Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Korean Topiramate Study Group. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled trial.
This randomized, double-blind, placebo-controlled study in epileptic children aged 3-12 years evaluated the effects of add-on melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy using a parental questionnaire. Quality of Life in Childhood Epilepsy is a questionnaire designed to assess a variety of age-relevant domains such as physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16 randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The questionnaire had good internal consistency reliability, because for most of the multi-item scales Cronbach's alpha reliability exceeded 0.5 (range: 0.59-0.94). To our knowledge, this is the first study assessing quality of life in epileptic children with add-on melatonin administration in the form of a randomized, double-blind, placebo-controlled trial. The study suggests a potential use of melatonin as an adjunct to antiepileptic therapy due to its diverse spectrum of action as an antioxidant, neuroprotector, and free radical scavenger, thus offering the advantage of reducing oxidant stress and subsequent damage. The beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood-brain barrier have the potential to improve quality of life in pediatric epilepsy. To evaluate the efficacy and safety of topiramate (TPM) as add-on therapy in medically intractable partial epilepsies.
                We used a multicenter double-blind placebo-controlled randomized parallel-group trial consisting of 12 weeks of baseline phase, 10 weeks of titration phase, and 8 weeks of stabilization phase. The primary efficacy variable was the median seizure frequency reduction rate (MSFRR), and the other efficacy variables included responder rate, seizure-free rate, and global evaluations by the patient and the physician. The patient should have partial epilepsies refractory to the maximally tolerable doses of one to two antiepileptic drugs (AEDs) and should have two or more episodes of clinical seizures every 4 weeks during the baseline phase. The target dose of study drugs was 600 mg/day. The study drugs were started at the initial dose of 50 mg/day and gradually increased to the target dose over a 10-week period.
                A total of 177 patients was randomized into the TPM group (n = 91) and the placebo (PLC) group (n = 86). Baseline median seizure frequencies were 5.6 episodes/4 weeks in the TPM and the PLC groups. Among those who were randomized, 174 patients (TPM, 89 patients; PLC, 85 patients) were available for the efficacy measurement by intention-to-treat analysis. The MSFRR was 51.3% for TPM and 9.1% for PLC, which was highly in favor of TPM (p = 0.0001). The responder rate was 50.6% for TPM and 12.9% for PLC (p = 0.001). Seven (7.9%) of 89 patients taking TPM became seizure free compared with one (1.2%) of 85 patients taking PLC (p = 0.004). The global evaluation greatly favored TPM (p = 0.001). The incidence of adverse events (AEs) was higher in the TPM (81.3%) than in the PLC (48.9%) group, with central nervous system (CNS)-related AEs being the most frequent. Among individual AEs, anorexia (20.9%) and abdominal pain or discomfort (20.9%) were the most common AEs in the TPM group. AEs precipitated early drop-out in seven (7.6%) patients taking TPM and three (3.5%) patients taking PLC. No serious systemic AEs were observed.
                TPM was highly effective and safe as add-on therapy in medically intractable partial epilepsies. Slower titration of TPM might be responsible for the lesser drop-out rate than previous trials, but the incidence of AEs was still high. The AE profile of TPM in Koreans was different from that in whites. The aim of the present study was to verify the clinical efficacy of melatonin (MLT) in children, adolescents and young adults with wake-sleep disorder and mental retardation, most of them on chronic anticonvulsant therapy for epileptic seizures, by means of a randomized, double-blind, placebo-controlled cross-over trial. Twenty-five patients (16 males, nine females), aged from 3.6 to 26 years (mean 10.5 years), all affected with mental retardation mostly with epileptic seizures, were randomized to oral synthetic fast-release MLT or placebo. Melatonin was initiated at the daily dose of 3 mg, at nocturnal bedtime. In case of inefficacy, MLT dose could be titrated up to 9 mg the following 2 weeks at increments of 3 mg/week, unless the patient was unable to tolerate it. The analysis of all the sleep logs disclosed a significant treatment effect of melatonin on sleep latency (P = 0.019). Melatonin was well tolerated in all patients and no side effects were reported. In conclusion, our study supports the efficacy of MLT in young patients with mental disabilities and epileptic seizures in improving the wake-sleep disorders such as time to fall asleep. Overall, MLT appeared to influence the seizure frequency poorly, though there may be occasional seizure worsening or improving. Such a dual effect requires further studies in young epileptic patients.
Included studies were of poor methodologic quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in patients with epilepsy.