Modafinil in Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Study type: Interventional

Summary: 
      Deficits in new learning and memory in MS are a major complaint of patients, and have been
      noted to be a significant contributor to disability by numerous researchers. Modafinil is a
      psychostimulant medication, FDA approved for the treatment of Narcolepsy, with potential
      application for the treatment of learning and memory dysfunction in MS. This randomized
      clinical trial tests the efficacy of Modafinil for the treatment of new learning and memory
      deficits in MS.

      Twenty subjects with clinically definite MS and objectively documented new learning
      impairment will be included in the study. All subjects will undergo baseline
      neuropsychological testing and EDSS to document current levels of functioning in new learning
      and memory abilities. Subjects will then be randomly assigned to either group 1 or group 2.
      Group 1 (n=10) will first undergo treatment with Modafinil (200 mg once per day in the
      morning) for 2 weeks. They will then undergo follow-up neuropsychological assessment and
      follow-up EDSS to evaluate any medication effects. After the follow-up evaluation, there will
      be a washout period of one week in which no medication will be administered. Group 1 will
      then receive a placebo medication for 2 weeks. A second follow-up evaluation will be
      conducted following this latter arm of the study. Group 2 (n=10) will follow the same
      pattern, but will receive the placebo medication during the first arm of the study and
      Modafinil during the 2nd arm of the study. The subjects and the experimenter administering
      the neuropsychological evaluation will be blind to group membership.
    

Detailed description: 
      Recent prevalence estimates of cognitive dysfunction in MS fall as high as 54-65%,21 with
      impairments having been documented in cognitive realms such as attention, executive control,
      working memory, and episodic memory. Deficits in long-term episodic memory in MS are a major
      complaint of patients, and have been noted to be a significant contributor to disability by
      numerous researchers.4,15,18 While the early studies of memory functioning in MS suggested
      that the memory impairment was due to difficulties in the retrieval of information from long
      term storage,19,26 more recent studies have challenged these conclusions. Specifically,
      research at KMRREC has clearly shown that verbal memory impairment in MS is primarily a
      function of poor acquisition of information, rather than retrieval failure.6,7,8 MS subjects
      require more trials to learn the same amount of information as healthy control subjects.
      However, once this learning has occurred, both MS and healthy control groups have comparable
      recall at 30-minutes, 90-minutes, and 1-week time periods (Appendix B).6,7,8 Given the
      apparent deficit in the acquisition of new information and the impact this deficit has on an
      individual's quality of life, the amelioration of this deficit is critical. The treatment of
      memory deficits has been the focus of research in numerous neurological populations, yet it
      has received little attention in MS.17 Although multiple authors have highlighted the need
      for cognitive rehabilitation techniques in MS,24,16 only a few existing cognitive
      rehabilitation programs have been aimed at improving attentional deficits,23 communication
      skills, 13 or memory and new learning within MS.1,2,14 In addition, few studies have examined
      the use of cognitive enhancing medications to treat cognitive deficits in MS. Greene and
      colleagues (2000) conducted a 12-week trial of Donepezil for the treatment of cognitive
      symptoms in MS, noting the medication to be useful for this population. Yet few other
      medication trials have been accomplished. Modafinil is a psychostimulant medication, FDA
      approved for the treatment of Narcolepsy, with potential application for the treatment of
      learning and memory dysfunction in MS.

      Two subtypes of the glutamate receptor channels have been implicated in memory functioning,
      the N-methyl-D-aspartate (NMDA) and AMPA subtypes. In addition, facilitation of glutamatergic
      transmission has been shown to promote long-term potentiation, which is hypothesized to be
      involved in the encoding of new memories (e.g. 3,5). One might therefore expect improvements
      in new learning and memory formation with the manipulation of glutamate and aspartate
      receptors. In contrast, facilitation of GABA transmission induces amnesia, while inhibiting
      GABA transmission enhances information retention. Therefore, the inhibition of GABA should
      additionally enhance new learning and memory functioning. Modafinil accomplishes both of
      these neurochemical effects.

      Animal studies have indicated that Modafinil significantly increases both aspartate and
      glutamate at the regional level, while decreasing the level of GABA through the inhibition of
      its release.20,12,10,22 In addition, Modafinil has been shown to exert its effect on specific
      brain regions, most notably for this study, in subregions of the hippocampus.11 Therefore,
      the application of Modafinil to an MS population with impairments in new learning has the
      potential to significantly improve cognitive functioning in this population, secondarily
      improving emotional symptoms and quality of life.

