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Abstract Depression is common in patients with epilepsy and the strongest predictor of poor quality of life. Few studies have assessed the association of uncontrolled seizures with depression. We used the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), a validated six-item self-report questionnaire, to assess the relationship between depression, seizure control, and antiepileptic drug (AED) and antidepressant drug usage. Two hundred ninety-eight patients were studied. Twenty percent of patients with any epileptic seizures over a 6-month period had NDDI-E scores > 15, consistent with major depression. Higher NDDI-E scores were associated with higher seizure frequency ( P < 0.0002). The prevalence ratio of NDDI-E scores > 15 in patients with no seizures versus any seizure in the past 6 months was 0.48 (95% CI = 0.26–0.88). Higher NDDI-E scores were associated with the number of AEDs taken ( P = 0.0023). Major depression is associated with uncontrolled seizures, with a prevalence double that of patients whose seizures are controlled.