Repurposing Drugs for Post–COVID-19 Fatigue Syndrome: Methylphenidate, Duloxetine, and Brexpiprazole : American Journal of Therapeutics

Secondary Logo

Journal Logo


Repurposing Drugs for Post–COVID-19 Fatigue Syndrome: Methylphenidate, Duloxetine, and Brexpiprazole

Manu, Peter MD

Author Information
doi: 10.1097/MJT.0000000000001471
  • Free

Persistent tiredness associated with cognitive deficits, “brain fog,” headache, myalgia, dyspnea, sleep abnormalities, and occupational disability has emerged as a common syndrome in patients with documented COVID-19 infection. Self-selected subjects in recently published studies present with a remarkably uniform clinical picture. Among 156 patients evaluated in New York City at a median time of 11 months after diagnosis, fatigue was present in 82%, “brain fog” in 67%, and headache in 60%.1 The symptoms worsened after physical exertion (86%) and stress (60%). In this group, formal testing demonstrated cognitive impairment in 60% of subjects. Across the Atlantic Ocean, in Milan, Italy, the most common symptoms reported by a cohort of 303 subjects assessed 12 months after infection were fatigue in 52%, muscle and joint pain in 48%, sleep disorders in 47%, and cognitive impairment in 36%.2 A prospective study of 96 patients with COVID-19 infection followed in Heidelberg, Germany, indicated that in 12 months 53% of patients reported fatigue.3 Symptoms suggesting posttraumatic stress, anxiety, or depressive disorder may also be present.

Experts have suggested that the post–COVID-19 fatigue syndrome (PCFS) shows great similarity with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS),4 a poorly understood condition that has been described after a variety of viral infections and shares many clinical and prognostic features with fibromyalgia. Pharmacological interventions in ME/CFS have been disappointing, a fate that might await PCFS as well. Yet the stakes are clearly higher for PCFS. The prevalence of ME/CFS is approximately 0.75%.5 On the other hand, a review of 18 cross-sectional studies indicated that 32% of individuals with a history of patients with COVID-19 reported fatigue 28 weeks after the onset of their acute illness.6 Given the fact that there are 48.6 million people in the United States who survived a documented COVID-19 infection,7 the prevalence of PCFS can be conservatively estimated at 4.7% or 15.5 million in December 2021.

A drug, or combination of drugs, will be effective for PCFS if it would eliminate or ameliorate fatigue. In addition, the treatment should increase physical endurance; prevent postexertional malaise; improve attention, concentration, and memory; correct nonrefreshing sleep; decrease pain; and restore euthymia. In my view, mostly based on recent publications, some of these goals can hopefully be achieved in carefully controlled trials of 3 pleiotropic medications already approved by the Food and Drug Administration, methylphenidate, duloxetine, and brexpiprazole.

Findings from a randomized controlled trial in healthy subjects have indicated that methylphenidate, approved for use as a psychostimulant, improves self-reported fatigue and declarative memory 24 hours after learning.8 Another high-quality, placebo-controlled investigation established that methylphenidate, taken as needed, was effective in relieving fatigue in patients with advanced cancer.9 Methylphenidate was also shown to improve mental fatigue and processing speed in patients with residual deficits after mild traumatic brain injury.10 Finally, an in-depth evaluation of 52 systematic reviews focusing on the treatment of fatigue in chronic physical health conditions singled out methylphenidate as a drug useful in diverse diseases, such as sarcoidosis, Parkinson disease, and infection with the human immunodeficiency virus.11

Duloxetine, a drug widely used for the treatment of major depression, generalized anxiety disorder, and neuropathic pain, has convincingly emerged as the most effective treatment of functional impairment in depressed patients, as demonstrated in a network metanalysis of 42 randomized controlled trials.12 Duloxetine has also been endorsed by the American College of Physicians and American Academy of Family Physicians as second-line treatment for chronic low back pain in patient not responding to nonsteroidal anti-inflammatory drugs.13 In a well-designed placebo-controlled trial in the United States, patients with fibromyalgia without a depressive disorder treated with duloxetine showed significant improvement in pain severity and in a global measure of fatigue, tiredness on awakening, and muscle stiffness.14 Clinically relevant improvements in patients' global impression and frequency of at least 30% decrease in pain severity in patients with fibromyalgia receiving duloxetine have been confirmed by a Cochrane analysis.14

