Fatigue is a frequently reported symptom in major depressive disorder, occurring in over 90% of patients. Clinical presentations of fatigue within major depressive disorder encompass overlapping physical, cognitive and emotional aspects. While this review addresses the epidemiology, burden, functional impact and management of fatigue in major depressive disorder, the main focus is on available pharmacotherapy options and their comparative efficacies. Our review of the effects of pharmacological treatments on fatigue in major depressive disorder found that medications with dopaminergic and/or noradrenergic action such as modafinil, flupenthixol and atomoxetine were most effective in improving symptoms of fatigue and low energy. However, significant variation across studies in assessment tools and study inclusion/exclusion criteria may have contributed to inconsistent findings. The efficacy of non-pharmacological interventions is also discussed, including light therapy and exercise.
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Chaudhuri A, Behan PO. Fatigue in neurological disorders. Lancet. 2004;363:978–88.
Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Phys. 2012;86:741–6.
Sharpe M, Wilks D. ABC of psychological medicine: fatigue. BMJ. 2002;325:480–3.
McIntyre R, Kennedy S, Bagby RM, Bakish D. Assessing full remission. J Psychiatry Neurosci. 2002;27:235–9.
Duncan KD. Fatigue: the predictors relevant to depression. Diss Abstr Int Sect B Sci Eng. 1996;56(10-B):5763.
Tylee A. Depression in Europe: experience from the DEPRES II survey. Eur Neuropsychopharmacol. 2000;10(Suppl. 4):S445–8.
Cahill CA. Differential diagnosis of fatigue in women. J Obstet Gynecol Neonatal Nurs. 1999;28:81–6.
Feyer A. Fatigue: time to recognise and deal with an old problem. BMJ. 2001;322:808–9.
Addington AM, Gallo JJ, Ford DE, Eaton WW. Epidemiology of unexplained fatigue and major depression in the community: the Baltimore ECA follow-up, 1981–1994. Psychol Med. 2001;31:1037–44.
Fried EI, Epskamp S, Nesse RM, Tuerlinckx F, Borsboom D. What are “good” depression symptoms? Comparing the centrality of DSM and non-DSM symptoms of depression in a network analysis. J Affect Disord. 2016;189:314–20.
Fried EI, Nesse RM. The impact of individual depressive symptoms on impairment of psychosocial functioning. PLoS One. 2014;9:e90311.
Bolling MY, Kohlenberg RJ. Reasons for quitting serotonin reuptake inhibitor therapy: paradoxical psychological side effects and patient satisfaction. Psychother Psychosom. 2004;73:380–5.
Aronson JK. Meyler’s side effects of psychiatric drugs. 1st edn. Oxford: Elsevier Science; 2008.
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41:1165–74.
Swindle R, Kroenke K, Braun L. Energy and improved workplace productivity in depression. In: Farquhar I, Summers K, Sorkin A, editors. Invest Heal Soc Econ Benefits Heal Care Innov. (Research Hum Cap Dev Vol. 14). Bingley, West Yorkshire: Emerald Group Publishing Limited; 2001:323–41.
Paykel ES. Remission and residual symptomatology in major depression. Psychopathology. 1998;31:5–14.
Ferentinos P, Kontaxakis V, Havaki-Kontaxaki B, Paparrigopoulos T, Dikeos D, Ktonas P, et al. Sleep disturbances in relation to fatigue in major depression. J Psychosom Res. 2009;66:37–42.
Burschka JM, Keune PM, Oy UH, Oschmann P, Kuhn P. Mindfulness-based interventions in multiple sclerosis: beneficial effects of Tai Chi on balance, coordination, fatigue and depression. BMC Neurol. 2014;14:165.
Fava M. Symptoms of fatigue and cognitive/executive dysfunction in major depressive disorder before and after antidepressant treatment. J Clin Psychiatry. 2003;6(Suppl. 14):30–4.
Stahl SM, Zhang L, Damatarca C, Grady M. Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry. 2003;64(Suppl. 14):6–17.
Ferentinos PP, Kontaxakis VP, Havaki-Kontaxaki BJ, Paplos KG, Soldatos CR. The measurement of fatigue in depression. Psychopathology. 2007;40:133–4.
Matza LS, Phillips GA, Revicki DA, Murray L, Malley KG. Development and validation of a patient-report measure of fatigue associated with depression. J Affect Disord. 2011;134:294–303.
Fehnel SE, Bann CM, Hogue SL, Kwong WJ, Mahajan SS. The development and psychometric evaluation of the Motivation and Energy Inventory (MEI). Qual Life Res. 2004;13:1321–36.
Ferentinos P, Kontaxakis V, Havaki-Kontaxaki B, Dikeos D, Lykouras L. Psychometric evaluation of the Fatigue Severity Scale in patients with major depression. Qual Life Res. 2011;20:457–65.
Saligan LN, Luckenbaugh DA, Slonena EE, Machado-Vieira R, Zarate CA. Development of a clinician-administered National Institutes of Health-Brief Fatigue Inventory: a measure of fatigue in the context of depressive disorders. J Psychiatr Res. 2015;68:99–105.
