Clozapine association with metabolic

The effects of neuroleptic drugs on serum lipids in adults have been reviewed (439). Haloperidol and the atypical neuroleptic drugs ziprasidone, risperidone, and aripipra-zole, are associated with lower risks of hyperlipidemia, whereas chlorpromazine, thioridazine, and the atypical drugs quetiapine, olanzapine, and clozapine are associated with higher risks. Treatment of the metabolic disturbances caused by neuroleptic drugs has also been reviewed (440). 

Caffeine has been associated with changes in the metabolism of clozapine (SEDA-20, 50 SEDA-22, 61). Seven schizophrenic patients taking clozapine monotherapy participated in a study of the effects of caffeine withdrawal from the diet (247). After a caffeine-free diet for 5 days, clozapine plasma concentrations fell by 50%. The authors suggested that schizophrenic patients treated with clozapine should have their caffeine intake medically supervised, and that monitoring of concentrations of clozapine and its metabolite may be warranted. 

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. 

Clozapine is mainly metabolized by CYP1A2, which is induced by the proton pump inhibitor omeprazole. In two patients co-medication with omeprazole and clozapine was associated with reduced plasma concentrations of clozapine of 42% and 45% (304). 

Dettling M, Sachse C, Muller-Oerlinghausen B, Roots I, Brockmoller J, Rolfs A, Cascorbi I. Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes no association with myeloperoxidase and cytochrome P4502D6. Pharmacopsychiatry 2000 33(6) 218-20. 

Maggs, J.L. Williams, D. Pirmohamed, M. Peirk, B.K. The metabolic formation of reactive intermediates from clozapine, a drug associated with agranulo[Pg.409]

Inhibits metabolizing enzymes (caffeine inhibits CYPl A2, which metabolizes clozapine). Inhibition of CYP by ginkgo t alpha-1 effects of risperidone. Valerian may worsen the sedative properties of haloperidol. Hops and phenothiazine have been associated with hyperthermia in dogs... 

Williams DP, Pirmohamed M, Naisbitt DJ, Uetrecht JP, Park BK (2000) Induction of metabolism-dependent and -independent neutrophil apoptosis by clozapine. Mol Pharmacol 58 207-216 Wolf B, Conradty M, Grohmann R, Ruther E, Witzgall H, Londong V (1989) A case of immune complex hemolytic anemia, thrombocytopenia, and acute renal failure associated with doxepin... 

Metabolism A prospective, naturalistic study of 809 patients that compared 10 antipsychotics found there were no significant relationships between any of the antipsychotic drugs and increased waist circumference, HOMA-IR or LDL-cholesterol levels [54 ]. Hypertriglyceridemia was associated with clozapine, reduced HDL-cholesterol with both clozapine and olanzapine, hypertension with perphenazine, and hyperglycaemia inversely with ziprasidone and positively with haloperidol. 

A review of the literature (1975-2011) on metabolic syndrome reported a prevalence of 14.7-69.3% in non-Euro-American societies [67" ]. Olanzapine was associated with the highest incidence of metabolic syndrome while clozapine was associated with the highest prevalence. 

Susceptibility factors A study of tumour necrosis factor-alpha (TNF-a) in 99 patients with bipolar depression found that treatment with olanzapine, quetiapine, risperidone, paliperidone or clozapine was associated with significantly greater TNF-a and a higher likelihood of metabolic syndrome [74FI TNF-a was greater in those with metabolic syndrome and there was a significant effect on the indirect relationship between antipsychotic treatment and elevated waist circumference. 

Metabolism A functional polymorphism (Val66Met) of the brain-derived neurotrophic factor gene was found to be associated with clozapine-induced metabolic syndrome (significantly with fasting glucose levels) in males but not in females [121 ]. The increase in triglyceride levels with clozapine has been shown to be strongly predictive of clinical improvemenf [122 ]. 

Some of the genetic aspects of clozapine-induced agranulocytosis have been evaluated (143). Polymorphisms of specific clozapine metabolizing enzyme systems were determined in 31 patients with agranulocytosis and in 77 without. Genotyping of a recently discovered G-463 A polymorphism of the myeloperoxidase gene and CYP2D6 showed no evidence of an association. 

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