Methylphenidate for the Treatment of Epilepsy-related Cognitive Deficits
Study Details
Study Description
Brief Summary
Methylphenidate (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 memory and thinking problems due to epilepsy. In this study, participants will be assigned randomly (i.e., by flip of a coin), to a group that takes MPH and a group that takes a placebo (sugar pill). Participants will not know the group to which they have been assigned. Tests of attention and memory will be completed before taking the study pills, at Week 4, and at Week 8. All participants will then have the option of taking MPH for the next two months, and attention and memory will be tested again at Week 16. The study will determine whether methylphenidate is helpful for the treatment of attention and memory problems in adults with epilepsy, and whether the medication is safe and beneficial when taken over an extended time period.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
The proposed study is a randomized, double-blind, crossover trial of MPH vs. placebo in subjects with epilepsy and impaired attention. In the blinded phase, subjects will receive placebo and MPH (20mg twice daily) for 4 weeks each, in randomized order. Subjects will then receive open-label MPH for 8 weeks (20mg twice daily). Cognitive tests will be performed at baseline, Week 4, Week 8, and at the end of the open-label period.
The primary aim is to evaluate the efficacy of MPH for the treatment of attentional dysfunction in subjects with epilepsy. It is expected that subjects will have improved attention when taking MPH compared to placebo, measured by the Conner's Continuous Performance Test (CPT). The effects of MPH on other cognitive functions that rely in part on attention, including memory (MCG Paragraph Test) and psychomotor speed (Symbol Digit Modalities Test), as well as the impact on an overall measure of divided attention, psychomotor speed, and response inhibition (Stroop Color Word Interference Test), will be ascertained. Improved performance when taking MPH compared to placebo is expected. Finally, the study will establish the effect of MPH on overall quality of life. It is hypothesized that there will be improvement in self-reported quality of life with MPH, but no change while taking placebo, as assessed by the Quality of Life in Epilepsy Patient Inventory.
Secondary analyses will determine the safety of MPH, including effects on seizure frequency, the impact on mood and subjective cognitive function, and continued efficacy over an open-label period. Epilepsy type, concurrent use of antiepileptic drugs that impair cognition, and history of head trauma will be assessed as covariates.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Methylphenidate Subjects who will receive methylphenidate in the double-blinded period; when assigned to the active drug, the dosage of MPH will begin at 10mg twice per day, at 8am and 12pm, for one week. The dosage will then increase to 20mg twice daily, at 8am and 12pm, for the next 3 weeks. |
Drug: Methylphenidate
10mg twice per day, at 8am and 12pm, for one week, then increased to 20mg twice daily, at 8am and 12pm, for the next 3 weeks during the double-blinded period. During the open-label extension phase, dosing will begin at 10mg twice per day, at 8am and 12pm, for one week. The dosage will then increase to 20mg twice daily, at 8am and 12pm, for the next 7 weeks.
Other Names:
|
| Placebo Comparator: Placebo Subjects who will receive placebo in the double-blinded period; when assigned to receive the placebo during the double-blinded period, subjects will be given a sugar pill for 4 weeks. The sugar pill will be taken twice per day, at 8am and 12pm. |
Other: Placebo
When assigned to receive the placebo during the double-blinded period, subjects will be given a sugar pill for 4 weeks. The sugar pill will be taken twice per day, at 8am and 12pm.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in Conner's Continuous Performance Test (CPT), Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Conner's Continuous Performance Test (CPT) d' value, a measure of attention, compared post-placebo vs. post-methylphenidate in a crossover design
Secondary Outcome Measures
- Change in MCG Paragraph Test, Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Total items recalled on the MCG Paragraph Test, a measure of memory, compared post-placebo vs. post-methylphenidate in a crossover design
- Change in MCG Paragraph Test Post-Open-Label [Baseline, Week 16]
Total items recalled on the MCG Paragraph Test, a measure of memory, compared across baseline and post-open-label.
- Change in Symbol Digit Modalities Test (SDMT), Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Total items completed on the Symbol Digit Modalities Test, a measure of psychomotor speed, compared post-placebo vs. post-methylphenidate in a crossover design
- Change in Symbol Digit Modalities Test (SDMT) Post-Open-Label [Baseline, Week 16]
Total items completed on the Symbol Digit Modalities Test, a measure of psychomotor speed, compared across baseline and post-open-label.
