Methylphenidate

Methylphenidate

PEP Topic 
Depression
Description 

Methylphenidate is a type of psychostimulant used to treat attention-deficit hyperactivity disorder and narcolepsy. Methylphenidate is closely related to amphetamine and is a schedule II drug. It is taken by mouth and available by numerous different brand names. It can be habit forming, and individuals can develop tolerance to its effects. Methylphenidate use for patients with cancer has been evaluated in anxiety, depression, fatigue, and cognitive impairment. Methylphenidate has been evaluated alone and as part of multimodal approaches combined with other interventions, such as exercise.

Effectiveness Not Established

Research Evidence Summaries

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.

doi: 10.1007/s11060-011-0723-1
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

Patients were randomized to receive one of the following three interventions for a total of four weeks:  immediate-release methylphenidate, 10 mg twice daily; sustained-release methylphenidate, 18 mg daily; or modafinil, 200 mg daily. Neurocognitive tests were performed prior to the intervention and were repeated approximately 30 days later, after completion of the intervention.

Sample Characteristics:

  • Twenty-four patients with primary brain tumors were included.
  • Mean age was 44.98 years.
  • The sample was 54% male and 46% female.
  • Most (62.5%) of patients’ tumors were in the left hemisphere.
  • Prior treatment history included radiation therapy (83%) and chemotherapy (87.5%). Of all the participants, 62.5% received chemotherapy during the study.

Setting:

  • Single site
  • Outpatient
  • MD Anderson Cancer Center, Houston, Texas

Phase of Care and Clinical Applications:

Patients were undergoing multiple phases of care.

Study Design:

The study was a randomized, clinical trial.

Measurement Instruments/Methods:

Objective Cognitive Function Instruments

  • Wechsler Adult Intelligence Scale, third edition (WAIS-III) Digit Span and Digit Symbol subtests
  • Trail Making Test (TMT) Parts A and B
  • Hopkins Verbal Learning Test (HVLT) Immediate Recall, Delayed Recall, and Delayed Recognition Trials
  • Multilingual Aphasia Examination Controlled Oral Word Association (MAE COWA) category
  • Lafayette Instrument Grooved Pegboard Test

Subjective Anxiety Instruments

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

Subjective Depression Instruments

  • Beck Depression Inventory (BDI)
  • Profile of Mood States (POMS) Questionnaire, Depression-Dejection Scale

Subjective Fatigue Instruments

  • Brief Fatigue Inventory (BFI)
  • POMS questionnaire, Fatigue-Inertia Scale

Subjective Sleep-Wake Disturbance Instrument

  • Brief Sleep Disturbance Scale (BSDS)

Results:

  • Over time, no differences were found in cognitive function in regard to attention or motor function.
  • Over time, mixed results were found in regard to the speed of processing:
    • The WAIS-III Digit Symbol subtest showed significant improvement (p = 0.02), but TMT Part A did not.
    • The HVLT Delayed Recognition Trial showed a signficiant decline (p = 0.03) in memory, but the other memory-related trials did not.
  • In regard to the use of either stimulant and executive function over time, the TMT Part B score improved significantly (p = 0.02); however, the MAE COWA score declined significantly (p = 0.02).
  • In regard to differences between the methylphenidate and modafinil treatment groups over time, researchers found the following:
    • A significant difference (p = 0.05) in attention. Attention-related scores of patients taking methylphenidate were stable on the WAIS-III Digit Span subtest; the scores of patients taking modafinil worsened over time.
    • A difference in the speed of processing as measured by TMT Part A. Patients using modafinil improved in comparison to patients taking methylphenidate, whose scores either remained stable or declined slightly (p = 0.05).
  • In regard to subjective measures of other symptoms, researchers noted, with use of either stimulant over time:
    • Significant improvement (p < 0.01) of depression, as measured by the BDI and POMS Depression-Dejection Scale.
    • Significant improvement (p = 0.04) of fatigue, as measured by the BFI.
    • Significant improvement of fatigue (p < 0.01), as measured by the POMS Fatigue-Inertia Scale.
    • Significant improvement (p = 0.03) of anxiety, as measured by the state subtest of the STAI.
  • No differences were found over time in regard to sleep-wake disturbances.
  • No differences were found between treatment groups in subjective symptom measures over time.

Conclusions:

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

Limitations:

  • The study had a small sample size, with less than 30 participants.
  • The study had risks of bias due to no control group and no blinding.
  • Participant withdrawals were 10% or greater.
  • The investigators were unable to achieve the sample size recommended by the power analysis due to poor accrual and a high drop-out rate (29%). Treatment groups differed significantly in regard to age (p = 0.02) and gender (p = 0.03). Age and gender influence neuropsychological test results.

Nursing Implications:

No evidence was provided to support the use of stimulants to improve cognitive function. The study supports the conduct of future research of this topic in studies with larger sample sizes and in randomized, clinical trials with a nonintervention arm.

