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Smoking-Related Anti-psychotic Dose Adjustment Could Improve Response

Dose adjustment of the atypical anti-psychotic drug clozapine, based on smoking behaviour, would help to counter inadequate antipsychotic response or lower intoxication.

Researchers in Harderwijk and Ermelo, the Netherlands, reported that clearance of clozapine and daily dose requirement were strongly associated with smoking behaviour, but a related genetic polymorphism seemed to have no significant clinical effect.

Clozapine was largely metabolised by the cytochrome P450 enzyme CYP1A2. Smoking powerfully induced this enzyme's activity, causing significantly lower clozapine serum concentrations with a given dose in smokers than in non-smokers, the researchers said. They also noted that a single nucleotide polymorphism identified at position 734 of the gene had recently been reported to affect the enzyme's inducibility.

Because this polymorphism in relation to smoking behaviour might be relevant to treatment with clozapine, the researchers studied the effect of genotype on clozapine clearance and dose requirement in 80 smoking and non-smoking schizophrenic patients receiving clozapine long-term.

Clozapine serum concentrations were determined by high-performance liquid chromatography and genotype by polymerase chain reaction analysis.

In smokers, the clozapine serum concentration corrected for dose was 2.5 times lower on average than in non-smokers, indicating enhanced clearance.

The mean required maintenance doses of clozapine for smokers was 382 mg/day and for non-smokers 197 mg/day.

Mean corrected-for-dose ratios and daily doses did not significantly vary between patients with the different genotypes in smokers or non-smokers.
Pharmacogenetics 2003;13:3:169-172. "The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement"

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