543344
research-article2014
MSJ0010.1177/1352458514543344Multiple Sclerosis JournalRA Marrie
MULTIPLE SCLEROSIS MSJ JOURNAL
Editorial
Psychiatric comorbidity in multiple sclerosis: It’s not the genes
Multiple Sclerosis Journal 2014, Vol. 20(14) 1803–1805 DOI: 10.1177/ 1352458514543344 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Ruth Ann Marrie
The interplay between comorbidity and chronic disease is extremely important, but receives inadequate attention in many chronic conditions.1 While psychiatric comorbidity has long been recognized as relevant in multiple sclerosis (MS), important questions remain. The relevance of psychiatric comorbidity relates to its higher than expected frequency in MS, as well as the adverse impact of psychiatric comorbidity on disease outcome. The lifetime prevalence of depression in the general population is 15–17%, but is as high as 50% in MS.2 Bipolar disorder and anxiety are also more common in MS patients than in the general population;3 the lifetime prevalence of anxiety is as high as 30%. Comorbid depression and anxiety are associated with lower health-related quality of life, independent of physical disability4; worse self-reported functioning5; increased health care utilization for symptoms such as pain6; and lower adherence to disease-modifying therapy (DMT).7 Although psychiatric comorbidity is more common than expected in MS, uncertainty remains regarding the reasons for this association. The expected cooccurrence of two conditions in an individual may occur for several reasons8: •• First, this may occur due to chance; •• Second, the presence of one chronic condition may increase health care utilization, leading to enhanced opportunities for diagnosis of a second condition; and •• Third, the conditions may be causally related, due to direct causation or shared risk factors. In this issue of Multiple Sclerosis Journal, Johannson et al.9 aimed to determine whether shared genetic susceptibility underlies the association between MS and depression, bipolar disorder and schizophrenia. Using the population-based administrative databases available in Sweden, the authors identified individuals with MS (n = 16,467), depression (n = 172,479), bipolar disorder (n = 30,761), and
schizophrenia (n = 22,781) and their siblings.9 They assessed the risk of developing MS in the cohorts with psychiatric conditions, and the risk of MS associated with having a sibling with a psychiatric condition.9 Johannson et al.9 confirmed previous findings that depression (hazard ratio (HR) 1.86; 95% CI: 1.72–2.01) and bipolar disorder (HR 1.86; 95% CI: 1.56–2.20) were more common in the MS population than in the general population. Conversely, the risk of MS increased in people with depression (HR 1.9; 95% CI: 1.7–2.0) and bipolar disorder (HR 1.8; 95% CI: 1.6–2.2); however, the risk of having schizophrenia was reduced in persons with MS (HR 0.71; 95% CI: 0.51–1.00) and the risk of MS was reduced in individuals with schizophrenia (HR 0.6; 95% CI: 0.4–0.9). Prior studies were inconsistent with respect to the risk of psychotic disorders in MS, possibly due to differences in case definitions (all psychoses versus schizophrenia alone) and the types of study controls.3,10 A potential concern with respect to the observed reduction in the risk of MS among individuals with schizophrenia is under-diagnosis.
Correspondence to: Ruth Ann Marrie Departments of Internal Medicine and Community Health Sciences, Health Sciences Center, University of Manitoba, GF-533, 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada. [email protected]
Having a sibling with a psychiatric condition was not associated with an increased risk of having MS. Previous studies in smaller, clinic-based populations suggest that a family history of depression is associated with an increased risk of depression in MS.11 In the Danish population, having a first-degree relative with MS was associated with a 1.3-fold increase in the risk of schizophrenia, but no increase in the risk of bipolar disorder.12 The findings of the present study argue against shared genetic susceptibility as an explanation for the increased burden of psychiatric comorbidity in MS. Other potential explanations include: structural brain abnormalities secondary to MS,13 consequences of immunological and inflammatory changes secondary to MS,14 or consequences of therapy for MS, including corticosteroids used for relapses, diseasemodifying and symptomatic therapies.15 As more effective DMTs emerge, a relevant question is whether
http://msj.sagepub.com 1803
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
Multiple Sclerosis Journal 20(14) the risks of developing psychiatric comorbidity may decline. Psychosocial factors, such as stress,11 lack of social support and unemployment may also play a role. The role of stress is of particular interest, as interventions to better manage stress could potentially reduce the risk of developing depression, for example.