A serotonin–dopamine activity modulator was approved for use as antipsychotic and for adjunctive A serotonin-dopamine activity modulator approved for use as antipsychotic and for adjunctive treatment of depressive disorders, brexpiprazole has shown promise for the treatment of post-traumatic stress disorder and for agitation in patients with cognitive impairment.15 The drug improves daytime alertness, sleep efficiency, sleep-dependent depressive symptoms,16 energy level, cognitive ability, and general functioning.17

Testing the benefits and adverse effects of methylphenidate, duloxetine, and brexipiprazole, or all other reasonable interventions for patients with “long-haul COVID-19,” should be rapidly pursued according to the framework implemented and funded by the US National Institutes of Health. The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program contains a large study of 3 repurposed drugs, ivermectin, fluvoxamine, and fluticasone,18 which will cost $155 million. A similar or larger financial commitment must be made to discover ways of managing the prolonged and disabling manifestations and suffering after the acute infection.


1. Tabacof L, Tosto-Mancuso J, Wood J, et al. Post-acute COVID-19 syndrome negatively impacts physical function, cognitive function, health-related quality of life and participation. Am J Phys Med Rehabil. 2022;101:48–52.
2. Lombardo MDM, Foppiani A, Peretti GM, et al. Long-term coronavirus disease 2019 complications in inpatients and outpatients: a one-year follow-up cohort study. Open Forum Infect Dis. 2021;8:ofab384.
3. Seeßle J, Waterboer T, Hippchen T, et al. Persistent symptoms in adult patients one year after COVID-19: a prospective cohort study. Clin Infect Dis. 2021:ciab611. Online ahead of print.
4. Komaroff AL, Bateman L. Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome?. Front Med (Lausanne). 2021;7:606824.
5. Lim EJ, Son CG. Prevalence of chronic fatigue syndrome (CFS) in korea and Japan: a meta-analysis. J Clin Med. 2021;10:3204.
6. Sandler CX, Wyller VBB, Moss-Morris R, et al. Long COVID and post-infective fatigue syndrome: a review. Open Forum Infect Dis. 2021;8:ofab440.
7. Available at: Accessed December 9, 2021.
8. Repantis D, Bovy L, Ohla K, et al. Cognitive enhancement effects of stimulants: a randomized controlled trial testing methylphenidate, modafinil, and caffeine. Psychopharmacology (Berl). 2021;238:441–451.
9. Pedersen L, Lund L, Petersen MA, et al. Methylphenidate as needed for fatigue in patients with advanced cancer. A prospective, double-blind, and placebo-controlled study. J Pain Symptom Manage. 2020;60:992–1002.
10. Johansson B, Andréll P, Rönnbäck L, et al. Follow-up after 5.5 years of treatment with methylphenidate for mental fatigue and cognitive function after a mild traumatic brain injury. Brain Inj. 2020;34:229–235.
11. Hulme K, Safari R, Thomas S, et al. Fatigue interventions in long term, physical health conditions: a scoping review of systematic reviews. PLoS One. 2018;13:e0203367.
12. Cao B, Xu L, Chen Y, et al. Comparative efficacy of pharmacological treatments on measures of self-rated functional outcomes using the Sheehan Disability Scale in patients with major depressive disorder: a systematic review and network meta-analysis. CNS Spectr. 2021:1–9.
13. Qaseem A, McLean RM, O'Gurek D, et al. Nonpharmacologic and pharmacologic management of acute pain from non-low back, musculoskeletal injuries in adults: a clinical guideline from the American College of Physicians and American Academy of family Physicians. Ann Intern Med. 2020;173:739–748.
14. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;2:CD010292.
15. Citrome L, Stensbol TB, Maeda K. The preclinical profile of brexpiprazole: what is its clinical relevance for the treatment of psychiatric disorders?. Expert Rev Neurother. 2015;15:1219–1229.
16. Krystal AD, Mittoux A, Meisels P, et al. Effects of adjunctive brexpiprazole on sleep disturbances in patients with major depressive disorder: an open-label, flexible-dose, exploratory study. Prim Care Companion CNS Disord. 2016;18.
17. Fava M, Okame T, Matsushima Y, et al. Switching from inadequate adjunctive or combination treatment options to brexpiprazole adjunctive to antidepressant: an open-label study on the effects on depressive symptoms and cognitive and physical functioning. Int J Neuropsychopharmacol. 2017;20:22–30.
18. Available at: Accessed December 9, 2021.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.