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The link between multiple sclerosis and depression

Key Points

  • Depression is more common in patients with multiple sclerosis (MS) than in the general population, and substantially impairs quality of life; suicide rates are also elevated in patients with MS

  • To advance research and clinical practice, depression in patients with MS will require a rigorous definition based on quantitative assessment

  • Structural brain changes on MRI account for almost 50% of the variance in the presence of MS-related depression; genetic, biochemical, immunological and psychosocial factors have also been implicated

  • Current disease-modifying therapies for MS do not seem to cause mood disorders

  • Treatment of MS-related depression requires further investigation: antidepressants are modestly effective, but adverse effects can preclude adequate dosing; cognitive–behavioural therapy is also effective

  • Randomized trials must address whether combining treatments improves outcomes

Abstract

Depression—be it a formal diagnosis based on consensus clinical criteria, or a collection of symptoms revealed by a self-report rating scale—is common in patients with multiple sclerosis (MS) and adds substantially to the morbidity and mortality associated with this disease. This Review discusses the prevalence and epidemiology of depression in patients with MS, before covering aetiological factors, including genetics, brain pathology, immunological changes, dysregulation of the hypothalamic–pituitary–adrenal axis, and psychosocial influences. Treatment options such as antidepressant drugs, cognitive–behavioural therapy, mindfulness-based therapy, exercise and electroconvulsive therapy are also reviewed in the context of MS-related depression. Frequent comorbid conditions, namely pain, fatigue, anxiety, cognitive dysfunction and alcohol use, are also summarized. The article then explores three key challenges facing researchers and clinicians: what is the optimal way to define depression in the context of diseases such as MS, in which the psychiatric and neurological symptoms overlap; how can current knowledge about the biological and psychological underpinnings of MS-related depression be used to boost the validity of this construct; and can intervention be made more effective through use of combination therapies with additive or synergistic effects, which might exceed the modest benefits derived from their individual components?

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References

  1. 1

    Charcot, J. M. Lectures on the Diseases of the Nervous System. Delivered at the Infirmary of La Salpêtrière [English translation by Thomas Savill] 194–195 (New Sydenham Society, 1877).

    Google Scholar 

  2. 2

    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th edn (American Psychiatric Publishing, 2013).

  3. 3

    Beck, A. T., Steer, R. A. & Brown, G. K. Beck Depression Inventory (BDI)-II Manual (The Psychological Corporation, 1996).

    Google Scholar 

  4. 4

    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 82, 174–181 (2014).

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 67, 361–370 (1983).

    CAS  PubMed  Google Scholar 

  6. 6

    Beck, A. T., Steer, R. A. & Brown, G. K. BDI—Fast Screen for Medical Patients Manual (The Psychological Corporation, 2000).

    Google Scholar 

  7. 7

    Benedict, R. H., Fishman, I., McClellan, M. M., Bakshi, R. & Weinstock-Guttman, B. Validity of the Beck Depression Inventory—Fast Screen in multiple sclerosis. Mult. Scler. 9, 393–396 (2003).

    CAS  PubMed  Google Scholar 

  8. 8

    Hornarmand, K. & Feinstein, A. Validation of the Hospital Anxiety and Depression Scale for use with multiple sclerosis patients. Mult. Scler. 15, 1518–1524 (2009).

    Google Scholar 

  9. 9

    Avarasala, J. R., Cross, A. H. & Trinkaus, K. Comparative assessment of Yale Single Question and Beck Depression Inventory Scale in screening for depression in multiple sclerosis. Mult. Scler. 9, 307–310 (2003).

    Google Scholar 

  10. 10

    Mohr, D. C., Hart, S. L., Julian, L. & Tasch, E. S. Screening for depression among patients with multiple sclerosis: two questions may be enough. Mult. Scler. 13, 215–219 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Kroenke, K., Spitzer, R. L., Williams, J. B. The PHQ-9: validity of a brief depression severity measure. J. Gen. Intern. Med. 16, 606–613 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Amtmann, D. et al. Comparing CESD-10, PHQ-9, and PROMIS depression instruments in individuals with multiple sclerosis. Rehabil. Psychol. 59, 220–229 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Sadnovik, A. D. et al. Depression and multiple sclerosis. Neurology 46, 628–632 (1996).

