Methylphenidate for the treatment of epilepsy-related cognitive deficits: a randomized, double-blind, placebo-controlled trial

哌醋甲酯治疗癫痫相关认知缺陷：一项随机、双盲、安慰剂对照试验

• 批准号: 10589709
• 负责人: Beth Ami Leeman-Markowski
• 金额: --
• 依托单位: VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589709
• 关键词: Activities of Daily Living; Adult; Adverse event; Anticonvulsants; Anxiety; Arousal; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Beck depression inventory; Blinded; Boston; Brain; Child; Clinical; Clinical Management; Cognition; Cognitive; Cognitive deficits; Color; Craniocerebral Trauma; Databases; Digit structure; Dose; Double-Blind Method; Epilepsy; Equipment and supply inventories; Etiology; FDA approved; Frequencies; Functional disorder; Healthcare Systems; Hospitals; Impact Seizures; Impaired cognition; Impairment; Impulsivity; Lesion; Measures; Medical; Memory; Methods; Modality; Moods; Neuropsychology; Outcome Measure; Patient Self-Report; Patients; Performance; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Post-Traumatic Epilepsy; Quality of Life Assessment; Quality of life; Randomized; Recording of previous events; Registries; Research; Risk; Ritalin; Safety; Seizures; Site; Speed; Stimulant; Syndrome; System; Testing; Titrations; Traumatic Brain Injury; Veterans; clinically relevant; cognitive ability; cognitive benefits; cognitive function; cognitive performance; cognitive process; cognitive testing; combat veteran; comorbidity; computerized; daily functioning; double-blind placebo controlled trial; efficacy evaluation; executive function; expectation; improved; medical schools; open label; performance tests; primary endpoint; primary outcome; psychiatric comorbidity; recruit; rehabilitation strategy; response; secondary analysis; side effect; sustained attention; treatment duration

Objective: The proposed study will determine the efficacy of methylphenidate (MPH) for the treatment of epilepsy-related attentional dysfunction. Epilepsy patients often have attention and other cognitive deficits, which can impair quality of life. The causes are typically multifactorial, including frequent seizures, interictal discharges, brain lesions, and antiseizure medication side effects. The comorbidity of attentional dysfunction and epilepsy may be partially explained by abnormalities in ascending reticular activating system networks. There are no FDA-approved medical therapies for epilepsy-related cognitive deficits, and rehabilitation strategies provide limited benefit. MPH is a stimulant, FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for epilepsy-related cognitive dysfunction. Studies of MPH in children with epilepsy and ADHD suggest efficacy and safety. Further, large database and registry studies found beneficial effects of MPH on seizure risk in children with and without epilepsy. Small, single-dose and open label trials of MPH in adults with epilepsy and attentional dysfunction suggest benefit and safety, but longer-duration, controlled trials with larger numbers of subjects are needed. The proposed study is a multi-site, randomized, double-blind, placebo-controlled trial of MPH, with an open- label extension period, to determine the efficacy of MPH for adult epilepsy-related attentional dysfunction. The study will also establish the effects of MPH on other attention-dependent cognitive processes ({i.e., a combined measure of} memory, psychomotor speed, and executive function) and quality of life. The hypothesis is that subjects will have improved cognitive function and quality of life with MPH compared to placebo. Secondary analyses will determine the impact of MPH on mood and subjective cognitive abilities, efficacy over an open-label period, and safety, including effects on seizure frequency. Research Plan/Methods: Subjects will include {186} adults with epilepsy and self-reported cognitive deficits, recruited from the Manhattan, Portland, Miami, and Boston VA hospitals. In the blinded phase, subjects will {be randomly assigned to} receive either placebo or MPH (titrated to 20 mg twice daily) for 8 weeks. Subjects will then receive open-label MPH for 8 weeks (titrated to 20 mg twice daily). Cognitive testing will be administered at baseline, the end of blinded treatment (Week 8), and the end of the open-label period (Week 16). The cognitive battery will include tests of attention (Continuous Performance Test), memory (MCG Paragraph Test), psychomotor speed (Symbol Digit Modalities Test), and a combined measure of divided attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test). Additional measures will include quality of life (Quality of Life in Epilepsy Patient Inventory-89), side effects (Adverse Events Profile), mood (Beck Depression Inventory-II), and anxiety Beck Anxiety Inventory). Twenty healthy subjects and 20 epilepsy patients without cognitive complaints, who will not receive the study drug, will be included to control for repeated testing. Clinical Relevance: If efficacious, MPH would be the first successful medical treatment for epilepsy-related cognitive deficits. Results will be of particular importance to combat Veterans and others with head injuries, as common sequelae of traumatic brain injury (TBI) are seizures and neuropsychological dysfunction. Improving cognition in Veterans with epilepsy can lead to greater independence with activities of daily living, increased employability, and better quality of life.

