Effects of methylphenidate on fatigue and depression: a randomized, double-blind, placebo-controlled trial

J Pain Symptom Manage. 2012 Jan;43(1):68-77. doi: 10.1016/j.jpainsymman.2011.03.026.


Context: Fatigue is highly prevalent in populations with advanced illness and is often associated with depressed mood. The role of psychostimulant therapy in the treatment of these conditions remains ill defined.

Objectives: To evaluate the response of fatigue and depression in patients with advanced illness to titrated doses of methylphenidate (MP) as compared with placebo.

Methods: In a randomized, double-blind, placebo-controlled trial, 30 hospice patients, both inpatients and outpatients, who had fatigue scores of at least four on a scale of zero to 10 (0=no fatigue and 10=worst fatigue), were randomly assigned to receive either 5mg of MP at 8 am and 1 pm or placebo. Doses of MP were titrated every three days according to response and adverse effects. Home care patients were monitored daily by telephone and visited by a research nurse on Study Days 0 (baseline), 3, 7, and 14. Fatigue was assessed using the Piper Fatigue Scale as the primary outcome measure and validated by the Visual Analogue Scale for Fatigue and the Edmonton Symptom Assessment Scale (ESAS) fatigue score. Subjects in inpatient facilities were interviewed or assessed by staff on an identical schedule. Depressive symptoms were assessed by the Beck Depression Inventory-II, Center for Epidemiologic Studies Depression Scale, and the ESAS depression score. Primary statistical analysis was conducted using repeated-measures multivariate analysis of the variance.

Results: Both MP- and placebo-treated groups had similar measures of fatigue at baseline. Patients taking MP were found to have significantly lower fatigue scores (Piper Fatigue Scale, Visual Analogue Scale for Fatigue, and ESAS) at Day 14 compared with baseline. The improvement in fatigue with MP treatment was dose-dependent; the mean average effective dose was 10mg on Day 3 and 20mg on Day 14 (dose range of 10-40 mg). Placebo-treated individuals showed no significant improvement in fatigue. For patients with clinically significant depression on Day 0, treatment with MP was associated with a significant reduction in all test indices for depressed mood. For the placebo group, the changes in measures of depression were less than observed in the treatment group but were inconsistent between assessment tools. No significant toxicities were observed.

Conclusion: MP reduced symptoms of fatigue and depression when compared with placebo. The effect of MP on fatigue was dose-dependent and sustained over the duration of the study.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Central Nervous System Stimulants / therapeutic use
  • Depression / complications*
  • Depression / diagnosis
  • Depression / drug therapy*
  • Double-Blind Method
  • Fatigue / complications*
  • Fatigue / diagnosis
  • Fatigue / drug therapy*
  • Female
  • Hospice Care / methods
  • Humans
  • Male
  • Methylphenidate / therapeutic use*
  • Middle Aged
  • Palliative Care / methods*
  • Placebo Effect
  • Terminal Care / methods*
  • Treatment Outcome


  • Central Nervous System Stimulants
  • Methylphenidate