Risk of discontinuation of risperidone after exposure to potentially interacting drugs: a nested case-control study in patients with schizophrenia.
BACKGROUND
The cytochrome P450 (CYP) 2D6 and 3A4 isozymes play an important role in the metabolism of risperidone. Concurrent use of drugs that inhibit or induce the action of these enzymes may increase or decrease levels of risperidone, thereby increasing the risk for discontinuation of risperidone or the need for supplemental treatment to control disease symptoms.


OBJECTIVE
This study examined the association between exposure to potentially interacting drugs and nonpersistence in a cohort of patients with schizophrenia newly starting treatment with risperidone.


METHODS
The data for this nested case-control study were obtained from the administrative health databases of the Régie de l'Assurance Maladie de Québec. The base cohort included patients aged > or = 15 years who began treatment with risperidone between July 2001 and December 2004. Cases consisted of those who were nonpersistent with risperidone either through drug discontinuation or the addition of/switch to a different atypical antipsychotic; noncases were those who persisted with risperidone through the end of their follow-up period. Exposure to CYP-inhibiting or CYP-inducing medications in the 1-, 3-, and 6-month windows before nonpersistence was compared between cases and noncases. The association between exposure to interacting medications and nonpersistence was analyzed using conditional logistic regression models to account for matching by time on treatment.


RESULTS
The base cohort included 20,840 patients, of whom 59.2% were female and 57.7% were aged > or = 65 years. Nonpersistence occurred in 10,913 patients (52.4%) during the study period. Between 40% and 50% of patients were exposed to potential CYP inhibitors, and 6% to 10% were exposed to potential CYP inducers. Exposure to CYP inhibitors over 3 and 6 months was associated with an increase in risk for nonpersistence of approximately 10% (odds ratio [OR] for 3-month exposure = 1.10 [95% CI, 1.06-1.14]; OR for 6-month exposure = 1.11 [95% CI, 1.07-1.15]), whereas exposure to CYP inducers was not associated with a significant change in risk. Exposure to potentially interacting drugs was more likely to lead to nonpersistence while patients were still new to risperidone (ie, in the first month of treatment). For instance, the OR for 6-month exposure to inhibiting drugs was 1.20 (95% CI, 1.04-1.39) in the 1st month of treatment and 1.11 (95% CI, 1.01-1.20) between the 6th and 12th months.


CONCLUSIONS
In this study, use of medications that are potential inhibitors of CYP2D6 and CYP3A4 appeared to be associated with an increased risk of nonpersistence with risperidone, particularly while patients were still new to treatment.
Ishak
K Jack
KJ
United BioSource Corporation(*), Montreal, Québec, Canada. jack.ishak@unitedbiosource.com
Tan
Ye
Y
Glass
Jennifer
J
Luong
Doanh
D
Caro
J Jaime
JJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D016022:Case-Control Studies; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000096:biosynthesis; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D018967:Risperidone / Q000008:administration & dosage* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D018967:Risperidone