Letter to the Editor: Rapid Clozapine Concentration Increase Following Augmentation with Low-Dose Fluvoxamine in 12-Year-Old with Childhood Onset Schizophrenia

To the Editor:

We discuss a case utilizing fluvoxamine to increase the clozapine plasma concentration in a child with treatment-refractory psychosis. This treatment occurred while he was admitted to an inpatient psychiatric unit at a state psychiatric hospital.

Clozapine requires individualized dosing to obtain a therapeutic serum concentration due to the large variability of clozapine clearance among patients. Its metabolism is primarily through the liver, especially through the CYP1A2 pathway (Jerling et al. 1997). Fluvoxamine is shown to be a major inhibitor of the CYP1A2 enzyme and can potentially increase clozapine concentrations after only one adjunctive dose (Wetzel et al. 1998). It is recommended to obtain a clozapine plasma concentration after at least 10 days on a stable fluvoxamine dose (Polcwiartek and Nielsen 2016), when both medications have reached a steady state. Plasma clozapine concentration of >350 ng/mL is linked to greater therapeutic response in adults (Perry et al. 1991). As there is currently no accepted concentration for children, we used this as our goal.

In this case, we discuss a 12-year-old male with autism spectrum disorder who later developed psychotic symptoms at age 11. Symptoms included auditory and visual hallucinations, paranoia, agitation, and Capgras delusions. As an outpatient, he trialed risperidone and haloperidol without significant clinical gains. Medical workup for psychosis was unrevealing, including chromosomal microarray and autoimmune encephalitis assessment. He did not have a history of tobacco or substance use, notable dietary changes or regimen, nor regular caffeine consumption during this treatment period. In the hospital, he was prescribed olanzapine titrated to 20 mg daily without improvement of psychosis. Given multiple failed trials and persistent impairment, clozapine was titrated over several months to a dose of 525 mg total daily without significant clinical benefit. The clozapine serum concentration on 525 mg was subthreshold at 199 ng/mL and a norclozapine concentration of 178 ng/mL. Instead of continuing to titrate the clozapine dose to attain a concentration >350 ng/mL, fluvoxamine was initiated at 12.5 mg at bedtime. The clozapine concentration drawn 4 days later demonstrated a significant increase in his concentration to 435 ng/mL and norclozapine 161 ng/mL. Fluvoxamine was increased to 25 mg total on day 4 (before the concentration receipt) toward the 25 mg daily initial dose as recommended in adults (Polcwiartek and Nielsen 2016) but was discontinued after 2 days due to increased sedation, which then improved. The patient presented again with significant sedation on day 11 without other medication changes. Clozapine concentration on day 12 was 548 ng/mL, and norclozapine concentration was 323 ng/mL. The weekly absolute neutrophil counts ranged from 2.10 to 4.18 K/mm³. He remained afebrile during this period (see Fig. 1).

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FIG. 1.

Clozapine, norclozapine, and total clozapine concentration variation within time and the influence of clozapine TDD and fluvoxamine TDD. Day 0 corresponds to the initiation of fluvoxamine. The X-axis (days) is out of proportion. TDD, total daily dose; total clozapine, clozapine+norclozapine.

Our data demonstrate a significant interaction between the fluvoxamine and clozapine with a rapid onset (within 4 days). A very small dose (12.5 mg) precipitated this change. Increasing to 25 mg resulted in significant sedation. As the clozapine concentration increased, this patient experienced sedation, constipation, vomiting, enuresis, and orthostatic hypotension (possibly led to a fall).

This case suggests that there should perhaps be earlier consideration of fluvoxamine augmentation to reduce the total dose required of clozapine and the goal of attaining a concentration >350 ng/mL. Low-dose fluvoxamine may be effective and more tolerable for youth. It may be prudent to obtain a clozapine concentration much earlier, especially if adverse effects are exhibited.