    Google Scholar 

  14. 14

    Kessler, R. C., Petukhova, M., Sampson, N. A., Zaslavsky, A. M. & Wittchen, H. U. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int. J. Methods Psychiatr. Res. 21, 169–184 (2012).

    PubMed  PubMed Central  Google Scholar 

  15. 15

    Narrow, W. E., Rae, D. S., Robins, L. N. & Regier, D. A. Revised prevalence estimates of mental disorders in the United States: using a clinical significance criterion to reconcile 2 surveys' estimates. Arch. Gen. Psychiatry 59, 115–123 (2002).

    PubMed  Google Scholar 

  16. 16

    Patten, S. B., Beck, C. A., Williams, J. V. A., Barbui, C. & Metz, L. M. Major depression in multiple sclerosis: a population-based perspective. Neurology 61, 1524–1527 (2003).

    CAS  PubMed  Google Scholar 

  17. 17

    Chwastiak, L. et al. Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Am. J. Psychiatry 159, 1862–1868 (2002).

    PubMed  Google Scholar 

  18. 18

    Marrie, R. A. et al. Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance. BMC Neurol. 13, 16 (2013).

    PubMed  PubMed Central  Google Scholar 

  19. 19

    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 7, e41910. (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Marrie, R. A. et al. The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated. Mult. Scler. 15, 385–392 (2009).

    CAS  PubMed  Google Scholar 

  21. 21

    Schubert, D. S. & Foliart, R. H. Increased depression in multiple sclerosis: a meta-analysis. Psychosomatics 34, 124–130 (1993).

    CAS  PubMed  Google Scholar 

  22. 22

    Thielscher, C., Thielscher, S. & Kostev, K. The risk of developing depression when suffering from neurological diseases. Ger. Med. Sci. 11, Doc02 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ron, M. A. & Logsdail, S. J. Psychiatric morbidity in multiple sclerosis: a clinical and MRI study. Psychol. Med. 19, 887–895 (1987).

    Google Scholar 

  24. 24

    Leach, L. S., Christensen, H., Mackinnon, A. J., Windsor, T. D. & Butterworth, P. Gender differences in depression and anxiety across the adult lifespan: the role of psychosocial mediators. Soc. Psychiatry Psychiatr. Epidemiol. 43, 983–998 (2008).

    PubMed  Google Scholar 

  25. 25

    Wood, B. et al. Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis. Mult. Scler. 19, 217–224 (2013).

    CAS  PubMed  Google Scholar 

  26. 26

    Dahl, O. P., Stordal, E., Lydersen, S. & Midgard, R. Anxiety and depression in multiple sclerosis. A comparative population-based study in Nord-Trøndelag County, Norway. Mult. Scler. 15, 1495–1501 (2009).

    PubMed  Google Scholar 

  27. 27

    Blaschek, A. et al. Neuropsychological aspects of childhood multiple sclerosis: an overview. Neuropediatrics 43, 176–183 (2012).

    PubMed  Google Scholar 

  28. 28

    Feinstein, A., Youl, B. & Ron, M. A. Acute optic neuritis: A cognitive and magnetic resonance imaging study. Brain 115, 1403–1415 (1992).

    PubMed  Google Scholar 

  29. 29

    Feinstein, A., Kartsounis, L. D., Miller, D. H., Youl, B. D. & Ron, M. A. Clinically isolated lesions of the type seen in multiple sclerosis: a cognitive psychiatric and MRI follow up study. J. Neurol. Neurosurg. Psychiatry 55, 869–876 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Zabad, R. K., Patten, S. B. & Metz, L. M. The association of depression with disease course in multiple sclerosis. Neurology 64, 359–360 (2005).

    PubMed  Google Scholar 

  31. 31

    Patten, S. B. & Metz, L. M. Hopelessness ratings in relapsing–remitting and secondary progressive multiple sclerosis. Int. J. Psychiatry Med. 32, 155–165 (2002).

    PubMed  Google Scholar 

  32. 32

    Arnett, P. A. & Randolph, J. J. Longitudinal course of depression symptoms in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 77, 606–610 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Rabinowitz, A. R. & Arnett, P. A. A longitudinal analysis of cognitive dysfunction, coping, and depression in multiple sclerosis. Neuropsychology 23, 581–591 (2009).

    PubMed  Google Scholar 

  34. 34

    Bianchi, V. et al. Mood and coping in clinically isolated syndrome and multiple sclerosis. Acta Neurol. Scand. 129, 374–381 (2014).

