Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants

Ann Pharmacother. 2007 Jun;41(6):1005-12. doi: 10.1345/aph.1H526. Epub 2007 May 22.


Objective: To evaluate the literature discussing the use of modafinil in the treatment of residual symptoms of fatigue in patients with depression.

Data sources: PubMed (1966-March 2007) and International Pharmaceutical Abstracts (1970-March 2007) were searched using the key words modafinil and depression. A manual search of the reference section of the articles retrieved was conducted to identify articles not indexed in either of these sources.

Study selection and data extraction: All articles published in English were evaluated. Studies were included if modafinil was used to treat patients with residual fatigue from depression and the effects were measured with validated fatigue subscales.

Data synthesis: One retrospective study, 5 open-label trials, and 2 randomized controlled clinical trials met the inclusion criteria for assessment of residual symptoms of fatigue as assessed by commonly used fatigue subscales after modafinil administration. Although improvement with fatigue has occurred with modafinil therapy, literature regarding the topic is limited by the lack of well-controlled clinical trials. Modafinil does appear to improve residual fatigue with depression as evidenced by open-label trials; however, the efficacy of this agent has not been duplicated in randomized controlled trials. The open-label trials that have been conducted often had no comparator and a small number of patients. In addition, outcome measures used in the studies were not consistent between trials. Modafinil appears to be well tolerated, with the main adverse effects being headache and nausea.

Conclusions: Open-label trials indicate that modafinil may be effective in ameliorating fatigue associated with depression; however, this effect has not been reproduced in randomized, double-blind, placebo-controlled clinical trials. Therefore, the use of modafinil for the treatment of residual fatigue is not recommended due to the lack of reproducible data of its efficacy. Long-term, adequately powered clinical trials should be conducted to determine its place in therapy.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Benzhydryl Compounds / therapeutic use*
  • Central Nervous System Stimulants / therapeutic use*
  • Depression / drug therapy*
  • Fatigue / drug therapy*
  • Humans
  • Modafinil


  • Antidepressive Agents
  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Modafinil