      Modafinil has been shown to be quite safe. Headaches are the most common side effect,29,9
      with other more common side effects including nausea, vomiting, nervousness, and anxiety.9
      Less common, but more serious side effects have included delusions and hallucinations,
      palpitations, chest pain, dyspnea, increased blood pressure, and EKG changes. 9 Modafinil has
      been applied to the treatment of Attention Deficit Hyperactivity Disorder, with results
      indicating Modafinil to be a viable treatment alternative to Dextroamphetamine in ADHD,28 and
      TBI,9 for the treatment of underarousal. Modafinil therefore demonstrates efficacy within
      other patient groups with neurological impairment.

      Rammohan et al 25 noted that 200mg/day of Modafinil significantly improved symptoms of
      fatigue in an MS sample and was tolerated quite well.25 Given that Modafinil has been proven
      to be a safe, effective treatment of arousal and fatigue, and its neurochemical effects are
      likely to enhance cognition, we are seeking to apply this medication for the treatment of
      cognitive deficits in MS. Due to the fact that Modafinil has been shown to act on glutamate
      and aspartate receptors, specifically influencing the hippocampus, it is hypothesized that
      treatment with this medication will result in better performance in tests of new learning and
      memory in an MS sample.

      Participants: Twenty subjects with clinically definite MS and objectively documented new
      learning impairment will be included in the study. Subjects will be excluded from
      participation in the presence of significant language comprehension deficits. Additional
      exclusion criteria are as follows: age greater than 60, less than 1-month post most recent
      exacerbation, current treatment with corticosteroids, significant neurological history aside
      from MS (e.g. epilepsy, TBI), significant substance abuse history as documented by the
      MAST,27 significant psychiatric history (e.g. Schizophrenia, Bipolar Disorder, Major
      Depression), non-fluency in the English language.

      Procedure: Please see study overview in Appendix C. Subjects will be recruited through
      physician referrals from the MS Clinic at UMDNJ in Newark, NJ (see letter of support,
      Appendix D). All potential subjects will undergo initial neuropsychological (NP) testing
      (Appendix E) to screen for study inclusion criteria, namely the presence of new learning
      impairment. Subjects will only be enrolled in the current protocol if they are classified as
      impaired in new learning and memory ability, with intact language abilities. Such impairment
      will be defined as performance at least 1.5 standard deviations (SD) below the mean of a
      healthy control sample on the Open Trial Selective Reminding Test. This test has been shown
      to be sensitive to deficits in new learning abilities commonly observed in MS. In addition,
      performance on the Token Test (see Appendix D) must be within normal limits. All subjects
      qualifying for the study will then undergo baseline neuropsychological testing to document
      current levels of functioning in new learning and memory abilities. Subjects will then be
      randomly assigned to either group 1 or group 2. A two-period crossover design will be used in
      which subjects will be randomly assigned to one of the two groups. Subjects in both groups
      will be seen by a physician (Dr. Greenwald) who will assess their current neurological status
      and complete the EDSS. Group 1 (n=10) will first undergo treatment with Modafinil (200 mg
      once per day in the morning) for 2 weeks. They will then undergo follow-up neuropsychological
      assessment and follow-up EDSS to evaluate any medication effects. After the follow-up
      evaluation, there will be a washout period of one week in which no medication will be
      administered. Group 1 will then receive a placebo medication for 2 weeks. A second follow-up
      evaluation will be conducted following this latter arm of the study. Group 2 (n=10) will
      follow the same pattern, but will receive the placebo medication during the first arm of the
      study and Modafinil during the 2nd arm of the study. Importantly, the subjects and the
      experimenter administering the neuropsychological evaluation will be blind to group
      membership. All subjects will be asked to keep a precise journal during both arms of the
      study, recording the time at which the medication was taken, any side effects, activities
      during the day, and any changes in cognition for each activity. They will be encouraged to
      contact the prescribing physician if they encounter any difficulties. See Table 1 for study
      protocol. A power analysis is presented in Appendix F.

      Statistical Analyses: A 2 (group) x 3 (testing sessions: baseline, 15 days, 37 days) repeated
      measures ANOVA will be performed. We hypothesize that there will be a significant interaction
      of time of testing by group. Cognitive performance is expected to improve from the 1st to the
      2nd testing sessions in the group 1, with just a mild practice effect documented in the group
      2. Additionally, we expect a return to baseline cognitive functioning from the 2nd to the 3rd
      NP assessment in Group 1, with an improvement in performance noted in group 2 due to
      medication effects. No main effects are anticipated. A linear regression will be used to
      examine the influence of memory performance and perception of memory abilities on changes in
      depression and anxiety at the various assessment intervals. We hypothesize that as memory
      improves, depression and anxiety levels will decrease. Additionally, as the perception of
      memory improves, depression and anxiety will also decrease.
    

Intervention name(s): Modafinil
Intervention type(s): Drug
Intervention MeSH terms: Modafinil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Multiple Sclerosis; Memory; New Learning; Fatigue