    CAS  PubMed  Google Scholar 

  35. 35

    Moore, P. et al. Multiple sclerosis relapses and depression. J. Psychosom. Res. 73, 272–276 (2012).

    PubMed  Google Scholar 

  36. 36

    O'Connor, A. B., Schwid, S. R., Herrmann, D. N., Markman, J. D. & Dwoekin, R. H. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 137, 96–111 (2008).

    PubMed  Google Scholar 

  37. 37

    Edhe, D. M. et al. Chronic pain in a large community sample of persons with multiple sclerosis. Mult. Scler. 9, 605–611 (2003).

    Google Scholar 

  38. 38

    Alschuler, K. N., Ehde, D. M. & Jensen, M. P. The co-occurence of pain and depression in adults with multiple sclerosis. Rehabil. Psychol. 48, 217–221 (2013).

    Google Scholar 

  39. 39

    Kroenke, K. et al. Reciprocal relationship between pain and depression: a 12 month longitudinal analysis in primary care. J. Pain 12, 964–973 (2011).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Kroencke, D. C., Lynch, S. G. & Denney, D. R. Fatigue in multiple sclerosis: relationship to depression, disability and disease pattern. Mult. Scler. 6, 131–136 (2000).

    CAS  PubMed  Google Scholar 

  41. 41

    Heesen, C. et al. Behavioral interventions in multiple sclerosis: a biopsychosocial perspective. Expert Rev. Neurother. 12, 1089–1100 (2012).

    CAS  PubMed  Google Scholar 

  42. 42

    Korostil, M. & Feinstein, A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult. Scler. 13, 67–72 (2007).

    CAS  PubMed  Google Scholar 

  43. 43

    Poder, K. et al. Social anxiety in a multiple sclerosis clinical population. Mult. Scler. 15, 393–398 (2009).

    CAS  PubMed  Google Scholar 

  44. 44

    Giordano, A. et al. Anxiety and depression in multiple sclerosis patients around diagnosis. J. Neurol. Sci. 307, 86–91 (2011).

    PubMed  Google Scholar 

  45. 45

    Burns, M. N., Nawacki, E., Siddique, J., Pelletier, D. & Mohr, D. C. Prospective examination of anxiety and depression before and during confirmed and pseudoexacerbations in patients with multiple sclerosis. Psychosom. Med. 75, 76–82 (2013).

    CAS  PubMed  Google Scholar 

  46. 46

    Ó Donnchadha, S. et al. Symptom overlap in anxiety and multiple sclerosis. Mult. Scler. 19, 1349–1354 (2013).

    PubMed  Google Scholar 

  47. 47

    Garfield, A. C. & Lincoln, N. B. Factors affecting anxiety in multiple sclerosis. Disabil. Rehabil. 34, 2047–2052 (2012).

    CAS  PubMed  Google Scholar 

  48. 48

    Feinstein, A., O'Connor, P., Gray, T. & Feinstein, K. The effects of anxiety on psychiatric morbidity in patients with multiple sclerosis. Mult. Scler. 5, 323–326 (1999).

    CAS  PubMed  Google Scholar 

  49. 49

    Quesnel, S. & Feinstein, A. Multiple sclerosis and alcohol: a study of problem drinking. Mult. Scler. 10, 197–201 (2004).

    PubMed  Google Scholar 

  50. 50

    Goretti, B. et al. Anxiety state affects information processing speed in patients with multiple sclerosis. Neurol. Sci. 35, 559–563 (2014).

    PubMed  Google Scholar 

  51. 51

    Rubio, J. M. et al. Epidemiology of chronic and nonchronic major depressive disorder: results from the national epidemiologic survey on alcohol and related conditions. Depress. Anxiety 28, 622–631 (2011).

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Bombardier, C. H. et al. Alcohol and drug abuse among persons with multiple sclerosis. Mult. Scler. 10, 35–40 (2004).

    CAS  PubMed  Google Scholar 

  53. 53

    Weiland, T. J. et al. The association of alcohol consumption and smoking with quality of life, disability and disease activity in an international sample of people with multiple sclerosis. J. Neurol. Sci. 336, 211–219, 2014.

    CAS  PubMed  Google Scholar 

  54. 54

    Rao, S. M., Leo, G. J., Bernardin, L. & Unverzagt, F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns and prediction. Neurology 41, 685–285 (1991).

