy . Thus, therapeutic drug monitoring (TDM) is recommended to optimize
[135]
clozapine treatment, particularly in difficult-to-treat patients with inadequate or no clozapine response or
those with unusual or intolerable adverse effects on conventional clozapine doses [135,136] . Clozapine
metabolism involves several CYP enzymes, particularly CYP1A2, providing the main metabolic pathway for
converting clozapine to its primary biologically active metabolite, norclozapine . Although inhibition of
[137]
CYP1A2 in drug interactions has been associated with an increase in adverse effects, patients with highly
inducible CYP1A2, as observed in smokers, may compromise clozapine efficacy by lowering its plasma
levels . Although one study did not , three other studies reported a significant correlation between the
[138]
[139]
lack of clozapine response and the ultrarapid activity of CYP1A2 [54-56] . This is one of the most consistent
pharmacokinetic findings associated with clozapine response. However, unlike CYP1A2, the ultra-rapid
[57]
activity of CYP2C19 was reported to be associated with an improvement in clozapine response . In
addition, genetic variance in the p-glycoprotein transporter gene (ABCB1) has been correlated with the
effectiveness of clozapine in a couple of studies [58,140] and another antipsychotic medication, risperidone, in
one study .
[141]

Pharmacodynamic genetic factors for clozapine efficacy
The findings from genetic studies investigating genetic variance in pharmacodynamic (PD) genetic factors,
such as transporters, neuropeptides, and receptors, have been inconsistent, perhaps due to inadequate study
samples failing to capture relatively rare polymorphisms. Genome-wide association Studies (GWAS)
provide an effective alternative to investigate relatively rare genetic polymorphisms affecting clozapine
response, but these studies require large sample sizes and can be enormously expensive, explaining their
scarcity in psychiatry. Therefore, the following paragraphs review significant findings from studies using the
candidate gene approach investigating the relationship between major neurotransmitter systems and
clozapine response [Table 2].