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Antidepressant Therapy of No Benefit in Chronic Fatigue Syndrome


  • In the adolescent population with chronic fatigue syndrome (CFS), does antidepressant therapy with fluoxetine improve severity of fatigue, ability to function, and/or neurocognitive function?

Clinical Bottom Lines

  1. Therapy with fluoxetine in patients with chronic fatigue syndrome does not improve subjective assessments of fatigue, severity of depression, functional impairment, sleep disturbances, neuropsychological function, cognitive function, or physical activity levels.(1)
  2. Outcomes with regard to the above variables did not differ when patients with depression or without depression were analyzed separately.
  3. Patients receiving fluoxetine experience side effects that lead to higher dropout rates than those seen for depressed patients without CFS.

Summary of Key Evidence

  1. 48 depressed patients and 59 non-depressed patients, all of whom met clinical criteria for the diagnosis of chronic fatigue syndrome, were randomized.  Depressed and non-depressed patients were randomized separately. (1)
  2. Patients were randomized in a double-blind fashion to receive either fluoxetine 20 mg, or placebo.  Therapy was continued for eight weeks.
  3. Clinical assessments were taken pre-treatment, at the end of the eight-week trial, and two months post-treatment.  Questionnaires and self-observation lists were administered for the following primary outcomes: fatigue severity, depression severity, sickness impact profile, physical activity, sleep quality scores, neuropsychological complaints, social interactions, self-efficacy expectations, and side effects.  Additional objective measures included neuropsychiatric testing and use of a motion-sensing device to measure physical activity.
  4. There were no differences between the fluoxetine-treated group and the placebo groups in the change from pretreatment to post-treatment for any primary outcome measured.  The mean differences in improvement in fatigue severity and depression severity were 0.164 (95 % CI 0.64 to 0.31) and 0.186 (-0.35 to 0.02) respectively. 
  5. Fifteen percent of patients in the fluoxetine group vs. 4% of patients in the placebo group withdrew due to side effects.  An intention-to-treat analysis was not done.

Additional Comments

  • Chronic fatigue syndrome likely represents at least several and likely many distinct clinical entities; no causal etiology has been identified.  Therefore, individual patients with chronic fatigue syndrome may have different responses to therapy.
  • Medications studied in randomized controlled trials for CFS include antidepressants, corticosteroids, dietary supplements, immunotherapy, and oral NADH.  None of these were proven efficacious in randomized, placebo-controlled clinical trials.(3)
  • Given the heterogeneous nature of patients with chronic fatigue syndrome, the n of 1 randomized, placebo-controlled trial may be a useful intervention in individual patients to determine treatment efficacy.


  1. Vercoulen JH, et al.  Randomised, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome.   Lancet, 1996; 347(9005):858-861.
  2. Mehta VK and Blume GB.  A randomized trial of fluoxetine in a patient with persistent fatigue.  Journal of the American Board of Family Practice, 1995; 8(3):230-232.
  3. Marshall GS.  Report of a workshop on the epidemiology, natural history, and pathogenesis of chronic fatigue syndrome in adolescents.  Journal of Pediatrics, 1999; 134(4):395-405.
  4. Reid S, et al.  Chronic fatigue syndrome. BMJ, 2000; 320(7230):292-296.

CAT Author: Sandra J. Bliss, MD

CAT Appraisers: Robert Schumacher, MD

Date appraised: July 19, 2000

Last updated February 16, 2003
Department of Pediatrics and Communicable Diseases
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