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ORIGINAL ARTICLES |
From University of California, San Francisco, Veterans Affairs Medical Center, San Francisco, California.
Address reprint requests to: David C. Mohr, PhD, Veterans Administration Medical Center, 4150 Clement St. (116-A) San Francisco, CA 94121. Email: dmohr{at}itsa.ucsf.edu
Received for publication March 1, 2002; revision received October 29, 2002.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHODS: Sixty patients with a relapsing form of MS and moderate to severe depression were randomly assigned to one of three validated 16-week treatments for depression: individual cognitive behavioral therapy, group psychotherapy, or sertraline. Assessments at baseline and treatment cessation included the primary outcome measure, fatigue assessment instrument (FAI), and Beck depression inventory (BDI).
RESULTS: The total FAI and the global fatigue severity subscale were significantly reduced over the course of treatment (p values <.02). Other subscales did not change significantly. Secondary analyses showed change in global fatigue severity was associated with change in BDI (p = .03) but change in total FAI was only marginally related to change in BDI (p = .05). These relationships were due entirely to change in mood (p values <.02) and not to change in cognitive or vegetative symptoms (p values >.17).
CONCLUSIONS: These findings suggest that treatment for depression is associated with reductions in the severity of fatigue symptoms, and that this relationship is due primarily to treatment related changes in mood.
Key Words: multiple sclerosis, • depression, • fatigue, • treatment, • psychotherapy.
Abbreviations: AI = ambulation index;; BDI = Beck depression inventory;; CBT = cognitive behavior therapy;; FAI = fatigue assessment instrument;; HMRA = hierarchical multiple regression analysis;; MS = multiple sclerosis;; SEGP = supportive-expressive group;; psychotherapy.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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350,000 people in the United States (1). Prevalence among women is about twice that found in men. MS is usually diagnosed between the ages of 20 and 40. MS can produce a wide variety of symptoms including, but not limited to, loss of function or feeling in limbs, loss of bowel or bladder control, sexual dysfunction, debilitating fatigue, blindness due to optic neuritis, loss of balance, pain, loss of cognitive functioning, and emotional changes (2, 3). Of the symptoms experienced by people with MS, fatigue is the most common and often the most debilitating, affecting up to 90% of all patients (4–6). Fatigue has a substantial impact on quality of life in MS by reducing physical exertion, interfering with the performance of responsibilities and work, and limiting social interactions (5–9).
The etiology of fatigue in MS is unclear. There is no evidence of a relationship between commonly used neuroimaging markers such as T2-weighted lesion burden or gadolinium-enhancing lesions (10–13). Neurological disability, measured by the Expanded Disability Status Scale (14), has also either been unrelated (9, 13, 15) or only weakly related to fatigue (16, 17).
A relationship between fatigue and depression has long been suspected in MS. Depression is common in MS. Lifetime morbidity of a diagnosable depressive disorder is over 50% (18) and point prevalence of significant depressive symptoms is very high (19). Several cross-sectional studies have reported an association between fatigue and depression (8, 9, 15), although such findings have not been universal (20). However, such cross-sectional data do not indicate causality. Data from successful trials of medications for the treatment of MS fatigue show no effect on depression (21, 22), suggesting that fatigue does not cause depression. While this leaves the possibility that depression may cause fatigue, empirical support for this hypothesis is virtually nonexistent. Despite this lack of evidence, recently published guidelines on the treatment of fatigue (23) identify treatment of depression as a potential treatment for fatigue. This study is the first to examine the effects of treating depression on fatigue in MS, and thus provides important evidence regarding current treatment guidelines.
While depression and fatigue are often assumed to be related in MS, why or how this relationship might exist has remained generally unarticulated. Given that both depression and MS fatigue likely have multifactorial etiologies, and that both disorders have potentially chronic as well as episodic components, any relationship between the two is likely complex. Nevertheless, there are two relatively parsimonious explanations, which are not mutually exclusive. One is that, because fatigue is a symptom of depression, the association is due to a methodological confound (24). This suggests that fatigue items should be removed from depression measures when analyzing outcomes. This has not commonly been done in previous research. The second explanation is that depressed mood is associated with increases in self-reported severity fatigue. For example, several studies have found an association between negative affect and physical symptom reporting in populations without MS and individuals high in negative affect may be more likely to attend to or complain about physical symptoms (25, 26). The present study aims to test the latter explanation.