Homsi, J., Nelson, K.A., Sarhill, N., Rybicki, L., LeGrand, S.B., Davis, M.P., & Walsh, D. (2001). A phase II study of methylphenidate for depression in advanced cancer. American Journal of Hospice and Palliative Care, 18, 403–407.

doi: 10.1177/104990910101800610
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Study Purpose:

A phase II study of methylphenidate for depression in patients with advanced cancer

Intervention Characteristics/Basic Study Process:

Patients who were identified as being depressed by a palliative medicine attending physician were treated with methylphenidate twice daily. Doses were titrated per regimen until response was obtained. Patients were assessed during a telephone call or bedside interview. The study timeframe was seven days.

Sample Characteristics:

  • N = 30
  • MALES: 50%, FEMALES: 50%
  • KEY DISEASE CHARACTERISTICS: Primary cancer sites: breast (5), esophagus (4), head and neck (4), lung (4), pancreas (4), colorectal (2), and other (7)
  • OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criterion was the answer of “yes” to the question, “Are you depressed?” with no current or previous antidepressant use.

Setting:

  • SITE: One center was included.
  • SETTING TYPE: Inpatients and outpatients were enrolled in the palliative care program.

Measurement Instruments/Methods:

  • Question, “Are you depressed?”
  • Other symptoms (anorexia, concentration problems, fatigue, and sedation) were assessed by a categorical rating (none, mild, moderate, or severe) before starting methylphenidate and daily thereafter.
  • Pain was assessed using a 0–10 scale.
  • Known side effects of methylphenidate also were assessed.
  • Satisfaction question: ”Are you satisfied with the way the drug affected your mood?” was asked at the end of the study on day seven.

Results:

Depression was resolved in all patients, most on day three. The maximum daily dose needed was 20 mg. Other symptoms also improved, mean pain scores significantly decreased, and all who responded to treatment were satisfied with therapy.

Limitations:

  • Small sample with no randomization
  • Long-term efficacy and side effect data are needed.
  • Single-site data are less transferable than multi-site data.

Ng, C.G., Boks, M.P., Roes, K.C., Zainal, N.Z., Sulaiman, A.H., Tan, S.B., & de Wit, N.J. (2014). Rapid response to methylphenidate as an add-on therapy to mirtazapine in the treatment of major depressive disorder in terminally ill cancer patients: A four-week, randomized, double-blinded, placebo-controlled study. European Neuropsychopharmacology, 24, 491–498.

doi: 10.1016/j.euroneuro.2014.01.016
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Study Purpose:

To evaluate whether adding methylphenidate to mirtazapine in the treatment of depression in terminally ill patients with cancer will cause an earlier antidepressant response compared to patients receiving mirtazapine and a placebo

Intervention Characteristics/Basic Study Process:

Patients initially were interviewed by a psychiatrist to confirm the diagnosis of major depressive symptoms using the Mini-International Neuropsychiatric Inventory. Patients were randomized and double-blinded (1:1) to receive either methylphenidate (MPH) or a placebo with mirtazapine (MTZ). Patients taking MTZ received a fixed dosage while MPH was first dosed at 5 mg BID then increased, if needed, after day 3. Outcomes were assessed at baseline and at six subsequent follow-up visits during the double-blind treatment on days 3, 6, 9, 14, 21, and 28. Assessments included the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression–Severity scale.

Sample Characteristics:

  • N = 88  
  • MEAN AGE = 59.52 years (group 1), 55.89 years (group 2 [placebo])
  • MALES: 78%, FEMALES: 22%
  • KEY DISEASE CHARACTERISTICS: Patients diagnosed with a major depressive disorder in the terminal disease stage of any type of cancer 
  • OTHER KEY SAMPLE CHARACTERISTICS: Receiving palliative care with a life expectancy less than three months; oncology or surgery departments or palliative care units; Malay, Chinese, Indian, and other ethnicities were included; 84% were inpatient in both groups

Setting:

  • SITE: Single-site    
  • SETTING TYPE: Multiple settings    
  • LOCATION: University Malaya Medical Centre, Kuala Lumpur, Malaysia

Phase of Care and Clinical Applications:

  • PHASE OF CARE: End-of-life care
  • APPLICATIONS: Palliative care 

Study Design:

Randomized, double-blinded, placebo-controlled study

Measurement Instruments/Methods:

  • Montgomery-Asberg Depression Rating Scale (MADRS): A clinician-rated scale for the assessment of depression that includes 10 items (nine are patient-reported and one is based on observation). 
  • Clinical Global Impression–Severity Scale (CGI-S): A single-item, clinician-rated scale that reflects the global severity of illness at time of assessment.

Results:

The MADRS scores at baseline did not differ between the groups; however, the MTZ+MPH group had a greater reduction in MADRS scores by day 28. These differences were noted from day 3 and were significant. The number of patients who responded to treatment also differed between the groups and was significantly greater in the MTZ+MPH group by day 28. There also were significant differences in the changes of CGI-S scores between the groups from day 3 till the end of the study.
 
Notably, adverse events of nervous system were seen in the MTZ+MPH group although most were mild. The high dropout rate was not statistically significant between the groups. The most common reasons for dropouts were death, neuropsychiatric symptoms, and personal reasons.

