Clozapine Therapy and Genotype

Clozapine is one of the most effective antipsychotics available in the treatment of schizophrenia and the only antipsychotic found to be effective in treatment-resistant schizophrenia (TRS). Clozapine is also used to reduce the risk of recurrent suicidal behavior in individuals with schizophrenia or schizoaffective disorder (1, 2). Compared with typical antipsychotics, clozapine is far less likely to cause movement disorders, known as extrapyramidal side effects, which include dystonia, akathisia, parkinsonism, and tardive dyskinesia. However, there are significant risks associated with clozapine therapy that limits its use to only the most severely ill individuals who have not responded adequately to standard drug therapy. Most notably, because of the risk of clozapine-induced agranulocytosis, clozapine treatment requires monitoring of white blood cell counts (WBC) and absolute neutrophil counts (ANC), and in the US, the FDA requires that individuals receiving clozapine be enrolled in a computer-based registry (3). There is also a propensity for clozapine use to induce metabolic effects, resulting in substantial weight gain (1). Clozapine is metabolized in the liver by the cytochrome P450 (CYP450) superfamily of enzymes. The CYP1A2 enzyme is the main CYP enzyme involved in clozapine metabolism, and CYP1A2 activity is a potential determinant of clozapine dose requirements (4). Other CYP enzymes involved in clozapine metabolism include CYP2D6, CYP3A4, and CYP2C19 (5). The FDA-approved drug label states that a subset of the population (2–10%) have reduced activity of CYP2D6 (“poor metabolizers” [PMs]) and these individuals may develop higher than expected plasma concentrations of clozapine with typical standard doses. Therefore, the FDA states that a dose reduction may be necessary in individuals who are CYP2D6 PMs (Table 1) (1). However, the Dutch Pharmacogenetics Working Group (DPWG, Table 2) does not recommend dose alterations based on genotype, though the gene-drug interaction is acknowledged (6). The DPWG further states that there is not a gene-drug interaction between and clozapine due to the limited effect of known genetic variants on CYP1A2 function (6). Consequently, neither the FDA nor the DPWG recommend dose alterations based on genotype. Additionally, clozapine clearance is affected by gender, tobacco use, and ethnicity, with further contributions from pharmacologic interactions. Females have lower CYP1A2 enzyme activity than males. Non-smokers have lower CYP1A2 activity than smokers and Asians and Amerindians have lower activity than Caucasians. Clozapine clearance can also be affected by co-medications that induce or inhibit CYP1A2 and the presence of inflammation or obesity (7, 8).