ERYTHROMYCIN INTERACTION WITH RISPERIDONE OR CLOMIPRAMINE IN AN ADOLESCENT

An adverse event is described which appeared when the macrolide antibi otic erythromycin was added to a regimen of risperidone 0.5 mg bid and clomipramine 50 mg tid in a 15-year-old male being treated for Touret te's, obsessive-compulsive, and attention-deficit hyperactivity disord ers. An acute onset of behavioral symptoms, including agitation, labil e mood, incessant talking, and argumentativeness, began within 24 h of starting the erythromycin and persisted for 9 days after its disconti nuation. It was followed by a return to stable functioning on the prio r risperidone-clomipramine regimen. Erythromycin, risperidone, and clo mipramine are all metabolized by the hepatic cytochrome P450 system. I t is postulated that the addition of erythromycin, a known inhibitor o f CYP3A and CYP1A2, resulted in alterations in the metabolism of clomi pramine and risperidone. Clomipramine metabolism is dependent upon the isoenzymes CYP2D6 and CYP1A2, and risperidone is a substrate for CYP2 D6. Erythromycin would inhibit demethylation of clomipramine at the 1A 2 isoenzyme and lead to a dual interaction between risperidone and clo mipramine at the CYP2D6 isoenzyme. The subsequent increases in plasma levels of clomipramine, risperidone, their metabolites, or a combinati on of these agents could explain the adverse effects noted in this pat ient. In the absence of risperidone, clomipramine could have been meta bolically cleared by CYP2D6. In the absence of clomipramine, risperido ne clearance would not be affected by erythromycin. So the proposed me chanism requires an interaction involving all three agents: erythromyc in, clomipramine, and risperidone. Alterations in plasma protein bindi ng may also have played a role, because all three agents are extensive ly protein bound. Caution is urged when prescribing erythromycin with psychotropic drugs that are highly protein bound and/or are metabolize d by the same P450 isoenzymes.