Association of clozapine-related metabolic disturbances with CYP3A4 expression in patients with schizophrenia

Abstract

Clozapine is effective in treatment-resistant schizophrenia; however, adverse effects often result in discontinuation of clozapine therapy. Many of the side-effects are associated with pharmacokinetic variations; therefore, the expression of major clozapine-metabolizing enzymes (CYP1A2, CYP3A4) in patients may predict development of adverse effects. In patients with schizophrenia (N = 96), development of clozapine concentration-dependent metabolic side-effects was found to be associated with pharmacokinetic variability related to CYP3A4 but not to CYP1A2 expression. In low CYP3A4 expressers, significant correlation was detected between fasting glucose level and clozapine concentration; moreover, the incidence of abnormal glucose level was associated with exaggerated clozapine concentrations (> 600 ng/ml). In low CYP3A4 expressers, exaggerated concentrations were more frequently observed than in normal/high expressers. Moderate/high risk obesity (BMI ≥ 35) more frequently occurred in low CYP3A4 expresser patients than in normal/high expressers. In patients with normal/high CYP3A4 expression and consequently with extensive clozapine-metabolizing capacity, norclozapine/clozapine ratio correlated with fasting glucose levels, triglyceride concentrations and BMI. Low CYP3A4 expression often resulting in exaggerated clozapine concentrations was considered to be as an important risk factor for some concentration-dependent adverse effects as normal/high CYP3A4 expression evoking high norclozapine/clozapine ratios. CYP3A4-status can identify patients with increased risk for metabolic side-effects and prevent their development by careful therapeutic strategy.

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

“…However, olanzapine is mostly metabolized by CYP1A2 (and to a lesser extent by CYP2D6 and CYP3A4) [88,89], clozapine is mainly metabolized by CYP3A4 and CYP1A2 (with CYP2D6 playing a minor role) [16,90], and loxapine is primarily metabolized by CYP1A2 (then by CYP3A4 and CYP2D6) [19]. Despite the fact that Menus et al [61] found no association between CYP1A2 expression and any ADR, some variants have been formerly linked to tardive dyskinesia [91,92] and to an increased risk of insulin and lipid elevation [93].…”

“…In the study of Menus et al [61], exaggerated clozapine concentrations (>600 ng/mL) were more frequently noted in low CYP3A4 expressers (22%) than in normal/high expressers (2.7%) (low vs. normal/high expressers: OR = 9.8 (95% CI 1.8-55.0), p = 0.009). They also noted an association between norclozapine formation and CYP3A4 expression (0.56 ± 0.17 vs. 0.98 ± 0.62, p < 0.0001).…”

“…Likewise, Thümmler et al [3] reported the case of a CYP2D6 *4/*41 (poor metabolizer-PM) 14-year-old female who showed weight gain and binge-eating behaviors when treated with clozapine and loxapine. According to the findings of Menus et al [61], a moderate/high risk of obesity in patients treated with clozapine was significantly more frequent in low CYP3A4 expressers (13.6% of CYP3A4 low expressers, 1.5% of CYP3A4 normal/high expressers, OR = 13.5 (95% CI 1.2-147.9), n = 87, p = 0.045). However, there was no association between CYP1A2 or CYP3A4 expression and blood glucose or lipid levels (p > 0.1).…”

“…Therefore, this issue has been corrected by the adjunction of fluvoxamine, a potent CYP1A2 inhibitor. Menus et al [61] demonstrated a contribution of CYP1A2 to norclozapine production (0.86 ± 0.55 vs. 1.17 ± 0.70, p = 0.0007). Yet, no association was found between CYP1A2 expression and blood glucose, TG, or cholesterol (total, HDL, and LDL) levels in patients (p > 0.1).…”

“…In patients treated with atypical APs, Grădinaru et al [77] found that the mean level of prolactin was higher for IMs than for extensive (normal) metabolizers (EMs) at each time point except baseline. Menus et al [61] noted a significant effect of CYP3A4 expression on constipation (47.1% in normal/high CYP3A4 expressers, 71.4% in low CYP3A4 expressers, OR = 3.6 (95% CI = 0.9-14.1), p = 0.06). Ivashschenko et al [73] found a significantly more frequent increased dream activity in CYP2D6 IMs compared to EMs (54 vs. 22%, p = 0.043).…”