Review article| Volume 73, 104698, May 2023

Download started.


Multiple sclerosis and anxiety: Is there an untapped opportunity for exercise?

  • Petra Šilić
    Corresponding author: Department of Kinesiology and Nutrition, College of Applied Health Sciences, University of Illinois Chicago, 1919 W. Taylor Street, AHSB 545, Chicago, IL, 60612, United States.
    Department of Kinesiology and Nutrition, University of Illinois Chicago, 1919 W. Taylor Street, AHSB 545, Chicago, IL 60612, United States
    Search for articles by this author
  • Robert W. Motl
    Department of Kinesiology and Nutrition, University of Illinois Chicago, 1919 W. Taylor Street, AHSB 545, Chicago, IL 60612, United States
    Search for articles by this author
  • Jennifer Duffecy
    Department of Psychiatry, University of Illinois Chicago, 912 S. Wood Street, MC 913, Chicago, IL 60612, United States
    Search for articles by this author


      • Anxiety symptoms and disorders are prevalent in persons with multiple sclerosis.
      • Anxiety negatively impacts physical function, cognition, and quality of life.
      • Evidence of efficacy of pharmacotherapy and psychotherapy on anxiety is limited.
      • Exercise is a promising treatment of anxiety is persons with multiple sclerosis.



      Anxiety symptoms and anxiety disorders are prevalent and burdensome, yet poorly managed in multiple sclerosis (MS). Indeed, anxiety disorders occur in 22% of people with MS, and anxiety can negatively impact physical function, cognition, and quality of life. Currently, there are no treatment guidelines available for anxiety in MS, based on limited information regarding the efficacy of pharmacotherapy and psychotherapy. Exercise training may be a promising avenue for treatment of anxiety in MS, and this is based, in part, on a wealth of evidence in the general population of adults. This review provides an overview of anxiety and evidence from meta-analyses and systematic reviews for current treatments options in the general population and MS. We further make a case for exercise as a novel treatment approach that requires focal examination in persons with MS.


      We conducted a scoping review of available research, including systematic reviews and meta-analyses, on anxiety and its prevalence, predictors, consequences, and treatments in MS. We then noted limitations with existing evidence regarding treatment options, and then provided a backdrop based on evidence from the general population for the novel proposition of exercise as treatment of anxiety in MS.


      Pharmacotherapy and psychotherapy treatments of anxiety may be efficacious, but come with significant limitations, especially for persons with MS. Exercise is a promising novel avenue for treatment of anxiety in MS, and has a positive side-effect profile.


      Anxiety is under-investigated and poorly treated in MS. There is a paucity of evidence for the relationship between exercise training and anxiety in MS, but the evidence in the general population supports the urgent need for systematic examination of the efficacy of exercise in treating anxiety symptoms and disorders in persons with MS.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Multiple Sclerosis and Related Disorders
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Adamson B.C.
        • Ensari I.
        • Motl R.W.
        Effect of exercise on depressive symptoms in adults with neurologic disorders: a systematic review and meta-analysis.
        Arch. Phys. Med. Rehabil. 2015; 96: 1329-1338
        • AlSaeed S.
        • et al.
        Fatigue, depression, and anxiety among ambulating multiple sclerosis patients.
        Front. Immunol. 2022; : 13
        • Altieri M.
        • et al.
        The psychological impact of Covid-19 pandemic on people with Multiple Sclerosis: a meta-analysis.
        Mult. Scler. Relat. Disord. 2022; 61103774
      1. Association, A.P., Diagnostic and Statistical Manual of Mental Disorders. 5 ed. 2013.