In contrast to previous studies, which have been cross sectional, the present study used data from a comparative outcome trial of three treatments for depression in MS (27). We hypothesized that these treatments would be associated with reductions in fatigue. We further hypothesized that changes in depression would be associated with changes in fatigue. We also analyzed the effects of depressive symptom clusters, including mood-related symptoms such as sadness, pessimism, or tearfulness, depressive thinking problems such as guilt and worthlessness, and vegetative signs, including changes in sleep and psychomotor retardation (28, 29).
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METHODS |
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Participants
Participants were a diagnostically homogeneous group of moderately to severely depressed patients with MS. Inclusion criteria were 1) a confirmed diagnosis of MS (30); 2) a relapsing-remitting or secondary progressive disease course confirmed by a neurologist (30, 31); 3) a score of 16 or more on the BDI (32); and 4) willingness to abstain from psychological or pharmacological treatment for depression other than that provided in the study during the treatment period.
Exclusion criteria were 1) other serious psychological disorders for which treatment would be inappropriate, including psychotic disorders, bipolar disorders, or active substance abuse; 2) meeting criteria for dementia by falling below the fifth percentile in three out of six areas of neuropsychological functioning, including attention and concentration, speed of processing, executive functioning, verbal memory and visual processing; 3) severe suicidality including ideation, plan, and intent; 4) treatment with corticosteroids within previous 14 days; 5) initiation of treatment with an interferon medication within previous 2 months; 6) current MS exacerbation; 7) other disorders of the central nervous system in addition to MS; 8) current or planned pregnancy; and 9) current psychological or pharmacological treatment for depression.
Treatments
Each Treatment was Administered Over 16 Weekly Sessions
Individual CBT consisted of 16 weekly, individual 50-minute meetings with a PhD-level psychologist once per week for 16 weeks. This treatment included standard CBT procedures (33). It also taught specific skills for the management of MS-related symptoms and problems, including fatigue management, management of mild cognitive impairment, pain management, stress management, skills for intimacy, communication and sexual dysfunction, and management of social difficulties secondary to MS impairments.
SEGP is a model of group therapy for people with medical diagnoses originally developed and validated as an intervention for women with breast cancer (34, 35). Groups of 5 to 9 patients and two PhD-level psychologists met for 16 weekly 90-minute sessions, which focused on enhancing emotional expression, particularly related to MS and the social and personal sequelae of the disease.
Sertraline is a commonly used as an antidepressant medication with MS patients (36). Treatment was initiated at 50 mg per day. The dosage was increased by 50 mg every four weeks until a dosage of 200 mg was reached, or until full remission was achieved.
Assessment Measures
All Assessments were Administered at Baseline and End of Treatment
FAI (37) is a 29-item measure that produces a total score, as well as four subscales, including Global Fatigue Severity (eg, "I am easily fatigued," or "Fatigue causes frequent problems for me," Situation-Specific Fatigue (eg, "Heat brings on my fatigue," or "Work brings on my fatigue"), Fatigue Consequences (eg, "My motivation is lower when I am fatigued," or "When I am fatigued I have difficulty concentrating"), and Responsiveness to Rest/Sleep (eg, "Rest lessens my fatigue" or "Sleep lessens my fatigue"). The total FAI score was the primary outcome measure.
BDI (32) is a commonly used 21-item measure of depression and was our primary outcome measure. The fatigue item was omitted. BDI factors include three subscales reflecting the three basic components of depression: mood (eg, sadness, pessimism, dissatisfaction, tearfulness, etc.), cognitive (eg, guilt, worthlessness, or feelings of failure), and vegetative signs (eg, changes in sleep or appetite) (28, 29). It should be noted that the term "cognitive symptoms" in the depression literature refers to depressive styles of thinking and not to neurocognitive deficits.
Neuropsychological screening measures were used to assess the following areas of neuropsychological function: 1) speed of processing was assessed using Symbol Digit Modalities Test (38), 2) attention and concentration were assessed using Digit Span (39), 3) verbal memory was assessed using the Rey Auditory Verbal Learning Test (40), 4) visual memory was assessed using the 7/24 (41), 5) expressive language was assessed using the Controlled Oral Word Association Test (40) and the Boston Naming Test (15-item version) (42), and 6) executive functioning was assessed using the California Card Sort Test (43). Neurological status was assessed with the use of AI (44).
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RESULTS |
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Preliminary Analyses
Because the focus of this study was on the relationship between depression and fatigue, as opposed to a pure clinical trial, only treatment completers were included in these analyses. Twenty-two patients completed CBT, 22 completed SEGP, and 16 completed sertraline. In addition to these participants, one participant dropped out of CBT, four dropped out of SEGP, and six dropped out of sertraline. Differences in attrition rate were not significantly different across treatment groups (p = .14). Attrition was unrelated to demographic, depression, fatigue, and impairment variables (p values >0.18). Completing participants in the three treatment conditions did not differ significantly in their demographics, pretreatment depression, measures of MS impairment, or neuropsychological status (all p values >.15). The type of medication the patients were taking for MS fatigue (eg, amantadine, pemoline) was unrelated to change in any of the fatigue outcome variables (p values >.19).