    CAS  PubMed  Google Scholar 

  55. 55

    Benedict, R. H. et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J. Int. Neuropsychol. Soc. 12, 549–558 (2006).

    PubMed  Google Scholar 

  56. 56

    Arnett, P. A. et al. Depression in multiple sclerosis: relationship to working memory capacity. Neuropsychology 13, 546–556 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Arnett, P. A. et al. Depressed mood in multiple sclerosis: relationship to capacity-demanding memory and attentional functioning. Neuropsychology 13, 434–446 (1999).

    CAS  PubMed  Google Scholar 

  58. 58

    Arnett, P. A., Higginson, C. I. & Randolph, J. J. Depression in multiple sclerosis: relationship to planning ability. J. Int. Neuropsychol. Soc. 7, 665–674 (2001).

    CAS  PubMed  Google Scholar 

  59. 59

    Lubrini, G., Perianez, J. A., Rios-Lago, M. & Frank, A. Velocidad de procesamiento en la esclerosis múltiple remitente recurrente: el papel de los síntomas depresivos [Spanish]. Rev. Neurol. 55, 585–592 (2012).

    CAS  PubMed  Google Scholar 

  60. 60

    Fann, J. R., Uomoto, J. M. & Katon, W. J. Cognitive improvement with treatment of depression following mild traumatic brain injury. Psychosomatics 42, 48–54 (2001).

    CAS  PubMed  Google Scholar 

  61. 61

    Kiy, G. et al. Decreased hippocampal volume, indirectly measured, is associated with depressive symptoms and consolidation deficits in multiple sclerosis. Mult. Scler. 17, 1088–1097 (2011).

    PubMed  Google Scholar 

  62. 62

    Joffe, R. T., Lippert, G. P., Gray, T. A., Sawa, G. & Horvath, Z. Personal and family history of affective illness in patients with multiple sclerosis. J. Affect. Disord. 12, 63–65 (1987).

    CAS  PubMed  Google Scholar 

  63. 63

    Minden, S. L., Orav, J. & Reich, P. Depression in multiple sclerosis. Gen. Hosp. Psychiatry 9, 426–434 (1987).

    CAS  PubMed  Google Scholar 

  64. 64

    Schiffer, R. B., Weitkamp, L. R., Wineman, N. M. & Guttormsen, S. Multiple sclerosis and affective disorder. Family history, sex and HLA-DR antigens. Arch. Neurol. 45, 1345–1348 (1988).

    CAS  PubMed  Google Scholar 

  65. 65

    Patten, S. B., Metz, L. M. & Reimer, M. A. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult. Scler. 6, 115–120 (2000).

    CAS  PubMed  Google Scholar 

  66. 66

    Julian, L. J. et al. ApoE alleles, depression and positive affect in multiple sclerosis. Mult. Scler. 15, 311–315 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Pujol, J., Bello, J., Deus, J., Martí-Vilalta, J. L. & Capdevila, A. Lesions in the left arcuate fasciculus region and depressive symptoms in multiple sclerosis. Neurology 49, 1105–1110 (1997).

    CAS  PubMed  Google Scholar 

  68. 68

    Pujol, J. et al Beck Depression Inventory factors related to demyelinating lesions of the left arcuate fasciculus region. Psychiatry Res. 99, 151–159 (2000).

    CAS  PubMed  Google Scholar 

  69. 69

    Bakshi, R. et al. Brain MRI lesions and atrophy are related to depression in multiple sclerosis. Neuroreport 11, 1153–1158 (2000).

    CAS  PubMed  Google Scholar 

  70. 70

    Feinstein, A. et al. Structural brain abnormalities in multiple sclerosis patients with major depression. Neurology 62, 586–590 (2004).

    CAS  PubMed  Google Scholar 

  71. 71

    Zorzon, M. et al. Depressive symptoms and MRI changes in multiple sclerosis. Eur. J. Neurol. 9, 491–496 (2002).

    CAS  PubMed  Google Scholar 

  72. 72

    Berg, D. et al. Lesion pattern in patients with multiple sclerosis and depression. Mult. Scler. 6, 156–162 (2000).

    CAS  PubMed  Google Scholar 

  73. 73

    Feinstein, A. et al. Diffusion tensor imaging abnormalities in depressed multiple sclerosis patients. Mult. Scler. 16, 189–196 (2010).