Objective: The proposed study will determine the efficacy of methylphenidate (MPH) for the treatment of epilepsy-related attentional dysfunction. Epilepsy patients often have attention and other cognitive deficits, which can impair quality of life. The causes are typically multifactorial, including frequent seizures, interictal discharges, brain lesions, and antiseizure medication side effects. The comorbidity of attentional dysfunction and epilepsy may be partially explained by abnormalities in ascending reticular activating system networks. There are no FDA-approved medical therapies for epilepsy-related cognitive deficits, and rehabilitation strategies provide limited benefit. MPH is a stimulant, FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD). It is unknown, however, if stimulants would be of benefit for epilepsy-related cognitive dysfunction. Studies of MPH in children with epilepsy and ADHD suggest efficacy and safety. Further, large database and registry studies found beneficial effects of MPH on seizure risk in children with and without epilepsy. Small, single-dose and open label trials of MPH in adults with epilepsy and attentional dysfunction suggest benefit and safety, but longer-duration, controlled trials with larger numbers of subjects are needed. The proposed study is a multi-site, randomized, double-blind, placebo-controlled trial of MPH, with an open- label extension period, to determine the efficacy of MPH for adult epilepsy-related attentional dysfunction. The study will also establish the effects of MPH on other attention-dependent cognitive processes ({i.e., a combined measure of} memory, psychomotor speed, and executive function) and quality of life. The hypothesis is that subjects will have improved cognitive function and quality of life with MPH compared to placebo. Secondary analyses will determine the impact of MPH on mood and subjective cognitive abilities, efficacy over an open-label period, and safety, including effects on seizure frequency. Research Plan/Methods: Subjects will include {186} adults with epilepsy and self-reported cognitive deficits, recruited from the Manhattan, Portland, Miami, and Boston VA hospitals. In the blinded phase, subjects will {be randomly assigned to} receive either placebo or MPH (titrated to 20 mg twice daily) for 8 weeks. Subjects will then receive open-label MPH for 8 weeks (titrated to 20 mg twice daily). Cognitive testing will be administered at baseline, the end of blinded treatment (Week 8), and the end of the open-label period (Week 16). The cognitive battery will include tests of attention (Continuous Performance Test), memory (MCG Paragraph Test), psychomotor speed (Symbol Digit Modalities Test), and a combined measure of divided attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test). Additional measures will include quality of life (Quality of Life in Epilepsy Patient Inventory-89), side effects (Adverse Events Profile), mood (Beck Depression Inventory-II), and anxiety Beck Anxiety Inventory). Twenty healthy subjects and 20 epilepsy patients without cognitive complaints, who will not receive the study drug, will be included to control for repeated testing. Clinical Relevance: If efficacious, MPH would be the first successful medical treatment for epilepsy-related cognitive deficits. Results will be of particular importance to combat Veterans and others with head injuries, as common sequelae of traumatic brain injury (TBI) are seizures and neuropsychological dysfunction. Improving cognition in Veterans with epilepsy can lead to greater independence with activities of daily living, increased employability, and better quality of life.