Primary Outcome Analyses
The means and standard deviations for the FAI outcomes are displayed in Table 1. Outcome for fatigue was compared across treatment groups using repeated measures ANOVA. The Total FAI was significantly reduced over the course of treatment [F(1,57) = 5.94, p = .018, eta2 = 0.094], although the difference between the treatments only reached marginal significance [F(2,57) = 3.09, p = .053, eta2 = 0.098]. The Global Fatigue Severity subscale also showed significant reductions over the course of treatment [F(1,57) = 8.08, p = .0062, eta2 = 0.12] and only marginal differences across treatments [F(2,57) = 2.90, p = .063, eta2 = 0.092]. Situation-Specific Fatigue showed only a marginal reduction over the course of treatment [F(1,57) = 2.94, p = .092, eta2 = 0.049], with no significant difference across treatments (p = .26). Fatigue Consequences and Responsiveness to Rest/Sleep showed no significant reduction over the course of treatment (p values >0.33), and no significant difference across treatments (p values >0.43).
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FAI Total Score
The coefficients of determination (R2) from the hierarchical regressions are displayed in Table 2. For each FAI score, there are four sets of HMRAs, one for the total BDI, and one for each of the subscales, mood, cognition, and vegetative symptoms. The coefficient of determination for the AI is only reported in the first analysis for each fatigue score, since it is the same in all subsequent analyses.
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Global Fatigue Severity
After controlling for AI, baseline fatigue, and baseline BDI, Week 16 BDI was significantly related to Week 16 Global Fatigue Severity (R2 = .06, p = .03). The residualized Week 16 Mood was also significantly related to Week 16 Global Fatigue Severity (R2 = .09, p = .01), but there was no significant relationship for the Cognitive or Vegetative Symptom subscores (p values >0.17).
Fatigue Consequences
The residualized Week 16 BDI was significantly related to Week 16 Fatigue Consequences (R2 = .08, p = .03). The residualized Week 16 Mood was also significantly related to Week 16 Fatigue Consequences (R2 = .09, p = .01), but there was no significant relationship for the Cognitive or Vegetative Symptom subscores (p values >.19).
Situation-specific Fatigue
Neither the residualized Week 16 BDI nor the residualized Mood, Cognitive, or Vegetative Symptom subscales were significantly related to Week 16 Situation-Specific Fatigue (p values >.31).
Responsiveness to Rest/Sleep
Neither the residualized Week 16 BDI nor the residualized Mood, Cognitive, or Vegetative Symptom subscales were significantly related to Week 16 Responsiveness to Rest/Sleep (p values >.31).
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DISCUSSION |
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We found no significant differences in the efficacy of treatments on fatigue across the three modalities. The time x treatment interactions approached significance for fatigue severity, suggesting that supportive group therapy may be less effective at reducing fatigue severity than CBT or sertraline. This is consistent with our previous findings that supportive group therapy is significantly less effective at reducing depression than either CBT or sertraline (27). Also consistent with the findings on outcomes for depression, there was no evidence that fatigue outcomes differed with either CBT or sertraline. These findings suggest that the effects of treatment on patients’ self-reported fatigue severity do not depend on factors unique to the treatments, such as a specific biological action of antidepressant medication or learning specific coping skills.
Because the study was not designed with a placebo control condition, it is possible that fatigue outcomes in the primary analyses resulted from nonspecific treatment factors, such as receiving attention from participating in a research study or coming in for regular appointments, rather than to change in depression. We therefore undertook a second set of analyses designed to examine if change in depression was associated with change in fatigue. Similar to the primary outcome analyses, change in depression was related to change inpatient self-reported global severity of fatigue. In contrast to the outcome analyses, the association between change in the total fatigue score and change in depression only reached marginal significance. This is likely because of the almost complete lack of an association between change in depression and change in two other FAI subscales: situation-specific fatigue or responsiveness to rest.
While the consequences of fatigue did not change reliably over the course of treatment, change in consequences in fatigue was related to change in depression. These findings could be suggestive of reverse causality that changes in consequences of fatigue cause depression. Alternatively, these findings may be due to a third variable, such as MS disease activity, that is independent of treatment but affects both the consequences of fatigue and depression (see below for a more thorough discussion). In any case, because this finding is novel and was not predicted, it should be replicated before it is interpreted.