Conclusions:

Although this was a small-scale study and the dropout rate was high, this study has implications for a small subset of patients. The addition of MPH to the standard treatment of depression may improve the response rates of terminally ill patients with cancer, beginning as early as three days after starting treatment. MPH must be used with caution due to side effects.

Limitations:

  • Small sample (< 100)
  • Risk of bias (sample characteristics)
  • Findings not generalizable
  • Subject withdrawals ≥ 10%
  • Other limitations/explanation: The percentage of males was higher in the placebo group. There was a high dropout rate, mostly because of death, but side effects and personal reasons also were mentioned. Well-designed, larger studies need to be done. A study using MPH alone would be useful. Some of the symptoms could be related to the disease rather than depression.

Nursing Implications:

Psychosocial assessment, which includes depression, is extremely important to the nursing profession. For those who care for terminally ill patients with cancer, having options to improve quality of life for a patient suffering from depression can have significant clinical implications. Using MPH may be one option to consider when seeking quick results in treating a major depressive disorder in terminally ill patients. MPH must be used with caution due to potential side effects, and the need for further research in this population is indicated.

Systematic Review/Meta-Analysis

Gong, S., Sheng, P., Jin, H., He, H., Qi, E., Chen, W., . . . Hou, L. (2014). Effect of methylphenidate in patients with cancer-related fatigue: A systematic review and meta-analysis. PloS One, 9(1), e84391.

doi: 10.1371/journal.pone.0084391
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Purpose:

To assess the safety and efficacy of methylphenidate for cancer-related fatigue. Secondary outcomes included depression, cognition, and adverse effects.

TYPE OF STUDY: Meta-analysis and systematic review

Search Strategy:

DATABASES USED: PubMed. EMBASE, PsycINFO, Cochrane Collaboration


KEYWORDS: Methylphenidate, dimethylphenidate, Ritalin, cancer, fatigue, asthenia, tiredness, and randomized controlled trial


INCLUSION CRITERIA:  Randomized controlled trials, adults older than 18 years, the trial examined efficacy of methylphenidate on fatigue, and results were sufficient to calculate effect sizes


EXCLUSION CRITERIA: None specified

Literature Evaluated:

TOTAL REFERENCES RETRIEVED: N = 374


EVALUATION METHOD AND COMMENTS ON LITERATURE USED: The Jadad scale was used for quality assessment.

Sample Characteristics:

  • N (studies) = 5
  • SAMPLE RANGE ACROSS STUDIES: 10–62
  • TOTAL PATIENTS INCLUDED IN REVIEW: 198
  • KEY SAMPLE CHARACTERISTICS: Three studies included mixed tumor types, one was in prostate, and one was in patients with primary brain tumor.

Phase of Care and Clinical Applications:

PHASE OF CARE: Mutliple phases of care

Results:

Meta-analysis was done with studies grouped according to the measure of fatigue that was used. In studies using the FACT-F (three studies), results showed a favorable effect of methylphenidate with a mean difference of -3.13 and a signficant overall effect (p -0.01). In studies using the BFI, results showed a favorable effect with mean difference of -0.69, but the Z test of overall effect was not significant. Methylphenidate had no effect on depression (two studies) or cognitive impairment (two studies). Studies varied widely in terms of the duration of treatment. Treatment for greater than four weeks was superior compared to placebo. However, treatment for less than four weeks did not show a significant effect compared to placebo. Rates of adverse effects between those getting methylphenidate and those getting a placebo were not significantly different. Those receiving methylphenidate had significantly more vertigo, anxiety, and nausea.

Conclusions:

Results suggest that treatment with methylphenidate for at least four weeks is effective in reducing cancer-related fatigue and is not associated with a high rate of adverse effects. Treatment with methylphenidate did not improve depression or cognitive impairment. Use of different methods of measurement of fatigue showed different results.

Limitations:

Few studies were included, and some of these had very small sample sizes. Included studies did not provide sufficient information on relevant concomitant conditions of patients, such as sleep disorders and anxiety. Dosages and dosage increase approaches with methylphenidate varied.

Nursing Implications:

Findings suggest that treatment with methylphenidate for at least four weeks can be helpful in managing cancer-related fatigue. However, the most appropriate dosages are not clear. Patients can experience side effects, and if methylphenidate is used, nurses need to monitor patients for side effects. Further large studies are needed to strengthen evidence related to effects and side effects of methylphenidate.

Rozans, M., Dreisbach, A., Lertora, J.J., & Kahn, M.J. (2002). Palliative uses of methylphenidate in patients with cancer: A review. Journal of Clinical Oncology, 20, 335–339.

doi: 10.1200/JCO.20.1.335
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Search Strategy:

DATABASES USED: MEDLINE

 

Literature Evaluated:

COMMENTS ON LITERATURE USED: Articles published from 1966–2000 related to methylphenidate use in patients with cancer or in palliative care

Sample Characteristics:

FINAL NUMBER STUDIES USED = 49 

Results:

The evidence in the review found that methylphenidate is useful for the treatment of depression in a variety of malignancies, with more than 80% improvement in depression and side effects in less than 20%.

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