Residual Fatigue in Unipolar and Bipolar Depression: A Systematic Review.

Background: Residual fatigue is a common and debilitating symptom in patients with unipolar and bipolar depression, even after achieving partial or full remission. It significantly impacts patients' quality of life and increases the risk of relapse. This systematic review aims to evaluate the prevalence and effectiveness of therapeutic options for residual fatigue in individuals with unipolar major depressive disorder (MDD) and bipolar disorder (BD).
Methods: A comprehensive search was conducted in the PubMed, SCOPUS, and Web of Science databases up to September 2024. The protocol for this systematic review was registered in PROSPERO. The search strategy included terms related to depression and residual fatigue. Studies were included if they provided data on adult patients diagnosed with MDD or BD, and if they measured the prevalence or treatment of residual fatigue. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale for non-randomized studies.
Results: Twenty studies were included in the review. The vast majority reported on MDD, and single papers investigated BD. Residual fatigue was reported by up to 83% of patients, and moderate to severe residual fatigue affected a smaller percentage. Pharmacological treatments, such as modafinil and to a lesser extent atomoxetine, demonstrated short-term reductions in residual fatigue.
Conclusion: Residual fatigue remains a significant challenge in the treatment of depression, persisting in a large portion of patients despite remission. Pharmacological interventions like modafinil appear promising, but more research is needed, especially in BD. Standardized assessment tools and longer-term studies are essential to better understand and treat residual fatigue.
Trial Registration: PROSPERO identifier: CRD42024543087.
(© 2025 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)