PMID: 10950477

Issn Print: 0271-0749

Publication Date: 1997/04/01


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Interaction of Sertraline With Clozapine

Narsimha R. Pinninti; Jose de Leon

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The selective serotonin reuptake inhibitors have an inhibitory effect on several P450 cytochrome isoenzymes. Fluoxetine and paroxetine are powerful inhibitors of CYP2D6, which is involved in the metabolism of most neuroleptics and antidepressants. Clozapine is not metabolized by CYP2D6. [1] Fluvoxamine is a powerful inhibitor of CYP1A2 [2,3] and increases clozapine levels. [4] Bertilsson and associates [5] estimated that CYP1A2 activity accounts for 70% of the variance of clozapine clearance. Two in vitro studies suggested that sertraline has a weak inhibitory effect on CYP1A2 (the inhibitory constant, IC50, was 350 and 673 times higher for sertraline than for fluvoxamine).
We describe a patient taking clozapine who showed very high clozapine levels during sertraline treatment. The clozapine levels decreased after sertraline discontinuation.
A 35-year-old white man who was given a diagnosis of paranoid schizophrenia according to DSM-III-R criteria was taking 600 mg/day of clozapine and 300 mg/day of sertraline. Total plasma clozapine concentration levels were 1,820 ng/mL (clozapine: 1,300 ng/mL and norclozapine 520 ng/mL). Sertraline was progressively decreased and stopped while clozapine levels were measured serially. Five days after the sertraline dosage was reduced to 150 mg/day, total clozapine levels were 2,020 ng/mL (clozapine: 1,400 ng/mL and norclozapine 620 ng/mL). Fifteen days later (and 5 days off sertraline) the total concentration level was 1,860 (clozapine: 1,300 ng/mL and norclozapine 560 ng/mL). Four weeks later (and 30 days off sertraline) the total concentration level decreased to 1,080 ng/mL (clozapine: 750 ng/mL and norclozapine 330 ng/mL). Therefore, the discontinuation of sertraline was followed by an approximate reduction of total clozapine levels of 40%.
This case suggests that a high dosage of sertraline may significantly increase clozapine levels. The high dosage of sertraline may have induced a clinically significant inhibition of CYP1A2.
Currently, it cannot be ruled out that sertraline may influence clozapine metabolism by inhibiting other isoenzymes. In that sense, it can be speculated that CYP3A4 may be involved in the metabolism of clozapine because clozapine levels are increased by fluoxetine [6] (norfluoxetine is an inhibitor of CYP3A4 [7]) and are decreased by carbamazepine and phenytoin [8] (inducers of CYP3A4). Clinical concentrations of sertraline and desmethylsertraline (a sertraline metabolite) inhibit CYP3A4. [7]
In conclusion, high dosages of sertraline appear to increase clozapine levels. This is probably explained by an inhibition of CYP1A2 by sertraline. It is also possible to speculate that an additional inhibitory effect of sertraline on clozapine metabolism by inhibiting CYP3A4 may have a less important role in clozapine metabolism.
Narsimha R.
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