    CAS  PubMed  Google Scholar 

  74. 74

    Kern, S. et al. Circadian cortisol, depressive symptoms and neurological impairment in early multiple sclerosis. Psychoneuroendocrinology 36, 1505–1512 (2011).

    CAS  PubMed  Google Scholar 

  75. 75

    Gold, S. M. et al. Smaller cornu ammonis 2–3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms. Biol. Psychiatry 68, 553–559 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Ysrraelit, M. C., Gaitán, M. I., Lopez, A. S. & Correale, J. Impaired hypothalamic-pituitary-adrenal axis activity in patients with multiple sclerosis. Neurology 71, 1948–1954 (2008).

    CAS  PubMed  Google Scholar 

  77. 77

    Melief, J. et al. HPA axis activity in multiple sclerosis correlates with disease severity, lesion type and gene expression in normal appearing white matter. Acta Neuropathol. 126, 237–249 (2013).

    PubMed  Google Scholar 

  78. 78

    Fassbender, K. et al. Mood disorders and dysfunction of the hypothalamic-pituitary-adrenal axis in multiple sclerosis: association with cerebral inflammation. Arch. Neurol. 55, 66–72 (1998).

    CAS  PubMed  Google Scholar 

  79. 79

    Gold, S. M. et al. Detection of altered hippocampal morphology in multiple sclerosis-associated depression using automated surface mesh modeling. Hum. Brain Mapp. 35, 30–37 (2014).

    PubMed  Google Scholar 

  80. 80

    Sabatini, U. et al. Involvement of the limbic system in multiple sclerosis patients with depressive disorders. Biol. Psychiatry 39, 970–975 (1996).

    CAS  PubMed  Google Scholar 

  81. 81

    Passamonti, L. et al. Neurobiological mechanisms underlying emotional processing in relapsing–remitting multiple sclerosis. Brain 132, 3380–3391 (2009).

    PubMed  Google Scholar 

  82. 82

    Altamura, A. C., Buoli, M. & Pozzoli, S. Role of immunological factors in the pathophysiology and diagnosis of bipolar disorder: comparison with schizophrenia. Psychiatry Clin. Neurosci. 68, 21–36 (2014).

    CAS  PubMed  Google Scholar 

  83. 83

    Zunszain, P. A., Hepgul, N. & Pariante, C. M. Inflammation and depression. Curr. Top. Behav. Neurosci. 14, 135–151 (2013).

    CAS  PubMed  Google Scholar 

  84. 84

    Lu, S. et al. Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis. Compr. Psychiatry 54, 953–961 (2013).

    PubMed  Google Scholar 

  85. 85

    Sukoff Rizzo, S. J. et al. Evidence for sustained elevation of IL-6 in the CNS as a key contributor of depressive-like phenotypes. Transl. Psychiatry 2, e199 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Gold, S. M. & Irwin, M. R. Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Neurol. Clin. 24, 507–519 (2006).

    PubMed  Google Scholar 

  87. 87

    Kim, Y. K. et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatry 31, 1044–1053 (2007).

    CAS  PubMed  Google Scholar 

  88. 88

    Vaccarino, V. et al. Association of major depressive disorder with serum myeloperoxidase and other markers of inflammation: a twin study. Biol. Psychiatry 64, 476–483 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Serafini, G. et al. The role of inflammatory cytokines in suicidal behavior: a systematic review. Eur. Neuropsychopharmacol. 23, 1672–1686 (2013).

    CAS  PubMed  Google Scholar 

  90. 90

    Karlović, D., Serreti, A., Vrkić, N., Martinac, M. & Marccˇinko, D. Serum concentrations of CRP, IL-6, TNF-α and cortisol in major depressive disorder with melancholic or atypical features. Psychiatry Res. 198, 74–80 (2012).

    PubMed  Google Scholar 

  91. 91

    Hughes, M. M. et al. Tryptophan depletion in depressed patients occurs independent of kynurenine pathway activation. Brain Behav. Immun. 26, 979–987 (2012).

    CAS  PubMed  Google Scholar 

  92. 92

    van Heesch, F. et al. Systemic tumor necrosis factor-α decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice. Behav. Brain Res. 253, 191–195 (2013).

    CAS  PubMed  Google Scholar 

  93. 93

    Craddock, D. & Thomas, A. Cytokines and late-life depression. Essent. Psychopharmacol. 7, 42–52 (2006).