Funding This work is supported in part by the MS Society of Canada (Don Paty Career Development Award).
This study had several notable strengths. These included the use of population-based databases and verification of MS diagnoses by linkage of the administrative data to the Swedish MS Registry. The careful analysis of the associations between MS and psychiatric disorders was also valuable.
1. Yancik R, Ganz PA, Varricchio CG, et al. Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 2001; 19: 1147–1151.
Limitations of the analysis should be carefully considered as well. First, while diagnoses of MS were verified, diagnoses of depression and schizophrenia were not. The authors required at least two diagnoses in the Swedish National Patient Register to classify an individual as affected, to improve diagnostic specificity; but under some conditions, two diagnoses are insufficient to ensure adequate specificity. This has been suggested by studies that focus on identifying psychiatric comorbidity in MS, using administrative data from other jurisdictions.3 Second, the prevalence of psychiatric comorbidity may have been underestimated, due to this study’s reliance on hospital claims data. Although specialist data were available from 2001 onward, mild cases of psychiatric comorbidity, particularly depression, may have been managed by primary care providers. Finally, the confounding due to socioeconomic factors, which may influence the risk of disease and access to care, was also not considered.
3. Marrie RA, Fisk JD, Yu BN, et al. Mental comorbidity and multiple sclerosis: Validating administrative data to support population-based surveillance. BMC Neurol 2013; 13: 16.
This study takes another step forward in understanding psychiatric comorbidity in MS, but it also highlights the gaps in our knowledge. Comprehensive studies are needed that simultaneously consider psychosocial and biological factors, including the roles of inflammation, as well as structural and functional abnormalities in the brain, and the role of MS therapies. Given the adverse impacts of psychiatric comorbidity in MS, a greater emphasis on early diagnosis and effective treatment of disease is also warranted.
7. Tarrants M, Oleen-Burkey M, Castelli-Haley J, et al. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult Scler Int 2011; 2011: 271321.
Conflict of interest Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, MS Society of Canada, MS Scientific Research Foundation, Rx & D Health Research Foundation, National MS Society, Consortium of MS Centers and the Manitoba Health Research Council. She has conducted clinical trials funded by Sanofi-Aventis.
References
2. Goldman Consensus Group. The Goldman Consensus statement on depression in multiple sclerosis. Mult Scler 2005; 11: 328–337.
4. Janssens ACJW, Van Doorn PA, De Boer JB, et al. Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis. Mult Scler 2003; 9: 397–403. 5. Gottberg K, Einarsson U, Fredrikson S, et al. A population-based study of depressive symptoms in multiple sclerosis in Stockholm county: Association with functioning and sense of coherence. J Neurol Neurosurg Psychiatry 2007;78: 60–65. 6. Alschuler KN, Jensen MP and Ehde DM. The association of depression with pain-related treatment utilization in patients with multiple sclerosis. Pain Med 2012; 13: 1648–1657.
8. Valderas JM, Starfield B, Sibbald B, et al. Defining comorbidity: Implications for understanding health and health services. Ann Fam Med 2009; 7: 357–363. 9. Johannson V, Lundholm C, Hillert J, et al. Multiple sclerosis and psychiatric disorders: Comorbidity and sibling risk in a nationwide Swedish cohort. Mult Scler J 2014; [in press]. 10. Patten SB, Svenson LW and Metz LM. Psychotic disorders in MS: Population-based evidence of an association. Neurology 2005; 65: 1123–1125. 11. Patten SB, Metz LM and Reimer MA. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult Scler 2000; 6: 115–120.
1804 http://msj.sagepub.com
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
RA Marrie 12. Eaton WW, Pedersen MG, Nielsen PR, et al. Autoimmune diseases, bipolar disorder, and nonaffective psychosis. Bipolar Disord 2010; 12: 638–646. 13. Feinstein A. Multiple sclerosis and depression. Mult Scler J 2011; 17: 1276–1281.