      2. Association, A.P. 2022 [cited 2022 3/28/2022]; Available from:

        • Aylett E.
        • Small N.
        • Bower P.
        Exercise in the treatment of clinical anxiety in general practice - a systematic review and meta-analysis.
        BMC Health Serv. Res. 2018; 18: 559
        • Bandelow B.
        • et al.
        Efficacy of treatments for anxiety disorders: a meta-analysis.
        Int. Clin. Psychopharmacol. 2015; 30: 183-192
        • Bandelow B.
        • Michaelis S.
        • Wedekind D.
        Treatment of anxiety disorders.
        Dialogues Clin. Neurosci. 2017; 19: 93-107
        • Beck A.T.
        • et al.
        An inventory for measuring clinical anxiety: psychometric properties.
        J. Consult. Clin. Psychol. 1988; 56: 893-897
        • Beiske A.G.
        • et al.
        Depression and anxiety amongst multiple sclerosis patients.
        Eur. J. Neurol. 2008; 15: 239-245
        • Boeschoten R.E.
        • et al.
        Prevalence of depression and anxiety in Multiple Sclerosis: a systematic review and meta-analysis.
        J. Neurol. Sci. 2017; 372: 331-341
        • Bruce J.M.
        • et al.
        Treatment adherence in multiple sclerosis: association with emotional status, personality, and cognition.
        J. Behav. Med. 2010; 33: 219-227
        • Butler E.
        • Matcham F.
        • Chalder T.
        A systematic review of anxiety amongst people with Multiple Sclerosis.
        Mult. Scler. Relat. Disord. 2016; 10: 145-168
        • Carpenter J.K.
        • et al.
        Cognitive behavioral therapy for anxiety and related disorders: a meta-analysis of randomized placebo-controlled trials.
        Depress. Anxiety. 2018; 35: 502-514
        • Caspersen C.J.
        • Powell K.E.
        • Christenson G.M.
        Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research.
        Public Health Rep. 1985; 100: 126-131
        • Cederberg K.L.J.
        • et al.
        Physical activity and self-reported sleep quality in adults with multiple sclerosis.
        Disabil. Health J. 2021; 14101133
        • Dennison L.
        • Moss-Morris R.
        • Chalder T.
        A review of psychological correlates of adjustment in patients with multiple sclerosis.
        Clin. Psychol. Rev. 2009; 29: 141-153
        • Ensari I.
        • et al.
        Meta-analysis of acute exercise effects on state anxiety: an update of randomized controlled trials over the past 25 years.
        Depress Anxiety. 2015; 32: 624-634
        • Ensari I.
        • Sandroff B.M.
        • Motl R.W.
        Intensity of treadmill walking exercise on acute mood symptoms in persons with multiple sclerosis.
        Anxiety Stress Coping. 2017; 30: 15-25
        • Eren F.
        • Demir A.
        • Ozkan B.
        Is there a relationship between anxiety and depression with respiratory functions in patients with relapsing-remitting multiple sclerosis?.
        Mult. Scler. Relat. Disord. 2021; 52103023
        • Federation T.M.S.I.
        Atlas of MS, 3rd Edition.
        The Multiple Sclerosis International Federation (MSIF), 2020
        • Fiest K.M.
        • et al.
        Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis.
        Mult. Scler. Relat. Disord. 2016; 5: 12-26
        • First M.B.
        Structured clinical interview for the DSM (SCID).
        Encycl.. Clin. Psychol. 2015; : 1-6
        • Garakani A.
        • et al.
        Pharmacotherapy of anxiety disorders: current and emerging treatment options.
        Front. Psychiatry. 2020; 11595584
        • Garfield A.C.
        • Lincoln N.B.
        Factors affecting anxiety in multiple sclerosis.
        Disabil. Rehabil. 2012; 34: 2047-2052
        • Gascoyne C.
        • et al.
        Effect of exercise interventions on anxiety in people with multiple sclerosis: a systematic review and meta-analysis.
        Int. J. MS Care. 2020; 22: 103-109
        • Ghasemi N.
        • Razavi S.
        • Nikzad E.
        Multiple sclerosis: pathogenesis, symptoms, diagnoses and cell-based therapy.
        Cell J. 2017; 19: 1-10
        • Giordano A.
        • et al.
        Anxiety and depression in multiple sclerosis patients around diagnosis.
        J. Neurol. Sci. 2011; 307: 86-91
        • Goretti B.
        • et al.
        Anxiety state affects information processing speed in patients with multiple sclerosis.
        Neurol. Sci. 2014; 35: 559-563
        • Hamilton M.
        The assessment of anxiety states by rating.
        Br. J. Med. Psychol. 1959; 32: 50-55
        • Harrison A.M.
        • et al.
        Beyond a physical symptom: the importance of psychosocial factors in multiple sclerosis pain.
        Eur. J. Neurol. 2015; 22: 1443-1452
        • Hartoonian N.
        • et al.
        Predictors of anxiety in multiple sclerosis.
        Rehabil. Psychol. 2015; 60: 91-98
        • Herring M.P.
        • Lindheimer J.B.
        • O'Connor P.J.
        The effects of exercise training on anxiety.
        Am. J. Lifestyle Med. 2014; 8: 388-403
        • Hofmann S.G.
        • Smits J.A.
        Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials.
        J. Clin. Psychiatry. 2008; 69: 621-632
        • Huang W.J.
        • Chen W.W.
        • Zhang X.
        Multiple sclerosis: pathology, diagnosis and treatments.
        Exp. Ther. Med. 2017; 13: 3163-3166
        • Huguet A.
        • et al.
        A systematic review of cognitive behavioral therapy and behavioral activation apps for depression.
        PLoS ONE. 2016; 11e0154248
        • Janssens A.C.
        • et al.
        Impact of recently diagnosed multiple sclerosis on quality of life, anxiety, depression and distress of patients and partners.
        Acta Neurol. Scand. 2003; 108: 389-395
        • Jones K.H.
        • et al.
        A large-scale study of anxiety and depression in people with Multiple Sclerosis: a survey via the web portal of the UK MS Register.
        PLoS ONE. 2012; 7: e41910
        • Julian L.J.
        Measures of anxiety: state-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A).
        Arthritis Care Res. (Hoboken). 2011; 63 (Suppl 110): S467-S472
        • Kalb R.
        • et al.
        Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course.
        Mult. Scler. 2020; 26: 1459-1469
        • Korostil M.
        • Feinstein A.
        Anxiety disorders and their clinical correlates in multiple sclerosis patients.
        Mult. Scler. 2007; 13: 67-72
        • Learmonth Y.C.
        • et al.
        Multiple sclerosis patients need and want information on exercise promotion from healthcare providers: a qualitative study.
        Health Expect. 2017; 20: 574-583
        • Learmonth Y.C.
        • et al.
        Investigating the needs and wants of healthcare providers for promoting exercise in persons with multiple sclerosis: a qualitative study.
        Disabil. Rehabil. 2018; 40: 2172-2180
        • Lenz E.R.
        • et al.
