Interest of Fluvoxamine as an Add-On to Clozapine in Children With Severe Psychiatric Disorder According to CYP Polymorphisms: Experience From a Case Series

Abstract

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.

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

“…In the study of Berel et al [11], the third patient was found to display a CYP2C9*1/*3 heterozygous genotype. Leading to a CYP2C9 IM phenotype, it could partly explain the low clozapine plasma levels.…”

“…In the case series of Berel et al [11], the second patient presented a CYP2D6 IM phenotype and a CYP3A5 *1/*1 polymorphism, and these profiles could have contributed to previous high aripiprazole and low haloperidol plasma levels.…”

“…Berel et al [11] reported in their case series two 11-year-old patients with low clozapine plasma levels, which were found to be CYP1A2 UM (CYP1A2*1F/*1F and CYP1A2*1/*1F, respectively). Therefore, this issue has been corrected by the adjunction of fluvoxamine, a potent CYP1A2 inhibitor.…”

“…Berel et al [11] reported four cases of children (1: CYP1A2 *1F/*1F (UM), 2: CYP2D6 *1/*41 (IM) CYP3A5 *1/*1, 3: CYP2C9 *1/*3 (IM), 4: CYP1A2 *1/*1F (UM)) presenting with behavioral disorders of various causes. In all these cases, low clozapine plasma levels led to a lack of therapeutic effect, corrected with fluvoxamine (CYP1A2 inhibitor) addition.…”

“…Major interindividual differences in their expression arise from genetic polymorphisms, leading to various metabolizing phenotypes [10] that determine the CYPs' level of activity. Furthermore, alterations in their activity by extrinsic inducers or inhibitors, can imbalance a previously well-tolerated treatment; conversely, it can potentiate a given medication [11]. As CYP metabolize most APs [12], some studies addressed the potential consequences of CYP2D6 polymorphisms in children and youth treated with antipsychotics [13].…”