Clozapine intoxication in COVID-19

Abstract

Mr. A, a 46-year-old Caucasian nonsmoker, lives at an institution for people with intellectual disabilities. He is known to have a severe intellectual disability of unknown cause aswell as schizophrenia, for which he takes 200mg of clozapine twice daily. The clozapine trough level at steady state was 553mg/L, the clozapine level/dose (C/D) ratio 1.4, and the clozapine/norclozapine (C/N) ratio 1.7 (Table 1). Mr.A's past medical history records several infections, including one episode of bacterial pneumonia, two of bronchitis, and an infection of the upper respiratory tract, not described in further detail (see Table 1). With the bronchitis episodes and the upper respiratory tract infection, the clozapine level did not rise further than 661 mg/L (C/D ratio, 1.7).With the bacterial pneumonia, the level rose to 1,183 mg/L (C/D ratio, 2.4). On several occasions, including during the bacterial pneumonia, halving the dosage of clozapine led to psychotic decompensation. On the basis of these clinical experiences, it was concluded that for this patient the dosage of clozapine could not be automatically halved when signs of inflammation appeared, given that in several cases respiratory tract infections had not resulted in a doubling of clozapinelevelsand halving the dosage resulted in lower, evidently subtherapeutic levels. In April 2020, during the COVID-19 pandemic,Mr. A was found to have sonorous wheezes, audible without stethoscope, but no further clinical symptoms or abnormal test results (seeTable 1 for the progression of the case).When COVID-19 was suspected (day 1), isolation measures were taken, a nasopharyngeal swab was collected, and a blood test was conducted. The clozapine level was in accordance with baseline. The rest of the blood tests showed no abnormalities, but the nasopharyngeal swab tested positive for COVID-19. From day 4 onward, Mr. A became increasingly ill. He was sweating and his face was pale, with blue lips. His temperature rose to 38.4°C. He also showed possible signs of clozapine intoxication, namely, ataxia and tremors. He was given oxygen and paracetamol. Given his history of psychotic decompensation after his clozapine dosage was halved during fever, from day 4 onward the dose given dependedonwhetherhistemperaturewas$38°C. If itwas, the dosagewas reduced to 300mg per day (days 4, 5, and 7); on day 6 the dosagewent back to 400mg/day (the patient's normal daily dose). During days 4 to 6, Mr. A seemed lethargic, withsweating, echolalia, andreduced initiative. His temperature fluctuated between 37.1 and 38.7°C. On day 7, the patient's condition deteriorated further, with a temperature of 39.4°C. Onauscultation, crackles couldbeheard at the base of the right lung. Because bacterial pneumonia was suspected in addition to COVID-19, the patient was given amoxicillin/clavulanic acid 500/125 mg t.i.d. for 7days andthebloodtestswere repeated.Hisco-medication in this period was atenolol, diazepam, esomeprazole, and lithium. The clozapine trough level turned out to be three times as high as usual: 1,814 mg/L. Because this was not a steady-state situation, a C/D ratio of 5 was calculated using themeandosageover thepast5days.TheC/Nratiowas 3.5. At this point clozapine was stopped altogether. From day 9 onward, the patient began to recover. At that point the clozapine level was 1,335 mg/L. From day 10 onward, after the clozapine had been discontinued for 48 hours, the clozapine dosage was cautiously increased again. On day 13, the clozapine level was 213 mg/L (dosage, 50 mg/ day), and on day 19, 107 mg/L (dosage 100 mg/day). On days 30 and 37, the serumclozapine levelswere normal, as were the C/D and C/N ratios; the patient had clinically recovered and the clozapine dosage had now been increased to 350 mg/day (Figure 1).