    PubMed  Google Scholar 

  94. 94

    Gold, S. M. et al. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J. Neurol. Neurosurg. Psychiatry 82, 814–818 (2011).

    PubMed  Google Scholar 

  95. 95

    Pokryszko-Dragan, A. et al. Stimulated peripheral production of interferon-γ is related to fatigue and depression in multiple sclerosis. Clin. Neurol. Neurosurg. 114, 1153–1158 (2012).

    CAS  PubMed  Google Scholar 

  96. 96

    Acharjee, S. et al. Altered cognitive–emotional behaviour in early experimental autoimmune encephalitis—cytokine and hormonal correlates. Brain Behav. Immun. 33, 164–172 (2013).

    CAS  PubMed  Google Scholar 

  97. 97

    Peruja, I. et al. Inflammation modulates anxiety in an animal model of multiple sclerosis. Behav. Brain Res. 220, 20–29 (2011).

    Google Scholar 

  98. 98

    Haji, N. et al. TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp. Neurol. 237, 296–303 (2012).

    CAS  PubMed  Google Scholar 

  99. 99

    Pollak, Y., Ovadia, H., Orion, E. & Yirmiya, R. The EAE-associated behavioral syndrome: II. Modulation by anti-inflammatory treatments. J. Neuroimmunol. 137, 100–108 (2003).

    CAS  PubMed  Google Scholar 

  100. 100

    Foley, F. W. et al. A prospective study of depression and immune dysregulation in multiple sclerosis. Arch. Neurol. 49, 238–244 (1992).

    CAS  PubMed  Google Scholar 

  101. 101

    Feinstein, A., O'Connor, P. & Feinstein, K. J. Multiple sclerosis, inteferon β-1b and depression: a prospective investigation. J. Neurol. 249, 815–820 (2002).

    PubMed  Google Scholar 

  102. 102

    Patten, S. B. et al. The relationship between depression and inteferon β-1a therapy in patients with multiple sclerosis. Mult. Scler. 11, 175–181 (2005).

    CAS  PubMed  Google Scholar 

  103. 103

    Jongen, P. J. et al. Health-related quality of life in relapsing remitting multiple sclerosis: patients during treatment with glatiramer acetate: a prospective, observational, international, multi-centre study. Health Qual. Life Outcomes 8, 133 (2010).

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Montalban, X. et al. Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study. Mult. Scler. 17, 1341–1350 (2011).

    CAS  PubMed  Google Scholar 

  105. 105

    Mendlewicz, J. et al. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int. Clin. Psychopharmacol. 21, 227–231 (2006).

    PubMed  Google Scholar 

  106. 106

    Müller, N. et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol. Psychiatry 11, 680–684 (2006).

    PubMed  Google Scholar 

  107. 107

    Tyring, A. et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomized phase III trial. Lancet 367, 29–35 (2006).

    CAS  PubMed  Google Scholar 

  108. 108

    Lynch, S. G., Kroencke, D. C. & Denney, S. R. The relationship between disability and depression in multiple sclerosis: the role of uncertainty, coping and hope. Mult. Scler. 7, 411–416 (2001).

    CAS  PubMed  Google Scholar 

  109. 109

    van der Werf, S. P., Evers, A., Jongen, P. J. & Bleijenberg, G. The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis. Mult. Scler. 3, 89–94 (2003).

    Google Scholar 

  110. 110

    Voss, W. D. et al. Contributing factors to depressed mood in multiple sclerosis. Arch. Clin. Neuropsychol. 17, 103–115 (2002).

    PubMed  Google Scholar 

  111. 111

    King, K. E. & Arnett, P. A. Predictors of dyadic adjustment in multiple sclerosis. Mult. Scler. 11, 700–707 (2005).

    PubMed  Google Scholar 

  112. 112

    McCabew, M. P. & De Judicibus, M. The effects of economic disadvantage on psychological well-being and quality of life among people with multiple sclerosis. J. Health Psychol. 10, 163–173 (2005).

    PubMed  Google Scholar 

  113. 113

    Goretti, B., Portaccio, E., Zipoli, V., Razzolini, L. & Amato, M. P. Coping strategies, cognitive impairment, psychological variables and their relationship with quality of life in multiple sclerosis. Neurol. Sci. 31 (Suppl. 2), S227–S230 (2010).

