Multiple sclerosis beyond EDSS: depression and fatigue

Journal of the Neurological Sciences 277, S1 (2009) S37 S41 Multiple sclerosis beyond EDSS: depression and fatigue Tjalf Ziemssen* MS Center, Neurological University Clinic, Dresden, Germany ARTICLE INFO ABSTRACT Keywords: Multiple sclerosis Depression Fatigue Interferon-beta Glatiramer acetate Treatment Depression and fatigue are common symptoms of multiple sclerosis and are the primary determinants of impaired quality of life in this demyelinating neurological disease. The twelve-month prevalence of major depression in patients with multiple sclerosis is around 15%. Untreated depression is associated with suicidal ideation, impaired cognitive function and poor adherence to immunomodulatory treatment. For these reasons, systematic screening and management of depressive symptoms is recommended for all patients with multiple sclerosis. There is some evidence that interferon-b treatment may exacerbate depressive symptoms and a switch to glatiramer acetate can be envisaged in patients treated with an interferon-b in whom depressive symptoms become an issue. Fatigue is present in over three-quarters of patients with multiple sclerosis. It is considered the most debilitating symptom of the disease and is a major reason for work absenteeism. There is growing evidence that immunomodulatory treatments, in particular glatiramer acetate, improve fatigue symptoms in patients with multiple sclerosis. 2009 Elsevier B.V. All rights reserved. 1. Introduction Although multiple sclerosis is quintessentially a progressive disabling neurological disease, patients experience of their disease extends beyond neurological disability to many other aspects of suffering, notably symptoms of fatigue, depression or pain. Neurologists have tended to focus on therapeutic strategies that aim to reduce the risk of relapses and of disability progression. However, it is important to realise that physicians and patients may well have divergent opinions on what is important in multiple sclerosis and this needs to be taken into account in drawing up a comprehensive approach to treatment. This divergence was elegantly demonstrated in a study of quality of life in multiple sclerosis patients in Scotland, in which patients and physicians were asked to rate which dimensions of quality of life, determined with the SF-36, were most important [1]. The physicians considered physical functioning and role limitations due to physical problems as the most important dimensions, whereas the patients identified the mental health and role limitations due to emotional problems. In addition, the study demonstrated that there was strictly no correlation between neurological disability, measured with the Expanded Disability Status Score, and quality of life, measured with the EuroQoL [1]. Indeed, even * E-mail address: Tjalf.Ziemssen@uniklinikum-dresden.de (T. Ziemssen). in patients with advanced disability, quality of life could be well preserved. 2. Quality of life in multiple sclerosis Several studies have investigated the determinants of quality of life in patients with multiple sclerosis. For example, an Italian study [2] identified a moderate inverse relationship between disability level and the physical composite score of the MSQOL-54 quality of life measure, and a moderate to strong inverse correlation between depression and fatigue severity on the one hand and both the physical and mental composite scores of the MSQOL-54 on the other. In a multivariate logistic regression analysis, depression, fatigue and disability level were identified as independent predictors of quality of life. A subsequent American study, using a similar approach, also found fatigue and depression to be independently associated with impaired quality of life [3]. Two further studies have identified depression to be the strongest determinant of impaired quality of life in patients with multiple sclerosis [4,5]. Depression and fatigue are thus important facets of the disease and need to be taken into account in how the disease is managed. In one of our recent trials, we could demonstrate that early stage MS patients significantly differ in their psychological distress when compared to healthy controls. 0022-510X/ $ see front matter 2009 Elsevier B.V. All rights reserved.

