Gehring, K., Patwardhan, S.Y., Collins, R., Groves, M.D., Etzel, C.J., Meyers, C.A., & Wefel, J.S. (2012). A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor. Journal of Neuro-Oncology, 107, 165–174.

To compare the effectiveness of immediate-release or sustained-release methylphenidate versus modafinil in improving cognitive function in patients with primary brain tumors.

Patients were randomized to receive one of the following three interventions for a total of four weeks.

• Immediate-release methylphenidate 10 mg twice a day
• Sustained-release methylphenidate 18 mg daily
• Modafinil 200 mg daily

Neurocognitive tests were done prior to the initiation of the intervention and repeated approximately 30 days later after completion of the intervention.

• A total of 24 patients participated in the study.
• Participants' average age was 44.98 years.
• The sample was 54% male and 46% female.
• 62.5% of patients’ tumors were in the left hemisphere.
• Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). A total of 62.5% were receiving chemotherapy during the study.
   

• Single site 
• Outpatient 
• University of Texas M.D. Anderson Cancer Center in Houston

Patients were in mutliple phases of care.

The study was conducted as a randomized clinical trial.

Objective Cognitive Function Instruments

• Wechsler Adult Intelligence Scale III (WAISIII)—digit span and digit symbol
• Trail Making Test—parts A and B
• Hopkins Verbal Learning Test (HVLT)—immediate recall, delayed recall, and delayed recognition
• Multilingual Aphasia Examination (MAE)—controlled oral word association (COWA)
• Lafayette Grooved Pegboard

Subjective Anxiety Instruments

• State-Trait Anxiety Inventory (STAI)—state and trait anxiety  
• Profile of Mood States (POMS)—tension-anxiety

Subjective Depression Instruments

• Beck Depression Inventory (BDI)
• Profile of Mood States (POMS)—depression-dejection

Subjective Fatigue Instruments

• Brief Fatigue Inventory (BFI)
• Profile of Mood States (POMS)—fatigue

Subjective Sleep-Wake Disturbance Instrument

• Brief Sleep Disturbance Scale (BSDS)

In regards to cognitive function, no differences were found over time with either stimulant in attention or motor function. Mixed results were found over time with stimulant use in speed of processing: significant improvement was found with the WAISIII digit symbol test (p = 0.02), but not with TMT-A. Similarly, a significant decline was found in memory as measured by the delayed recognition subtest of the HVLT (p = 0.03), but not with other subtests of that measure. When evaluating any stimulant use over time in regard to executive function, a significant improvement was found as measured by the TMT-B (p = 0.02) but a significant decline was found as measured by the COWA (p = 0.02). When evaluating differences between the methylphenidate and modafinil treatment groups over time, a significant difference was found in attention (p = 0.05): patients on methylphenidate had stable scores as measured by the digit span test and those on modafinil had worse scores over time. Likewise, a difference was seen in speed of processing (only as measured by the TMT-A) that found patients on modafinil improved in comparison to patients on methylphenidate, who either remained stable or had slight declines (p = 0.05)

In subjective measures of other symptoms, significant improvement was found over time with any stimulant use in depression as measured by the BDI (p < 0.01) and the POMS-Depr (p < 0.01), fatigue as measured by the BFI (p = 0.04) and POMS-fatigue (p < 0.01), and anxiety as measured by the STAI-state (p = 0.03). In contrast, no differences were seen over time for sleep-wake disturbances. No differences were found between treatment groups in subjective symptom measures over time.

Although the study found some improvements in specific cognitive domains over time (e.g., executive function, speed of processing), it is unclear whether these improvements were because of the use of a stimulant, a specific medication (modafinil versus methylphenidate), or other variables such as practice effects (related to the absence of alternative forms for neuropsychological tests). It is difficult to make any definitive interpretations based on this small study, because findings are confounded by the use of two different stimulants (one with two different dosing schedules) and the lack of a control group (patients who were not receiving stimulants).

• The sample size was small with less than 30 participants.
• The lack of a control group introduced a risk of bias.
• The key sample group had differences that could influence the results.
  • The study was unable to meet the sample size recommended by power analysis because of poor accrual and a substantial dropout rate (29%). 
  • The treatment groups varied significantly in age (p = 0.02) and gender (p = 0.03), both of these characteristics are known to influence neuropsychological test results.
• More than 10% of subjects withdrew from the study.

The study does not provide any support at this time to recommend the use of stimulants to improve cognitive function. Future research studies with larger sample sizes and randomized clinical trials with a nonintervention arm are warranted.