- Change in Stroop Word Color Interference Test, Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Stroop Word Color Interference Test time for completion of interference trials, an overall measure of divided attention, psychomotor speed, and response inhibition, compared post-placebo vs. post-methylphenidate in a crossover design
- Change in Stroop Word Color Interference Test Post-Open-Label [Baseline, Week 16]
Stroop Word Color Interference Test time for completion of interference trials, an overall measure of divided attention, psychomotor speed, and response inhibition, compared across baseline and post-open-label.
- Change in Overall Subjective Quality of Life, Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Self-reported quality of life, as assessed by the Quality of Life in Epilepsy Patient Inventory (QOLIE-89), compared post-placebo vs. post-methylphenidate in a crossover design. Range of scores 0-100, with higher scores representing better quality of life.
- Change in Overall Subjective Quality of Life Post-Open-Label [Baseline, Week 16]
Self-reported quality of life, as assessed by the Quality of Life in Epilepsy Patient Inventory (QOLIE-89), compared across baseline and post-open-label. Range of scores 0-100, with higher scores representing better quality of life.
- Change in Conner's Continuous Performance Test (CPT) Post-Open-Label [Baseline, Week 16]
Conner's Continuous Performance Test (CPT) d' value, a measure of attention, with change compared from baseline to post-open-label
Other Outcome Measures
- Change in Adverse Events, Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Adverse events, as assessed by the Adverse Events Profile (AEP), compared post-placebo vs. post-methylphenidate in a crossover design
- Change in Adverse Events Post-Open-Label [Baseline, Week 16]
Adverse events, as assessed by the Adverse Events Profile (AEP), compared across baseline and post-open-label.
- Change in Mood, Post-Placebo vs. Post-Methylphenidate [Week 4, Week 8]
Change in symptoms of depression, as assessed by the Beck Depression Inventory-II (BDI-II). Range 0-63; Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe depressive symptomatology.
- Change in Mood Post-Open-Label [Baseline, Week 16]
Change in symptoms of depression, as assessed by the Beck Depression Inventory-II (BDI-II). Range 0-63; Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe depressive symptomatology. Compared across baseline and post-open-label.
Eligibility Criteria
Criteria
- SUBJECTS WITH EPILEPSY Participants will include subjects with epilepsy, based on clinical history, imaging studies and ictal and/or interictal EEG interpreted by a clinical epileptologist. Seizures may be either symptomatic or idiopathic, primary generalized or focal-onset, and traumatic or non-traumatic in etiology. Subjects must have self-reported cognitive dysfunction.
Subjects must meet the following eligibility criteria:
-
Age > or = 18 years old;
-
IQ > or = 70, estimated by the Wechsler Test of Adult Reading (WTAR);
-
Capacity to provide informed consent;
-
Ability to live independently and complete activities of daily living;
-
Stable seizure frequency at the time of enrollment, such that the subject's treating physician does not believe a change in anticonvulsant regimen to be warranted during the trial (the anticonvulsant drugs should remain unchanged during the 16 weeks of participation unless absolutely required clinically due an unanticipated change in seizure frequency or severity);
-
Fluency in English.
Exclusion criteria
-
Psychogenic, non-epileptic spells;
-
Diagnosis of dementia (i.e., Alzheimer's disease);
-
Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable neoplasm with no plans for resection will not be cause for exclusion;
-
Alcohol or illicit drug abuse within the past year, as this may affect cognition by other mechanisms. This information may be obtained by self-report, from the referring physician or by medical record. Subjects will also undergo urine drug testing at the baseline visit. Chronic, stable use of marijuana will not be cause for exclusion. In cases of intermittent, recreational use, it will be required that subjects refrain from marijuana for 2 weeks prior to testing. Cannabidiol use will be permitted.
-
Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or focal-onset seizures with impaired awareness within 24 hours of neuropsychological testing. This restriction will avoid testing during a post-ictal state. This timing is conservative, based on practice as well as prior studies of post-ictal cognitive function demonstrating return to baseline within one day (Dodrill and Ojemann, 2007; Helmstaedter, Elger, & Lendt, 1994).