    PubMed  Google Scholar 

  114. 114

    Mohr, D. C., Goodkin, D. E., Nelson, S., Cox, D. & Weiner, M. Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis. Psychosom. Med. 64, 803–809 (2002).

    PubMed  PubMed Central  Google Scholar 

  115. 115

    Arnett, P., Barwick, F. H. & Beeney, J. E. Depression in multiple sclerosis: review and theoretical proposal. J. Int. Neuropsychol. Soc. 14, 691–724 (2008).

    PubMed  Google Scholar 

  116. 116

    Hopman, W. M. et al. Factors associated with health-related quality of life in multiple sclerosis. Can. J. Neurol. Sci. 34, 160–166 (2007).

    PubMed  Google Scholar 

  117. 117

    Marrie, R. A., Horwitz, R., Cutter, G. & Tyry, T. Cumulative impact of comorbidity on quality of life in MS. Acta Neurol. Scand. 125, 180–186 (2012).

    CAS  PubMed  Google Scholar 

  118. 118

    Feinstein, A. An examination of suicidal intent in patients with multiple sclerosis. Neurology 59, 674–678 (2002).

    PubMed  Google Scholar 

  119. 119

    Sadovnick, A. D., Eisen, K., Ebers, G. C. & Paty, D. W. Cause of death in patients attending multiple sclerosis clinics. Neurology 41, 1193–1196 (1991).

    CAS  PubMed  Google Scholar 

  120. 120

    Stenager, E. N. & Stenager, E. Suicide and patients with neurologic diseases. Methodologic problems. Arch. Neurol. 49, 1296–1303 (1992).

    CAS  PubMed  Google Scholar 

  121. 121

    Mohr, D. C., Hart, S. L., Fonareva, I. & Tasch, E. S. Treatment of depression for patients with multiple sclerosis in neurology clinics. Mult. Scler. 12, 204–208 (2006).

    CAS  PubMed  Google Scholar 

  122. 122

    Kessing, L. V., Harhoff, M. & Andersen, P. K. Increased rate of treatment with antidepressants in patients with multiple sclerosis. Int. Clin. Psychopharmacol. 23, 54–59 (2008).

    PubMed  Google Scholar 

  123. 123

    Cetin, K. et al. Antidepressant use in multiple sclerosis: epidemiologic study of a large community sample. Mult. Scler. 13, 1046–1053 (2007).

    CAS  PubMed  Google Scholar 

  124. 124

    Koch, M. W., Glazenborg, A., Uyttenboogaart, M., Mostert, J. & De Keyser, J. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD007295. http://dx.doi.org/10.1002/14651858.CD007295.pub2.

  125. 125

    Schiffer, R. B. & Wineman, N. M. Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am. J. Psychiatry 147, 1493–1497 (1990).

    CAS  PubMed  Google Scholar 

  126. 126

    Ehde, D. M. et al. Efficacy of paroxetine in treating major depressive disorder in persons with multiple sclerosis. Gen. Hosp. Psychiatry 30, 40–48 (2008).

    PubMed  Google Scholar 

  127. 127

    Solaro, C. et al. Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin. Neuropharmacol. 36, 114–116 (2013).

    CAS  PubMed  Google Scholar 

  128. 128

    Shafey, H. The effect of fluoxetine in depression associated with multiple sclerosis. Can. J. Psychiatry 37, 147–148 (1992).

    CAS  PubMed  Google Scholar 

  129. 129

    Scott, T. F., Nussbaum, P., McConnell, H. & Brill, P. Measurement of treatment response to sertraline in depressed multiple sclerosis patients using the Carroll scale. Neurol. Res. 17, 421–422 (1995).

    CAS  PubMed  Google Scholar 

  130. 130

    Barak, Y., Ur, E. & Achiron, A. Moclobemide treatment in multiple sclerosis patients with comorbid depression: an open-label safety trial. J. Neuropsychiatry Clin. Neurosci. 11, 271–273 (1999).

    CAS  PubMed  Google Scholar 

  131. 131

    Dean, G. A double-blind trial with an antidepressant drug, imipramine, in multiple sclerosis. S. Afr. Med. J. 43, 86–87 (1969).

    CAS  PubMed  Google Scholar 

  132. 132

    Silberberg, D. & Armstrong, R. Tranylcypromine in multiple sclerosis. Lancet 2, 852–853 (1965).