S38 T. Ziemssen / Journal of the Neurological Sciences 277 (2009) S37 S41 Psychological distress in these patients is associated with neurological disability but it is also present in patients with minimal to no neurological disability. Psychological distress was identified as an independent predictor for MS related quality of life [6]. 3. Depression in multiple sclerosis The prevalence of major depression in patients with multiple sclerosis is relatively high. A Canadian health survey [7] has reported a twelve-month prevalence rate for major depression over twice as high in subjects with multiple sclerosis compared to subjects without, with an age- and gender-adjusted hazard ratio of 2.3 [95% confidence interval: 1.6 to 3.3]. The twelve-month prevalence of major depression in patients with multiple sclerosis was 15.7%, compared to 9.1% in subjects with other chronic diseases and 4.0% in subjects without chronic disease (Table 1) [7]. Prevalence was similar in men and women and particularly high (25.7%) in young adults aged between 18 and 45 years (Table 1). Depressive symptoms emerge early in the course of the disease, with scores on the Beck Depression Inventory (BDI) being over four times higher in patients with a mean disease duration of 17 months compared to age- and gender-matched controls [8]. The lifetime prevalence of major depression in patients with multiple sclerosis has been estimated at around 50% [9]. Major depression is associated with suicidal ideation, which is encountered in around one quarter of patients with multiple sclerosis [10]. This is often unrecognised and one study reported that a third of suicidal patients had not received psychological help and two-thirds had not been proposed antidepressant medication [10]. Table 1 Twelve-month prevalence of major depressive disorder in the Canadian Community Health Survey. From ref. [7]. Patient group N Prevalence [95% confidence interval] No chronic disease 36,145 4.0 [3.7 4.3] Any chronic disease 78,604 9.1 [8.9 9.4] Multiple sclerosis 322 15.7 [10.9 20.6] Men 13.1 [4.4 21.8] Women 16.7 [10.8 23.1] Age 18 45 years 25.7 [15.6 35.7] Age >45 years 8.4 [3.8 13.1] 4. Pathogenesis of depression in multiple sclerosis A variety of mechanisms may underlie the high prevalence of depression in patients with multiple sclerosis. Firstly, this may be understood as reactive stress and depression following the diagnosis and uncertainties about prognosis and the future in general. In the absence of adequate social support, and if inappropriate coping strategies are implemented, then this can reinforce and perpetuate the stressful reaction. If the patient does not possess the necessary psychological resources to break this vicious circle, chronic clinical depression can develop over the course of time. Secondly, the neuroinflammatory disease process in multiple sclerosis may contribute to the development or aggravation of depression. The release of pro-inflammatory cytokines such as interferon-g, TNF-a or interleukin-6 may produce symptoms that reinforce an underlying tendency for depression, including loss of appetite, sleep disturbances, asthenia or weight loss. Moreover, biological and psychological factors may interact to exacerbate depressive symptoms, for example stress leads to activation of the hypothalamus pituitary adrenal axis and of the sympathetic nervous system, which in turn can, under certain circumstances stimulate the immune system to release pro-inflammatory cytokines [8,11]. In this context, the observation that resolution of depression in multiple sclerosis is accompanied by a reduction in the production of pro-inflammatory cytokines is consistent with a dynamic relationship between neuroinflammation and depression [12]. In this study, patients with comorbid diagnoses of relapsing remitting multiple sclerosis and major depressive disorder were treated with cognitive behavioural therapy or sertraline. Following initiation of treatment, depressive symptoms, as measured with the BDI, resolved. In parallel, the secretion of interferon-g from peripheral mononuclear lymphocytes in response to myelin oligodendrocyte glycoprotein declined [12]. Finally, structural changes in the brain due to neurodegeneration may contribute to the development of depression. For example, a magnetic resonance imaging (MRI) study evaluated the relationship between depressive and anxiety symptoms and MRI markers of disease in 95 patients with multiple sclerosis [13]. Severity of depressive symptoms, measured with the Hamilton Depression and Anxiety Rating Scale, and the presence of a DSM-IV diagnosis of major depression correlated weakly with lesion load in the right frontal areas and the extent of atrophy of the right temporal areas. The severity of depression was also related significantly with total temporal lobe volume and right hemisphere brain volume. These associations led the authors of this study to conclude that organic brain damage may contribute to the development of depression. In another study [14], patients with a DSM-IV diagnosis of major depression presented a higher T2 lesion load in the left medial inferior prefrontal cortex and a higher left anterior temporal CSF volume, a marker of brain atrophy, compared to euthymic multiple sclerosis patients. These two variables accounted for 42% of the variance in depression score. 