        Collaborative development of middle-range nursing theories: toward a theory of unpleasant symptoms.
        ANS Adv. Nurs. Sci. 1995; 17: 1-13
        • Lenz E.R.
        • et al.
        The Middle-Range Theory of Unpleasant Symptoms: an Update.
        Adv. Nurs. Sci. 1997; 19: 14-27
        • Leonavicius R.
        • Adomaitiene V.
        Features of sleep disturbances in multiple sclerosis patients.
        Psychiatr. Danub. 2014; 26: 249-255
        • Lester K.
        • Stepleman L.
        • Hughes M.
        The association of illness severity, self-reported cognitive impairment, and perceived illness management with depression and anxiety in a multiple sclerosis clinic population.
        J. Behav. Med. 2007; 30: 177-186
        • Marck C.H.
        • et al.
        The effect of the Australian bushfires and the COVID-19 pandemic on health behaviours in people with multiple sclerosis.
        Mult. Scler. Relat. Disord. 2021; 53103042
        • Marrie R.A.
        • et al.
        The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review.
        Mult. Scler. 2015; 21: 305-317
        • Marrie R.A.
        • et al.
        Diabetes and anxiety adversely affect cognition in multiple sclerosis.
        Mult. Scler. Relat. Disord. 2019; 27: 164-170
        • Matysiak M.
        • et al.
        The influence of COVID-19 pandemic lockdown on the physical activity of people with multiple sclerosis. The role of online training.
        Mult. Scler. Relat. Disord. 2022; : 63
        • Maust D.
        • et al.
        Psychiatric rating scales.
        Handb. Clin. Neurol. 2012; 106: 227-237
        • McKay K.A.
        • et al.
        Psychiatric comorbidity is associated with disability progression in multiple sclerosis.
        Neurology. 2018; 90: e1316-e1323
        • Minden S.L.
        • et al.
        Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS: report of the Guideline Development Subcommittee of the American Academy of Neurology.
        Neurology. 2014; 82: 174-181
        • Morrow S.A.
        • Rosehart H.
        • Pantazopoulos K.
        Anxiety and depressive symptoms are associated with worse performance on objective cognitive tests in MS.
        J. Neuropsychiatry Clin. Neurosci. 2016; 28: 118-123
        • Motl R.W.
        • Pilutti L.A.
        The benefits of exercise training in multiple sclerosis.
        Nat. Rev. Neurol. 2012; 8: 487-497
        • Motl R.W.
        • et al.
        Physical activity and cognitive function in multiple sclerosis.
        J. Sport Exerc. Psychol. 2011; 33: 734-741
        • Motl R.
        • et al.
        Health behaviors, wellness, and multiple sclerosis amid COVID-19.
        Arch. Phys. Med. Rehabil. 2020; 101: 1839-1841
        • Moumdjian L.
        • et al.
        Impact of the COVID-19 pandemic on physical activity and associated technology use in persons with multiple sclerosis: an international rims-sig mobility survey study.
        Arch. Phys. Med. Rehabil. 2022; 103: 2009-2015
        • Munn Z.
        • et al.
        Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach.
        BMC Med. Res. Methodol. 2018; 18: 143
        • Otte C.
        Cognitive behavioral therapy in anxiety disorders: current state of the evidence.
        Dialogues Clin. Neurosci. 2011; 13: 413-421
        • Palmer L.C.
        • et al.
        The Impact of COVID-19 lockdown restrictions on exercise behavior among people with multiple sclerosis enrolled in an exercise trial: qualitative interview study.
        JMIR Rehabil. Assist. Technol. 2022; 9: e42157
        • Pedullà L.
        • et al.
        Physical activity in multiple sclerosis: meeting the guidelines at the time of the COVID-19 pandemic.
        J. Neurol. Phys. Ther. 2023;
        • Pekmezi D.
        • Motl R.
        Targeting physical inactivity using behavioral theory in chronic, disabling diseases.
        Exerc. Sport. Sci. Rev. 2022;
        • Peres D.S.
        • et al.
        Prevalence of depression and anxiety in the different clinical forms of multiple sclerosis and associations with disability: a systematic review and meta-analysis.
        Brain Behav. Immun. Health. 2022; 24100484
        • Petruzzello S.J.
        • et al.
        Anxiety and mood changes associated with acute cycling in persons with multiple sclerosis.
        Anxiety Stress Coping. 2009; 22: 297-307
        • Pilutti L.A.
        • et al.
        Randomized controlled trial of a behavioral intervention targeting symptoms and physical activity in multiple sclerosis.
        Mult. Scler. 2014; 20: 594-601
        • Podda J.
        • et al.
        Predictors of clinically significant anxiety in people with multiple sclerosis: a one-year follow-up study.
        Mult. Scler. Relat. Disord. 2020; 45102417
        • Reade J.W.
        • et al.
        What Would You Say? Expressing the difficulties of living with multiple sclerosis.
        J. Neurosci. Nurs. 2012; 44: 54-63
        • Ribbons K.
        • et al.
        Anxiety Levels Are Independently Associated With Cognitive Performance in an Australian Multiple Sclerosis Patient Cohort.
        J. Neuropsychiatry Clin. Neurosci. 2017; 29: 128-134
        • Richardson E.V.
        • et al.
        Models and materials for exercise promotion in comprehensive multiple sclerosis care: completion of the ‘exercise in medicine’ development process.
        Disabil. Rehabil. 2022; 44: 7475-7483
        • Rossi S.
        • et al.
        Neuroinflammation drives anxiety and depression in relapsing-remitting multiple sclerosis.
        Neurology. 2017; 89: 1338-1347
        • Salter A.
        • et al.
        Comorbidity is associated with disease activity in MS.
        Find. CombiRx Trial. 2020; 95: e446-e456
        • Schreier A.M.
        • et al.
        Post-treatment symptoms of pain, anxiety, sleep disturbance, and fatigue in breast cancer survivors.
        Pain Manag. Nurs. 2019; 20: 146-151
        • Sheehan D.V.
        • et al.
        The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
        J. Clin. Psychiatry. 1998; 59 (Supplquiz 34-57): 22-33
        • Silveira S.L.
        • Pilutti L.A.
        • Motl R.W.
        No evidence of associations among body composition and symptoms in persons with multiple sclerosis.
        Rehabil. Psychol. 2020; 65: 80-86
        • Skerrett T.N.
        • Moss-Morris R.
        Fatigue and social impairment in multiple sclerosis: the role of patients' cognitive and behavioral responses to their symptoms.
        J. Psychosom. Res. 2006; 61: 587-593
        • Smith M.J.
        • Liehr P.R.
        Middle Range Theory For Nursing.
        Springer Publishing Company, 2018: 424 (4 ed)
        • Smits J.A.
        • et al.
        Threat reappraisal as a mediator of symptom change in cognitive-behavioral treatment of anxiety disorders: a systematic review.
        J. Consult. Clin. Psychol. 2012; 80: 624-635
      3. Spielberger, C., et al., Manual for the State-Trait Anxiety Inventory (Form Y1 – Y2). Vol. IV. 1983.