-
Prior status epilepticus in the past year;
-
Neurosurgery within the past 6 months, as there may be recovery in cognition post-operatively;
-
Current pregnancy or pregnancy planned during the trial;
-
Breastfeeding;
-
Concurrent treatment with a monoamine oxidase inhibitor (MAOI; e.g., selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue), or use of an MAOI within 14 days of beginning the trial (due to the risk of hypertensive crisis);
-
Structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or coronary artery disease, as complications due to small MPH-related increases in heart rate and blood pressure may be of concern in these populations;
-
History of a suicide attempt in the past year;
-
Psychotic or bipolar disorders, due to the risk of psychotic or manic symptom exacerbation;
-
Concurrent use of medications for erectile dysfunction (e.g., tadalafil, sildenafil), due to an increased risk of priapism;
-
Use of medications that may lower seizure threshold (e.g., tramadol, immediate release bupropion);
-
Known allergy to methylphenidate;
-
Use of narcotic or other sedating medications within 6 hours of testing (i.e., diphenhydramine), which may interfere with cognition;
-
Uncontrolled hypertension;
-
Concurrent severe major medical illness (e.g., cancer requiring chemotherapy or resection).
- CONTROLS *DO NOT UNDERGO ANY DRUG OR PLACEBO INTERVENTION Two additional subject groups will be included, to control for effects of repeated testing in the open-label extension phase: healthy subjects and epilepsy patients without cognitive complaints, who will not receive the study drug at any point during the study.
Epilepsy patients without cognitive complaints must otherwise meet all of the above inclusion criteria, and will be excluded for the following:
-
Psychogenic, non-epileptic spells;
-
Diagnosis of dementia (i.e., Alzheimer's disease);
-
Other progressive neurologic illness (i.e., malignant brain tumor). A benign, stable neoplasm with no plans for resection will not be cause for exclusion;
-
Alcohol or illicit drug abuse within the past year. This information may be obtained by self-report, from the referring physician or by medical record. Subjects will also undergo urine drug testing at the baseline visit. Chronic, stable use of marijuana will not be cause for exclusion. In cases of intermittent, recreational use, it will be required that subjects refrain from marijuana for 2 weeks prior to testing. Cannabidiol use will be permitted.
-
Generalized tonic-clonic or other generalized motor seizure(s) within 48 hours or focal-onset seizures with impaired awareness within 24 hours of neuropsychological testing.
-
Prior status epilepticus in the past year;
-
Neurosurgery within the past 6 months;
-
History of a suicide attempt in the past year;
-
Psychotic disorders;
-
Use of narcotic or other sedating medications within 6 hours of testing, which may interfere with cognition;
-
Concurrent severe major medical illness (e.g., cancer requiring chemotherapy or resection).
Healthy controls must meet the following inclusion criteria:
-
Age > or = 18 years old;
-
IQ > or = 70, estimated by the Wechsler Test of Adult Reading (WTAR);
-
Capacity to provide informed consent;
-
Ability to live independently and complete activities of daily living;
-
Fluency in English.
Healthy controls will be excluded based on the following criteria:
-
History of seizures, epilepsy, or psychogenic, non-epileptic spells;
-
Diagnosis of dementia (i.e., Alzheimer's disease);
-
Other progressive neurologic illness (i.e., malignant brain tumor);
-
Moderate or severe traumatic brain injury, or mild trauma within the past 6 months;
-
Alcohol or illicit drug abuse within the past year. This information may be obtained by self-report. Subjects will also undergo urine drug testing at the baseline visit. Chronic, stable use of marijuana will not be cause for exclusion. In cases of intermittent, recreational use, it will be required that subjects refrain from marijuana for 2 weeks prior to testing.
-
History of a suicide attempt in the past year;
-
Psychotic disorders;
-
Use of narcotic or other sedating medications within 6 hours of testing, which may interfere with cognition;
-
Ongoing major neurological or medical illness (e.g., cancer requiring chemotherapy or resection).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Miami VA Healthcare System | Miami | Florida | United States | 33125 |
| 2 | VA New York Harbor Healthcare System | New York | New York | United States | 10010 |
| 3 | VA Portland Health Care System | Portland | Oregon | United States | 97239 |
Sponsors and Collaborators
- VA New York Harbor Healthcare System
- Portland VA Medical Center
- Miami VA Healthcare System
Investigators
- Principal Investigator: Beth Leeman-Markowski, MD, NY Harbor VA Healthcare System
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 000