B is a 9-year-old African boy who was born at term after a normal pregnancy. He was placed in foster care at the age of 3 years old due to severe physical and psychological violence within the family and severe neglected care. He barely had contact with his mother and his father. His family background is marked with a psychotic disorder in one first-degree relative. He quickly presented a delay in language and motor skills. An ear, nose, and throat (ENT) exploration and audiometry were performed at the age of 4 years old without any abnormalities. He did not receive speech therapy or psychomotor therapy. His academic performances were severely impaired due to his global and severe neurodevelopmental delay. School was quickly impossible and interrupted due to repetitive admission in psychiatry for tantrums and severe outbursts. Around the age of 8 years old, B presented an increase of behavioral disorders occurring at school and at home, leading to several hospitalizations for severe outbursts, self-harm, and aggressive behaviors. At the same time, he reported a progressive onset of visual and auditory hallucinations. Risperidone was initiated at 2 mg/day but without any efficacy.
At the admission in our unit, B presented delusional ideas, hallucinations, and mental automatism. He exhibited a disorganized and dissociative motor behavior, disorganized processes of thinking with speech disorder, and cognitive impairment. A clinical examination did not find any abnormality, and the result of a standard blood workup (CBC and liver and kidney function) was normal. After an extensive screening panel (see Supplementary Figure 2 for details of the screening panel), no organic cause was retrieved, and the diagnosis of EOS was retained. Aripiprazole was introduced at 15 mg/day and associated with levomepromazine at 15 mg/day. However, the patient's tolerance was questioned with a severe sedation and a worsening of delusions and hallucinations. The aripiprazole plasma level showed an overdose at 835 ng/mL (therapeutic reference range: 150-500 ng/mL) regardless of the proper dosage-weight ratio. Aripiprazole was then switched to haloperidol gradually at up to 1.5 mg/day. There was no improvement regarding positive symptoms. The haloperidol and levomepromazine plasma levels showed an underdose, respectively, at 1.1 and 5 ng/mL. After excluding all known food or drug interactions, a heterogenous genotype CYP metabolism was suspected. Pharmacogenetic testing for cytochromes was performed, and it identified CYP2D6*1/*10 and CYP2D6*1/*41 heterozygous genotypes and a CYP3A5*1/*1 homozygous genotype (see Table 1). These genotypes are associated with a partial deficiency in CYP2D6 activity and an ultra-rapid metabolizer phenotype CYP3A5, respectively. Therefore, these genotypes are genetic explanations of the high aripiprazole plasma level and low haloperidol plasma level. Given the resistance to two atypical antipsychotics and one typical antipsychotic and the severity and the burden of the psychotic features, the off-label use of clozapine was legitimate. However, during a progressive increase of clozapine dosage (300 mg/day), we reported a low clozapine plasma level (124 ng/mL). After a multidisciplinary staff consensus, we decided to add on fluvoxamine to clozapine. A few days after fluvoxamine's introduction (50 mg/day), the patient presented an extreme sedation and QTc prolongation, requiring a transfer to the pediatric cardiology department for continuous monitoring and discontinuation of the drugs. Indeed a relatively high levomepromazine plasma level (140 ng/mL; therapeutic reference range in adults: 5-25 ng/mL) was retrieved due to CYP2D6 inhibition by fluvoxamine. The clozapine plasma level was low (139 ng/mL). Therefore, the extreme sedation was secondary to an overdose of levomepromazine, leading to the discontinuation of the drug. Clozapine was introduced once again in association with a low dose of fluvoxamine (25 mg/day). Within the next days after fluvoxamine's introduction, the plasma clozapine level dramatically increased (see Figure 1), which was associated with an important improvement of the clinical state regarding positive symptoms (66% reduction in the SAPS) and a reduction of aggressive behavior. Regarding tolerance, besides the drug interactions described above, we did not report any other side effect, and no hematological adverse event was reported (see Supplementary Figure 1).