Abstracts

Rationale: Zonisamide (ZNS) is a widely used antiepileptic drug (AED) that is generally considered safe and well tolerated. However, psychiatric adverse events (PAE) and cognitive adverse events (CAE) have been associated with ZNS exposure. The prevalence of these adverse events is unclear. In addition, risk factors for PAE and CAE associated with the discontinuation of ZNS are essentially unknown. Methods: A computerized prospective database entering information for each clinic visit for all patients attending MINCEP Epilepsy Care was queried to identify all patients who initiated ZNS between March 2000 and Sept 2008. Medical charts were reviewed to confirm information in the database and to obtain additional information. Patients were categorized as 1) discontinued ZNS during the follow-up period, 2) still using ZNS at the last follow-up visit. In order to attribute an adverse event to ZNS, the adverse event had to resolve after ZNS was discontinued. Separate case-control studies were performed to identify risk factors associated with the discontinuation of ZNS due to PAE or CAE. The case-control study design included two control patients for each index case. Multivariate binary logistic regression was used for analysis. Results: 433 patients initiated ZNS at MINCEP during the study period. PAE and CAE were the most frequently identified reasons for terminating ZNS therapy. ZNS was discontinued due to PAE in 30 (7%) and due to CAE in 25 (6%) patients. Depressed mood was the most common reason for discontinuation in the PAE group; four patients (0.92%) were hospitalized for being a danger to themselves or others. In the CAE group, the most common reasons for discontinuation of ZNS were language impairment and cognitive slowing. The majority of patients developed PAE or CAE within the first 3 months of exposure and discontinued ZNS within five months. Independent variables associated with termination of ZNS therapy due to PAE were past psychiatric history (OR 5.9 [1.7-20.1], p=0.005); symptomatic generalized epilepsy (OR 3.8 [1.2-12.2], p=0.027); and lower maximum ZNS serum concentration achieved (mean PAE=17.9 mg/L [SD=11.8] vs control=34.7 mg/L [SD=19.0]) (OR 1.1[1.0-1.2], p<0.001). Independent variables associated with discontinuing ZNS due to CAE were greater number of concomitant AEDs (OR 2.7[1.3-5.8], p=0.011) and lower maximum ZNS serum concentration achieved (mean CAE=16.6 mg/L [SD=14.5] vs control=30.6 mg/L [SD=16.5]) (OR 1.1[1.0-1.1], p=0.002). Cognitive function, titration rate, and the use of psychotropic medications were not found to be associated with ZNS discontinuation.