        • Stahl S.M.
        Don't ask, don't tell, but benzodiazepines are still the leading treatments for anxiety disorder.
        J. Clin. Psychiatry. 2002; 63: 756-757
        • Tan-Kristanto S.
        • Kiropoulos L.A.
        Resilience, self-efficacy, coping styles and depressive and anxiety symptoms in those newly diagnosed with multiple sclerosis.
        Psychol. Health Med. 2015; 20: 635-645
        • Thompson E.
        Hamilton Rating Scale for Anxiety (HAM-A).
        Occup. Med. (Chic. Ill). 2015; 65 (601-601)
        • Tsivgoulis G.
        • et al.
        Associations of the expanded Disability Status Scale with anxiety and depression in multiple sclerosis outpatients.
        Acta Neurol. Scand. 2007; 115: 67-72
        • Uhr L.
        • Rice D.R.
        • Mateen F.J.
        Sociodemographic and clinical factors associated with depression, anxiety, and general mental health in people with multiple sclerosis during the COVID-19 pandemic.
        Mult. Scler. Relat. Disord. 2021; 56103327
        • Vissicchio N.A.
        • et al.
        Illness intrusiveness: a key part of the cognition-mood link in multiple sclerosis.
        Rehabil. Psychol. 2022;
        • Zigmond A.S.
        • Snaith R.P.
        The hospital anxiety and depression scale.
        Acta Psychiatr. Scand. 1983; 67: 361-370