5. Treatment of depression in multiple sclerosis Depression in patients with multiple sclerosis is in general under-recognised by neurologists and consequently undertreated. For example, a recent survey conducted in the United States [15] reported that two thirds of multiple sclerosis patients fulfilling diagnostic criteria for a major depressive disorder received no antidepressant medication. An important advantage of successfully treating depression is that patients are more likely to remain compliant with their immunomodulatory treatment for multiple sclerosis if they are no longer depressed. A study of determinants of treatment adherence to interferon-b 1b identified depression as one of three factors associated with an increased risk of discontinuing treatment within six months, the others being therapeutic expectations and the experience of influenza-like symptoms [16]. However, when depression was treated with psychotherapy or antidepressant medication, adherence was significantly higher ( p = 0.003), with 86% of treated patients

T. Ziemssen / Journal of the Neurological Sciences 277 (2009) S37 S41 S39 remaining adherent to interferon-b after six months compared to only 38% of depressed patients who went untreated [17]. Diagnosis of MS 6. Immunomodulatory treatments and depression in multiple sclerosis The effects of immunomodulatory treatment on depression in patients with multiple sclerosis have not been fully elucidated. For glatiramer acetate (GA), there is no evidence that this treatment aggravates depression, and it has been suggested that GA may have a beneficial effect on depression due to stimulation of the production of brain-derived neurotrophic factor (BDNF) in the nervous system [18 20], although this remains to be demonstrated in the clinic. With respect to interferon-b, its impact on depression is controversial, with some suspicion that it may aggravate depression. The bulk of the evidence is not consistent with the notion that interferon-b may trigger depression in euthymic patients, although it may increase the risk of depression in susceptible individuals or aggravate preexisting depression [21]. For example, a prospective study in 56 patients initiating treatment with interferon-b 1a im suggested that increases in depression after initiation of treatment were related to the level of depression two weeks before starting interferon-b treatment [22]. 7. Screening for depression in multiple sclerosis Given the importance of depression for quality of life in multiple sclerosis and the potential consequences of untreated depression, it is important to screen patients systematically for depression when they are diagnosed with multiple sclerosis and throughout the course of the disease. A consensus group of US neurologists have recently proposed recommendations for screening of depressive affective disorders in patients with multiple sclerosis [23]. These propose that neurologists perform an initial screen for depression using the BDI at the time of diagnosis. Patients who score 13 on this test should undergo an in-depth diagnostic interview including questions about a previous history of depressive disorders. Patients fulfilling diagnostic criteria for a current depressive episode should be prescribed an antidepressant or psychotherapy or both. The consensus guidelines also recommend the development and testing of integrated treatment algorithms for the comprehensive management of the risk of depression in patients with multiple sclerosis [23]. In this context, we could suggest the approach illustrated in Fig. 1. For patients with confirmed depression at the time of diagnosis, and for those with a previous history of depression, GA is the immunomodulatory treatment of choice, as it is associated with a lower risk of aggravation or triggering of depressive episodes. For patients who score <13 on the BDI and who have no previous history of affective disorders, either GA or an interferon-b can be proposed as an immunomodulatory treatment, and quarterly monitoring for emergence of depressive symptoms with the BDI should be put in place. If symptoms are subsequently detected (BDI score 13), this should be confirmed in a complete diagnostic interview. If a current depressive episode is confirmed, then antidepressant therapy should be initiated, and if patients are being treated with an interferon-b, a switch to GA should be envisaged. Quarterly monitoring No No Step 3: Treatment MS: IFN or GA Step 1: Screening BDI questionnaire BDI > 13 Step 2: Diagnostic interview Current MDE or history of depression Yes Yes Step 3: Treatment MS: GA Depression: AD/CBT Fig. 1 Algorithm for management of depression in patients with multiple sclerosis. AD, antidepressant; BDI, Beck Depression Inventory; CBT, cognitive behavioural therapy; IFN, interferon-b; GA, glatiramer acetate; MDE, major depressive episode; MS, multiple sclerosis. 