Clinical Use of Clozapine Serum Level and Management of Adverse Effects in an Adolescent with Difficult to Treat Schizophrenia

A Systematic Review of Clozapine Concentration–Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders

“…Only 2 studies 60,61 provided limits of quantification or detection, and the stability was measured using the coefficient of variation. Three studies measured plasma concentrations 61–63 and 4 studies 7,58–60 measured serum concentrations.…”

“…The possible effects of valproate, which may be both a mild inducer and mild inhibitor, were ignored. Bez et al, 59 stated that the patient was taking 4 mg/d of drospirenone, a progesterone derivative. The limited available data suggest that although estrogens can inhibit clozapine metabolism, progesterone derivatives do not inhibit clozapine metabolism.…”

“…Figure 1 shows our method for identifying 37 potential articles and the subsequent exclusion of 30 articles, yielding 7 articles describing 7 studies. 7,[58][59][60][61][62][63] Seven other studies were excluded because we could not verify whether the concentrations were taken during trough and steady-state conditions.…”

“…Fluvoxamine, an extremely potent inhibitor of clozapine metabolism, was discussed in 1 60 of the 7 studies, which probably contributed to significant increases in the clozapine C/D ratio in patients who took it. Therefore, patients taking fluvoxamine should be excluded from the calculation of the mean C/D ratio in 61 Bez et al 59 Jiménez-Fernández et al 63 Kumra et al 7 Piscitelli et al 62 Schulz et al 58 Wohkittel et al 60 Item *Only potent inducers, such as carbamazepine, phenytoin, and phenobarbital, were considered. Only potent inhibitors, such as fluvoxamine or ciprofloxacin, were considered.…”

“…The clozapine C/D ratio was extremely high at 2.54 ng/ mL per mg/d in an Asian American female adolescent with borderline obesity. 59 The patient with ID 63 received a low dose of clozapine (mean dose = 102 mg/d) and had a mean clozapine concentration of 55 ng/mL, which is low for reaching linear pharmacokinetics and providing an accurate estimation of the minimum therapeutic dose for clozapine. 42 To calculate weighted mean clozapine C/D ratios in patients with psychotic disorders, we excluded the case diagnosed with ID 63 and 2 of the samples that were severely confounded by fluvoxamine cotreatment, 60 a potent inhibitor that likely phenoconverts the patient into a clozapine PM and border-line obesity.…”