Piper BF, Dibble SL, Dodd MJ, Weiss MC, Slaughter RE, Paul SM. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum. 1998;25:677–84.
Chung KF, Yu BYM, Yung KP, Yeung WF, Ng TH, Ho FYY. Assessment of fatigue using the Multidimensional Fatigue Inventory in patients with major depressive disorder. Compr Psychiatry. 2014;55:1671–8.
Ameringer S, Elswick RK, Menzies V, Robins J, Starkweather A, Walter J, et al. Psychometric evaluation of the Patient-Reported Outcomes Measurement Information System Fatigue-Short Form across diverse populations. Nurs Res. 2016;65:279–89.
Stahl SM. The psychopharmacology of energy and fatigue. J Clin Psychiatry. 2002;63:7–8.
Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci. 2014;36:39–46.
Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2012;8:22–32.
Holsen LM, Lancaster K, Klibanski A, Whitfield-Gabrieli S, Cherkerzian S, Buka S, et al. HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience. 2013;250:732–42.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Association; 2013.
World Health Organization. International statistical classification of diseases and related health problems. Geneva: World Health Organization; 2016.
Cuthbert BN, Insel TR. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 2013;11:126.
Dillon DG, Rosso IM, Pechtel P, Killgore WDS, Rauch SL, Pizzagalli DA. Peril and pleasure: an RDoC-inspired examination of threat responses and reward processing in anxiety and depression. Depress Anxiety. 2014;31:233–49.
Güzel Özdemir P, Boysan M, Smolensky MH, Selvi Y, Aydin A, Yilmaz E. Comparison of venlafaxine alone versus venlafaxine plus bright light therapy combination for severe major depressive disorder. J Clin Psychiatry. 2015;76:e645–54.
Miller RG. Fatigue and therapeutic exercise. J Neurol Sci. 2006;242:37–41.
Fava M, Ball S, Nelson JC, Sparks J, Konechnik T, Classi P, et al. Clinical relevance of fatigue as a residual symptom in major depressive disorder. Depress Anxiety. 2014;31:250–7.
Moher D, Tetzlaff J, Altman D. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85–93.
Lam RW, Endicott J, Hsu M-A, Fayyad R, Guico-Pabia C, Boucher M. Predictors of functional improvement in employed adults with major depressive disorder treated with desvenlafaxine. Int Clin Psychopharmacol. 2014;29:239–51.
Shen J, Hossain N, Streiner DL, Ravindran AV, Wang X, Deb P, et al. Excessive daytime sleepiness and fatigue in depressed patients and therapeutic response of a sedating antidepressant. J Affect Disord. 2011;134:421–6.
Dunlop BW, Crits-Christoph P, Evans DL, Hirschowitz J, Solvason HB, Rickels K, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2007;27:614–9.
Han C, Wang S-M, Kwak K-P, Won W-Y, Lee H, Chang CM, et al. Aripiprazole augmentation versus antidepressant switching for patients with major depressive disorder: a 6-week, randomized, rater-blinded, prospective study. J Psychiatr Res. 2015;66–67:84–94.
Konuk N, Atasoy N, Atik L, Akay O. Open-label study of adjunct modafinil for the treatment of patients with fatigue, sleepiness, and major depression treated with selective serotonin reuptake inhibitors. Adv Ther. 2006;23:646–54.
Valle-Jones JC, Swarbrick DJ. Once daily flupenthixol in the treatment of elderly depressed patients: a multi-centre trial in general practice. Curr Med Res Opin. 1981;7:543–9.
Lundt L. Modafinil treatment in patients with seasonal affective disorder/winter depression: an open-label pilot study. J Affect Disord. 2004;81:173–8.
Papakostas GI, Petersen TJ, Burns AM, Fava M. Adjunctive atomoxetine for residual fatigue in major depressive disorder. J Psychiatr Res. 2006;40:370–3.
Sogaard J, Lane R, Latimer P, Behnke K, Christiansen P, Nielsen B, et al. A 12-week study comparing moclobemide and sertraline in the treatment of outpatients with atypical depression. J. Psychopharmacol. 1999;13:406–14.
Bould H, Wiles N, Potokar J, Cowen P, Nutt DJ, Peters TJ, et al. Does baseline fatigue influence treatment response to reboxetine or citalopram in depression? An open label randomized controlled trial. J Psychopharmacol. 2012;26:663–9.
Cheon E-J, Lee K-H, Park Y-W, Lee J, Koo B-H, Lee S-J, et al. Comparison of the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder unresponsive to selective serotonin reuptake inhibitors: a randomized, prospective, open-label study. J Clin Psychopharmacol. 2017;37:193–9.
Liverant GI, Sloan DM, Pizzagalli DA, Harte CB, Kamholz BW, Rosebrock LE, et al. Associations among smoking, anhedonia, and reward learning in depression. Behav Ther. 2014;45:651–63.
Kennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. Pharmacological treatments. Can J Psychiatry. 2016;61:540–60.
Cashman JR, Ghirmai S. Inhibition of serotonin and norepinephrine reuptake and inhibition of phosphodiesterase by multi-target inhibitors as potential agents for depression. Bioorganic Med Chem. 2009;17:6890–7.
Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002;47:27–38.
Gerrard P, Malcolm R. Mechanisms of modafi nil: a review of current research. Neuropsychiatr Dis Treat. 2007;3:349–64.
Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, et al. The other face of depression, reduced positive affect: the role of catecholamines in causation and cure. J Psychopharmacol. 2007;21:461–71.
Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA. Cognitive behavioral treatment of residual symptoms in primary major depressive disorder. Am J Psychiatry. 1994;151:1295–9.
Baldwin DS, Papakostas GI. Symptoms of fatigue and sleepiness in major depressive disorder. J Clin Psychiatry. 2006;67(Suppl. 6):9–15.
Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D project results: a comprehensive review of findings. Curr Psychiatry Rep. 2007;9:449–59.
Hewett K, Chrzanowski W, Jokinen R, Felgentreff R, Shrivastava RK, Gee MD, et al. Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder. J Psychopharmacol. 2010;24:521–9.
Papakostas GI, Nutt DJ, Hallett LA, Tucker VL, Krishen A, Fava M. Resolution of sleepiness and fatigue in major depressive disorder: a comparison of bupropion and the selective serotonin reuptake inhibitors. Biol Psychiatry. 2006;60:1350–5.
Hewett K, Chrzanowski W, Schmitz M, Savela A, Milanova V, Gee M, et al. Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. J Psychopharmacol. 2009;23(5):531–8.
Freeman MP, Fava M, Gommoll C, Chen C, Greenberg WM, Ruth A. Effects of levomilnacipran ER on fatigue symptoms associated with major depressive disorder. Int Clin Psychopharmacol. 2016;31:100–9.
Thase ME, Gommoll C, Chen C, Kramer K, Sambunaris A. Effects of levomilnacipran extended-release on motivation/energy and functioning in adults with major depressive disorder. Int Clin Psychopharmacol. 2016;31:332–40.
Ravindran AV, Kennedy SH, O’Donovan MC, Fallu A, Camacho F, Binder CE. Osmotic-release oral system methylphenidate augmentation of antidepressant monotherapy in major depressive disorder: results of a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2008;69:87–94.
No funding was received for the preparation of this article.
Conflict of interest
Sidney H. Kennedy has received research funding or honoraria from the following sources: Abbott, Allergan, AstraZeneca, BMS, Brain Cells Inc., Brain Canada, Canadian Institutes for Health Research, Clera, Janssen, Lundbeck, Lundbeck Institute, Ontario Mental Health Foundation, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, St. Jude Medical, Sunovion and Xian-Janssen. Helia Ghanean and Amanda K. Ceniti have no conflicts of interest directly relevant to the content of this article.
Helia Ghanean and Amanda K. Ceniti are joint first authors.
Appendix: Search Strategy for Review of Pharmacological Interventions for Fatigue in Major Depressive Disorder
Appendix: Search Strategy for Review of Pharmacological Interventions for Fatigue in Major Depressive Disorder
((fatigu*) OR (energy) OR (anerg*) OR (FSS) OR (Fatigue Severity Scale) OR (FAD) OR (Fatigue Associated with Depression) OR (MAF) OR (Multidimensional Assessment of Fatigue) OR (PFS) OR (Piper Fatigue Scale) OR (BFI) OR (Brief Fatigue Inventory) OR (MFS) OR (Mental Fatigue Scale) OR (MEI) OR (Motivation and Energy Inventory))
((MDD) OR (depression) OR (major depressive disorder))
((antidepress*) OR (SSRI) OR (selective serotonin reuptake inhibit*) OR (TCA) OR (tricyclic) OR (MAOI) OR (monoamine oxidase inhibitor) OR (SNRI) OR (serotonin norepinephrine reuptake inhibit*) OR (fluoxetine) OR (fluvoxamine) OR (paroxetine) OR (sertraline) OR (*citalopram) OR (duloxetine) OR (*venlafaxine) OR (amitriptyline) OR (nortriptyline) OR (*pramine) OR (maprotiline) OR (doxepin) OR (nomifensine) OR (protriptyline) OR (phenelzine) OR (moclobemide) OR (selegiline) OR (tranylcypromine) OR (isocarboxazid) OR (bupropion) OR (mirtazapine) OR (*zodone) OR (amoxapine) OR (reboxetine) OR (lithium) OR (carbamazepine) OR (lamotrigine) OR (benzodiazepine) OR (alprazolam) OR (*ketamine) OR (*milnacipran))
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Ghanean, H., Ceniti, A.K. & Kennedy, S.H. Fatigue in Patients with Major Depressive Disorder: Prevalence, Burden and Pharmacological Approaches to Management. CNS Drugs 32, 65–74 (2018). https://doi.org/10.1007/s40263-018-0490-z