    CAS  PubMed  Google Scholar 

  133. 133

    Mohr, D. C. et al. Brain lesion volume and neuropsychological function predict efficacy of treatment for depression in multiple sclerosis. J. Consult. Clin. Psychol. 71, 1017–1024 (2003).

    PubMed  Google Scholar 

  134. 134

    Julian, L. J. & Mohr, D. C. Cognitive predictors of response to treatment for depression in multiple sclerosis. J. Neuropsychiatry Clin. Neurosci. 18, 356–363 (2006).

    PubMed  Google Scholar 

  135. 135

    Thomas, P. W., Thomas, S., Hillier, C., Galvin, K. & Baker, R. Psychological interventions for multiple sclerosis. Cochrane Database of Systematic Reviews, Issue 1, Art. No.: CD004431. http://dx.doi.org/10.1002/14651858.CD004431.pub2.

  136. 136

    Mohr, D. C., Boudewyn, A. C., Goodkin, D. E., Bostrom, A. & Epstein, L. Comparative outcomes for individual cognitive–behavior therapy, supportive–expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis. J. Consult. Clin. Psychol. 69, 942–949 (2001).

    CAS  PubMed  Google Scholar 

  137. 137

    Askey-Jones, S., David, A. S., Silber, E., Shaw, P. & Chalder, T. Cognitive behaviour therapy for common mental disorders in people with multiple sclerosis: a bench marking study. Behav. Res. Ther. 51, 648–655 (2013).

    CAS  PubMed  Google Scholar 

  138. 138

    Hind, D. et al. Cognitive behavioural therapy for the treatment of depression in people with multiple sclerosis: a systematic review and meta-analysis. BMC Psychiatry 14, 5 (2014).

    PubMed  PubMed Central  Google Scholar 

  139. 139

    Mohr, D. C. et al. Telephone-administered cognitive–behavioural therapy for the treatment of depressive symptoms in multiple sclerosis. J. Consult. Clin. Psychol. 68, 356–361 (2000).

    CAS  PubMed  Google Scholar 

  140. 140

    Hind, D. et al. The acceptability of computerised cognitive behavioural therapy for the treatment of depression in people with chronic physical disease: a qualitative study of people with multiple sclerosis. Psychol. Health 25, 699–712 (2010).

    PubMed  Google Scholar 

  141. 141

    Grossman, P. et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology 75, 1141–1149 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Mohr, D. C. et al. A randomized trial of stress management for the prevention of new brain lesions in MS. Neurology 79, 412–419 (2012).

    PubMed  PubMed Central  Google Scholar 

  143. 143

    Feinstein, A., Rector, N. & Motl, R. Exercising away the blues: can it help multiple sclerosis-related depression? Mult. Scler. 19, 1815–1819 (2013).

    PubMed  Google Scholar 

  144. 144

    Fregni, F. & Pascual-Leone, A. Transcranial magnetic stimulation for the treatment of depression in neurologic disorders. Curr. Psychiatry Rep. 7, 381–390 (2005).

    PubMed  Google Scholar 

  145. 145

    Urban-Kowalczyk, M. et al. Electroconvulsive therapy in patient with psychotic depression and multiple sclerosis. Neurocase 14, 452–455 (2014).

    Google Scholar 

  146. 146

    Rasmussen, K. G. & Keegan, B. M. Electroconvulsive therapy in patients with multiple sclerosis. J. ECT 23, 179–180 (2007).

    PubMed  Google Scholar 

  147. 147

    Mattingley, G., Baker, K., Zorumski, C. F. & Fiegiel, G. S. Multiple sclerosis and ECT: possible value of gadolinium-enhanced magnetic resonance scans for identifying high-risk patients. J. Neuropsychiatry Clin. Neurosci. 4, 145–151 (1992).

    Google Scholar 

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Acknowledgements

The authors wish to acknowledge the support of the endMS Network and the Multiple Sclerosis Society of Canada.

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All authors contributed equally to researching data for the article, developing the discussions of its content, writing the article, and reviewing and editing the manuscript before submission.

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Correspondence to Anthony Feinstein.

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A.F. has received honoraria from Biogen, Merck Serono, Novartis and Teva. The other authors declare no competing interests.

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Feinstein, A., Magalhaes, S., Richard, JF. et al. The link between multiple sclerosis and depression. Nat Rev Neurol 10, 507–517 (2014). https://doi.org/10.1038/nrneurol.2014.139

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