14. Irwin MR and Miller AH. Depressive disorders and immunity: 20 Years of progressand discovery. Brain Behav Immunity 2007; 21: 374–383. 15. Ciriaco M, Ventrice P, Russo G, et al. Corticosteroidrelated central nervous system side effects. J Pharmacol Pharmacother 2013; 4: S94–98.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
http://msj.sagepub.com 1805
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
research-article2014
MSJ0010.1177/1352458514543344Multiple Sclerosis JournalRA Marrie
MULTIPLE SCLEROSIS MSJ JOURNAL
Editorial
Psychiatric comorbidity in multiple sclerosis: It’s not the genes
Multiple Sclerosis Journal 2014, Vol. 20(14) 1803–1805 DOI: 10.1177/ 1352458514543344 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Ruth Ann Marrie
The interplay between comorbidity and chronic disease is extremely important, but receives inadequate attention in many chronic conditions.1 While psychiatric comorbidity has long been recognized as relevant in multiple sclerosis (MS), important questions remain. The relevance of psychiatric comorbidity relates to its higher than expected frequency in MS, as well as the adverse impact of psychiatric comorbidity on disease outcome. The lifetime prevalence of depression in the general population is 15–17%, but is as high as 50% in MS.2 Bipolar disorder and anxiety are also more common in MS patients than in the general population;3 the lifetime prevalence of anxiety is as high as 30%. Comorbid depression and anxiety are associated with lower health-related quality of life, independent of physical disability4; worse self-reported functioning5; increased health care utilization for symptoms such as pain6; and lower adherence to disease-modifying therapy (DMT).7 Although psychiatric comorbidity is more common than expected in MS, uncertainty remains regarding the reasons for this association. The expected cooccurrence of two conditions in an individual may occur for several reasons8: •• First, this may occur due to chance; •• Second, the presence of one chronic condition may increase health care utilization, leading to enhanced opportunities for diagnosis of a second condition; and •• Third, the conditions may be causally related, due to direct causation or shared risk factors. In this issue of Multiple Sclerosis Journal, Johannson et al.9 aimed to determine whether shared genetic susceptibility underlies the association between MS and depression, bipolar disorder and schizophrenia. Using the population-based administrative databases available in Sweden, the authors identified individuals with MS (n = 16,467), depression (n = 172,479), bipolar disorder (n = 30,761), and
schizophrenia (n = 22,781) and their siblings.9 They assessed the risk of developing MS in the cohorts with psychiatric conditions, and the risk of MS associated with having a sibling with a psychiatric condition.9 Johannson et al.9 confirmed previous findings that depression (hazard ratio (HR) 1.86; 95% CI: 1.72–2.01) and bipolar disorder (HR 1.86; 95% CI: 1.56–2.20) were more common in the MS population than in the general population. Conversely, the risk of MS increased in people with depression (HR 1.9; 95% CI: 1.7–2.0) and bipolar disorder (HR 1.8; 95% CI: 1.6–2.2); however, the risk of having schizophrenia was reduced in persons with MS (HR 0.71; 95% CI: 0.51–1.00) and the risk of MS was reduced in individuals with schizophrenia (HR 0.6; 95% CI: 0.4–0.9). Prior studies were inconsistent with respect to the risk of psychotic disorders in MS, possibly due to differences in case definitions (all psychoses versus schizophrenia alone) and the types of study controls.3,10 A potential concern with respect to the observed reduction in the risk of MS among individuals with schizophrenia is under-diagnosis.
Correspondence to: Ruth Ann Marrie Departments of Internal Medicine and Community Health Sciences, Health Sciences Center, University of Manitoba, GF-533, 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada. [email protected]
Having a sibling with a psychiatric condition was not associated with an increased risk of having MS. Previous studies in smaller, clinic-based populations suggest that a family history of depression is associated with an increased risk of depression in MS.11 In the Danish population, having a first-degree relative with MS was associated with a 1.3-fold increase in the risk of schizophrenia, but no increase in the risk of bipolar disorder.12 The findings of the present study argue against shared genetic susceptibility as an explanation for the increased burden of psychiatric comorbidity in MS. Other potential explanations include: structural brain abnormalities secondary to MS,13 consequences of immunological and inflammatory changes secondary to MS,14 or consequences of therapy for MS, including corticosteroids used for relapses, diseasemodifying and symptomatic therapies.15 As more effective DMTs emerge, a relevant question is whether
http://msj.sagepub.com 1803
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
Multiple Sclerosis Journal 20(14) the risks of developing psychiatric comorbidity may decline. Psychosocial factors, such as stress,11 lack of social support and unemployment may also play a role. The role of stress is of particular interest, as interventions to better manage stress could potentially reduce the risk of developing depression, for example.
Funding This work is supported in part by the MS Society of Canada (Don Paty Career Development Award).
This study had several notable strengths. These included the use of population-based databases and verification of MS diagnoses by linkage of the administrative data to the Swedish MS Registry. The careful analysis of the associations between MS and psychiatric disorders was also valuable.
