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

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.

Descriptors of Cytochrome Inhibitors and Useful Machine Learning Based Methods for the Design of Safer Drugs

Roughly 2.8% of annual hospitalizations are a result of adverse drug interactions in the United States, representing more than 245,000 hospitalizations. Drug–drug interactions commonly arise from major cytochrome P450 (CYP) inhibition. Various approaches are routinely employed in order to reduce the incidence of adverse interactions, such as altering drug dosing schemes and/or minimizing the number of drugs prescribed; however, often, a reduction in the number of medications cannot be achieved without impacting therapeutic outcomes. Nearly 80% of drugs fail in development due to pharmacokinetic issues, outlining the importance of examining cytochrome interactions during preclinical drug design. In this review, we examined the physiochemical and structural properties of small molecule inhibitors of CYPs 3A4, 2D6, 2C19, 2C9, and 1A2. Although CYP inhibitors tend to have distinct physiochemical properties and structural features, these descriptors alone are insufficient to predict major cytochrome inhibition probability and affinity. Machine learning based in silico approaches may be employed as a more robust and accurate way of predicting CYP inhibition. These various approaches are highlighted in the review.

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

BackgroundDespite 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 CYPs polymorphisms in youth, the use of fluvoxamine as add on to clozapine could help reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile, as it has already been described in adults.Case ReportWe report four pediatric cases with severe psychiatric disorders underlying our experience with CYPs 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 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 drugs interactions when fluvoxamine is considered. Hence, we propose a detailed step by step multidisciplinary protocol.ConlusionThe results pointed out the positive clinical effects of fluvoxamine as add-on to clozapine in youth with severe neurodevelopmental disorders but stresses the need for caution regarding drugs interactions.