Abstracts

Rationale: Psychiatric illness is well known to be overrepresented in epilepsy, but the literature is sparse in terms of treatment strategies in pediatrics. Anxiety is particularly common in pediatric epilepsy and associated with a variety of seizure types. Treatment of social anxiety and generalized anxiety may involve use of typical benzodiazepines for symptomatic relief or to prevent exacerbations. Clobazam is a 1,-5-benzodiazepine that differs from typical benzodiazepines commonly used in neurology and psychiatry. Clobazam has regulatory approval in the US as an adjunct treatment for Lennox-Gastaut Syndrome and in practice is used for many different seizure types. It has also been found effective for anxiety in Europe, Asia, and Australia. The goal of this study is to test the hypothesis that clobazam is an effective treatment for seizure control and anxiety symptoms in the same patient. Methods: In order to closely mimic clinical practice, the protocol was structured as an open-label, adjunctive, flexible dose, proof-of-concept, clinical trial. Participants were recruited if they had established epilepsy requiring ongoing use of anticonvulsant medicines, plus clinically significant anxiety symptoms. Although multiple seizures types were allowed, most participants had suspected focal onset seizures. At baseline, DSM-V diagnoses were established with a psychiatrist-administered semi-structured interview (K-SADS: Kiddie Schedule for Anxiety, Depression and Schizophrenia). Symptom measures were obtained with well validated, commonly used, standardized parent and child questionnaires and clinician summative ratings. Examples of measures include the Behavioral Assessment System for Children (BASC), Pediatric Anxiety Rating Scale (PARS), and Multidimensional Anxiety Scale (MASC). Trial duration was 10 weeks and involved a flexible dose paradigm, starting at 5-10mg BID and increasing to 10-20mg BID as tolerated or as symptom control was achieved. Outcome measures included clinical global improvement (CGI) for anxiety and epilepsy, clinical global assessment of function (C-GAS), as well as scores on specific measures. Results: Eighteen participants have been enrolled (mean age 13.2, 17 female), two dropped out, and eleven have completed the trial. Five remain active in the trial. All had epilepsy requiring medication treatment; seizure frequency ranged from daily to once per month. Anxiety disorders were uniformly present. Generalized Anxiety Disorder was present in all except one, social anxiety disorder was present in 9/18, and unspecified depression in 10/18. 10/13 completed the trial and continued taking clobazam clinically. Three subjects became tired at maximal dosages, but remained in the trial at reduced dosages. In the 11/13 participants who completed the trial, anxiety symptoms and seizure control improved as evidenced by CGI-I scores of 1 or 2 and significant changes in anxiety scales. Mean CGI improvement scores for epilepsy were 1.27 at week 6 and 1.09 at week 10. Improvement scores for anxiety were 1.64 at week 6 and 1.27 at week 10. Mean CGAS scores improved from 57.5 at baseline to 70 at week 6 and 73.9 at week 10. Anxiety rating scales improved in the sample, with a baseline PARS mean score of 17.5, to 6.4 at week 10, and 4.7 at week 14. Conclusions: Clobazam is effective in the simultaneous treatment of both anxiety and epilepsy in children and adolescents. Significant improvement, especially for seizure control, occurs early in the course of treatment. Clobazam appears to be well tolerated, especially when a flexible dosing paradigm is utilized. The unique structure of the clobazam molecule may offer distinct advantages that allow it to simultaneously treat both conditions with minimal side effects. Clobazam may be a valuable tool for treatment of epilepsy and anxiety comorbidity in pediatrics. Funding: Investigator initiated study funded by Lundbeck Pharmaceuticals,