1. Yancik R, Ganz PA, Varricchio CG, et al. Perspectives on comorbidity and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 2001; 19: 1147–1151.
Limitations of the analysis should be carefully considered as well. First, while diagnoses of MS were verified, diagnoses of depression and schizophrenia were not. The authors required at least two diagnoses in the Swedish National Patient Register to classify an individual as affected, to improve diagnostic specificity; but under some conditions, two diagnoses are insufficient to ensure adequate specificity. This has been suggested by studies that focus on identifying psychiatric comorbidity in MS, using administrative data from other jurisdictions.3 Second, the prevalence of psychiatric comorbidity may have been underestimated, due to this study’s reliance on hospital claims data. Although specialist data were available from 2001 onward, mild cases of psychiatric comorbidity, particularly depression, may have been managed by primary care providers. Finally, the confounding due to socioeconomic factors, which may influence the risk of disease and access to care, was also not considered.
3. Marrie RA, Fisk JD, Yu BN, et al. Mental comorbidity and multiple sclerosis: Validating administrative data to support population-based surveillance. BMC Neurol 2013; 13: 16.
This study takes another step forward in understanding psychiatric comorbidity in MS, but it also highlights the gaps in our knowledge. Comprehensive studies are needed that simultaneously consider psychosocial and biological factors, including the roles of inflammation, as well as structural and functional abnormalities in the brain, and the role of MS therapies. Given the adverse impacts of psychiatric comorbidity in MS, a greater emphasis on early diagnosis and effective treatment of disease is also warranted.
7. Tarrants M, Oleen-Burkey M, Castelli-Haley J, et al. The impact of comorbid depression on adherence to therapy for multiple sclerosis. Mult Scler Int 2011; 2011: 271321.
Conflict of interest Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, MS Society of Canada, MS Scientific Research Foundation, Rx & D Health Research Foundation, National MS Society, Consortium of MS Centers and the Manitoba Health Research Council. She has conducted clinical trials funded by Sanofi-Aventis.
References
2. Goldman Consensus Group. The Goldman Consensus statement on depression in multiple sclerosis. Mult Scler 2005; 11: 328–337.
4. Janssens ACJW, Van Doorn PA, De Boer JB, et al. Anxiety and depression influence the relation between disability status and quality of life in multiple sclerosis. Mult Scler 2003; 9: 397–403. 5. Gottberg K, Einarsson U, Fredrikson S, et al. A population-based study of depressive symptoms in multiple sclerosis in Stockholm county: Association with functioning and sense of coherence. J Neurol Neurosurg Psychiatry 2007;78: 60–65. 6. Alschuler KN, Jensen MP and Ehde DM. The association of depression with pain-related treatment utilization in patients with multiple sclerosis. Pain Med 2012; 13: 1648–1657.
8. Valderas JM, Starfield B, Sibbald B, et al. Defining comorbidity: Implications for understanding health and health services. Ann Fam Med 2009; 7: 357–363. 9. Johannson V, Lundholm C, Hillert J, et al. Multiple sclerosis and psychiatric disorders: Comorbidity and sibling risk in a nationwide Swedish cohort. Mult Scler J 2014; [in press]. 10. Patten SB, Svenson LW and Metz LM. Psychotic disorders in MS: Population-based evidence of an association. Neurology 2005; 65: 1123–1125. 11. Patten SB, Metz LM and Reimer MA. Biopsychosocial correlates of lifetime major depression in a multiple sclerosis population. Mult Scler 2000; 6: 115–120.
1804 http://msj.sagepub.com
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
RA Marrie 12. Eaton WW, Pedersen MG, Nielsen PR, et al. Autoimmune diseases, bipolar disorder, and nonaffective psychosis. Bipolar Disord 2010; 12: 638–646. 13. Feinstein A. Multiple sclerosis and depression. Mult Scler J 2011; 17: 1276–1281.
14. Irwin MR and Miller AH. Depressive disorders and immunity: 20 Years of progressand discovery. Brain Behav Immunity 2007; 21: 374–383. 15. Ciriaco M, Ventrice P, Russo G, et al. Corticosteroidrelated central nervous system side effects. J Pharmacol Pharmacother 2013; 4: S94–98.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
http://msj.sagepub.com 1805
Downloaded from msj.sagepub.com at Wegner Health Science Information Center on January 25, 2015
