Clozapine toxicity

Case Example Because of a patient s partial response to 5 months of clozapine therapy at 600 mg/day, risperidone was added for augmentation (started with 0.5 mg b.i.d. and increased to 1 mg b.i.d. after 1 week). Before this addition, the clozapine plasma level was 344 ng/mL, but after 2 weeks of risperidone augmentation, the level was elevated to 598 ng/mL with no adverse effects and substantial clinical benefit. In another report, there was an increase in the steady-state plasma levels of clozapine (675 mg/day) and its active metabolite norclozapine after the addition of risperidone 2 mg/day in a patient treated for 2 years. Before the addition of risperidone, her clozapine and norclozapine levels were 829 and 1,384 ng/mL, respectively. Two days after risperidone was added, these levels rose to 980 and 1,800 ng/mL. Clozapine dosage was reduced to 500 mg/day, and after 5 days of combined treatment with 4 mg/day of risperidone, the clozapine and norclozapine levels were 110 and 760 ng/mL, respectively. Aside from some mild oculogyric crises, she had no symptoms of clozapine toxicity or clinical changes during the period of cross-tapering. In another case, risperidone was added to clozapine because the patient had relapsed after discontinuation of fluphenazine and had not responded to clozapine. The addition of risperidone resulted in an acute remission of psychosis ( 100). 

Szymanski S, Lieberman JA, Picou D, et al. A case report of cimetidine-induced clozapine toxicity. J Clin Psychiatry 1991 52 21-22. 

However, in another case the addition of nefazodone appeared to produce clozapine toxicity (23). 

Clozapine toxicity has been attributed to the effects of cytokines during an acute infection (226). 

A 39-year-old man with schizophrenia and diabetes, who had taken clozapine 300 mg/day and glipizide 10 mg/day for a year, took lisinopril 5 mg/day for newly diagnosed hypertension. On several occasions afterwards he had roughly a doubling of his blood concentrations of clozapine and norclozapine. He had typical effects of clozapine toxicity. After replacement of lisinopril by diltiazem, the blood concentrations of clozapine and norclozapine returned to the values that were present before lisinopril was introduced. 

Clozapine toxicity occurred in a 42-year-old man after he was given modafinil 300 mg/day, a central stimulant, to combat sedation associated with clozapine (450 mg/day) (260). He complained of dizziness, had an unsteady gait, and fell twice. His serum clozapine concentration was 1400 ng/ml, which suggested a metabolic interaction between clozapine and modafinil. The authors suspected that inhibition of CYP2C19 by modafinil had reduced clozapine clearance. 

Cohen LG, Chesley S, Eugenio L, Flood JG, Fisch J, Goff DC. Erythromycin-induced clozapine toxic reaction. Arch Intern Med 1996 156(6) 675-7. 

Dequardo JR. Modafinil-associated clozapine toxicity. Am J Psychiatry 2002 15917) 1243—4. 

CLOZAPINE MACROLIDES- ERYTHROMYCIN t clozapine levels with risk of clozapine toxicity Clozapine is metabolized by CYPIA2, which is moderately inhibited by erythromycin. Erythromycin is a potent inhibitor of CYP3A4, which has a minor role in the metabolism of clozapine. This may lead to 1 clearance and therefore t levels of clozapine Cautious use advised... 

Clozapine toxicity occurred after modafinil administration to reverse sedation associated with clozapine (10). 

Agranulocytosis (and systemic lupus erythematosus) are autoimmune syndromes that can be drug-induced. They are type II reactions involving IgM and IgG antibodies that bind to circulating blood cells. The patient was probably treated with clozapine for his psychosis (see clozapine toxicity. Chapter 29). The answer is (D). 

A study in healthy subjects found no evidence of an interaction between clozapine and erythromycin, but three case reports describe clozapine toxicity (seizures in one patient, drowsiness, incoordination and incontinence in another and neutropenia in the third) when the patients were given erythromycin. 

Fluoxetine, paroxetine, sertraline and possibly citalopram can raise serum clozapine levels. Escitalopram is predicted to interact similarly. Particularly lai e increases in clozapine levels can occur with fluvoxamine. Clozapine toxicity has been seen in some patients. 

Infections Clozapine toxicity has been previously reported during an acute infection [SEDA-30, 63]. Two cases have been reported in which the plasma concentration of clozapine increased as a result of an inflammatory reaction, and signs of intoxication were observed. [93 ]. These developments were associated with cholecystitis in a 53-year-old man and bacterial pneumonia in a 41-year-old man. 

It can be difficult to dispute clozapine toxicity as the cause of death at an inquest, with the associated implication that clozapine dosage was inappropriate. This is because blood clozapine and norclozapine often rise after death, e.g. clozapine x5 norclozapine x4. If you have regularly (e.g. yearly in apparently successful therapy) measured plasma clozapine in life, this places you in a much stronger position to answer questions about the possible role of clozapine in a death. 

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