8. Fatigue Fatigue is among the most common symptoms of multiple sclerosis, affecting at least 75% of patients [24], for many of whom it constitutes one of worst and most distressing features [25]. Fatigue is reported in all clinical phenotypes of multiple sclerosis and affects patients of all ages [26]. This symptom is an integral part of the disease process which is usually present at the time of diagnosis and in some cases represents one of the reasons for which patients originally consult a neurologist. Fatigue is not closely related to physical signs of disability or with MRI markers of disease activity, although it does seem to increase when the patient experiences relapses [25,27]. Fatigue is a major cause of unemployment in patients with multiple sclerosis [28 30]. 9. Immunomodulatory treatments and fatigue in multiple sclerosis A number of studies have investigated the relationship between fatigue in multiple sclerosis and immunomodulatory treatments. For example, a retrospective study of patients included in a Canadian registry evaluated changes in fatigue impact following initiation of immunomodulatory treatment with an interferon-b or with GA [31]. Of 218 patients evaluated overall, 195 presenting with relapsing remitting disease, 85 were treated with an interferon-b and 133 with GA. Patients were assessed with the Fatigue Impact Scale (FIS) [32] at baseline and again six months after starting treatment. The FIS is a 40-item questionnaire on which subjects rate the impact of their fatigue on a range of activities of daily living, each item being scored on a four-point Likert scale. Possible scores ranges from 0 to 160, with a higher score indicating a greater fatigue impact. The FIS comprises three subscales measuring the impact of fatigue on physical, social, and cognitive function.

S40 T. Ziemssen / Journal of the Neurological Sciences 277 (2009) S37 S41 Table 2 Proportion of patients improving six months after initiating an immunomodulatory treatment, as measured with the Fatigue Impact Scale (FIS) score and its subscores. From ref. [31]. Interferon-b GA P Total score 12.9% 24.8% 0.033 Physical subscore 14.1% 28.6% 0.013 Cognitive subscore 10.6% 21.1% 0.045 Social subscore 14.1% 18.9% 0.369 Probability values were determined with the c 2 test. GA: glatiramer acetate. Table 3 Outcome in a prospective study of fatigue in treatment-naive multiple sclerosis patients twelve months after initiating glatiramer acetate treatment. From ref. [33]. Baseline Twelve months P Mean total FIS score 34.6 27.0 <0.001 Fatigue VAS 4.47 3.43 <0.001 Patients without days off work 34.4% 68.8% <0.001 Probability values were determined with the Wilcoxon signed rank test. FIS: Fatigue Impact Scale; VAS: visual analogue scale. The outcome reported was the proportion of patients who improved between the two evaluations, an improvement being defined as a decrease in FIS scores of at least one standard deviation. Although patients improved in both treatment groups, the proportion of patients improving was significantly higher (24.8%) in those treated with GA compared to those treated with an interferon-b (12.9%). A significantly higher proportion of patients improving in the GA group was also observed for the physical and cognitive subscores of the FIS (Table 2). A second study assessed fatigue prospectively in 291 patients with relapsing remitting multiple sclerosis starting treatment with GA in Germany [33]. Fatigue was assessed with the FIS and with a visual analogue scale before treatment and after one year. In addition, the study evaluated the number of days taken off work due to multiple sclerosis in the 215 patients in full-time employment. A significant decrease in the severity of fatigue measured with the visual analogue scale and in fatigue impact measured with the FIS and its subscales was observed twelve months after initiating GA treatment (Table 3). In addition, this was associated with a reduction by a factor of two in the number of patients needing to take time off work because of their disease. 10. Conclusions Depression and fatigue are extremely important facets of a patient s experience of multiple sclerosis and represent major determinants of quality of life. It is important to investigate these symptoms carefully at the time of diagnosis and throughout the course of the disease. The potential impact of immunomodulatory treatment on these symptoms should be taken into account when making treatment decisions. Depression and fatigue should not be considered as secondary issues but as an integral part of disease presentation and management. 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