We examined the hypotheses that changes in fatigue were due specifically to mood, cognitive, and/or vegetative symptoms of depression. The data indicated that change in fatigue related to depression was due to almost entirely to changes in mood (sadness, pessimism, dissatisfaction, etc.) rather than changes vegetative symptoms (eg, energy loss, changes in sleep, appetite change, etc.) or cognitive symptoms (eg, guilt, worthlessness, etc.). The finding that changes in mood are related to fatigue is consistent with previous research showing that negative affect is related to increases in self-reported somatic symptoms (25). Perhaps the most parsimonious explanation for such findings is that distress affects the internal scaling employed by patients such that patients who are more distressed tend to rate their symptoms as more severe (26, 45, 46).
Another possible, but not mutually exclusive, explanation of these results is that there is a common underlying MS disease mechanism responsible for both depressive mood and fatigue severity. MS disease involves autoimmune activation characterized by increases in proinflammatory cytokines such as gamma-interferon and tumor necrosis factor-
(47, 48). MS exacerbation, which is caused by immune activation, is known to result in increases in depressive symptoms (49, 50). While increases in MS disease activity likely cause depression, this relationship is likely dynamic and reciprocal. Treatment for depression has been shown to reduce MS-related proinflammatory cytokines in MS (51). Thus, treatment for depression may reduce proinflammatory cytokines related to MS symptoms, thereby altering disease processes that may in part be responsible for fatigue.
There are several methodological issues that must be considered in evaluating these data. The primary methodological problem was the absence of a control condition. We did not include a control condition because we felt it would be unethical to deprive depressed patients of treatment for 16 weeks. However, whereas the lack of a control condition limits our ability to rule out the possibility of reverse causation, the failure of effective fatigue medications to produce changes in depression (21, 22) suggests that reverse causation is unlikely in this case. A second methodological limitation is alpha slippage due to multiple analyses, particularly in the secondary analyses. As such, it is particularly important to view these results in the context of the existing literature. Our finding that the treatment of depression and changes in mood are related to the severity of fatigue symptoms is consistent with most of the existing cross sectional studies both within MS (8, 9, 15). A third problem with the analyses that examine the amount of change in depression due to fatigue is that both fatigue and depression are assessed via self report. Thus, we cannot rule out the possibility that some of the shared variance may be due to similar assessment methods, rather than shared variance of the underlying variables.
These findings suggest that treatment for depression may reduce the subjective severity of fatigue symptoms in patients with MS. The reductions in fatigue seen during treatment for depression compare favorably with medications used to treat fatigue. The effect size for change in overall fatigue during treatment for depression accounted for over 9% of the variance, whereas the effect size for global severity of fatigue was over 12%. In contrast amantadine, the primary medication recommended for the treatment of fatigue in MS (23), accounts for 5% of the change in fatigue over time, based on estimates derived from data presented in Krupp’s report of a clinical trial (21). These findings do not suggest that treatment of depression should be a substitute for medications; because medications have different methods of action the effects are likely somewhat independent. Furthermore, this study and Krupp’s study used different entry criteria and different outcome variables, making it impossible to make meaningful inferences about any differences across the studies. However, we use this comparison to demonstrate how refractory fatigue is to symptomatic treatment, and to argue that for MS patients with both depression and fatigue, treatment of depression may be a useful adjunct treatment. Future research examining the additive effect of two treatments could provide a useful step forward in improving care for this potentially debilitating symptom.
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ACKNOWLEDGMENTS |
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This article has been cited by other articles:
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  L. M. Arnold Understanding Fatigue in Major Depressive Disorder and Other Medical Disorders Psychosomatics, May 1, 2008; 49(3): 185 - 190. [Abstract] [Full Text] [PDF]
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D C Mohr, S L Hart, L Julian, and E S Tasch Screening for depression among patients with multiple sclerosis: two questions may be enough Multiple Sclerosis, March 1, 2007; 13(2): 215 - 219. [Abstract] [PDF]
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L Julian, N M Merluzzi, and D C Mohr The relationship among depression, subjective cognitive impairment, and neuropsychological performance in multiple sclerosis Multiple Sclerosis, January 1, 2007; 13(1): 81 - 86. [Abstract] [PDF]
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D C Mohr, S L Hart, I Fonareva, and E S Tasch Treatment of depression for patients with multiple sclerosis in neurology clinics Multiple Sclerosis, April 1, 2006; 12(2): 204 - 208. [Abstract] [PDF]
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 R J Siegert and D A Abernethy Depression in multiple sclerosis: a review J. Neurol. Neurosurg. Psychiatry, April 1, 2005; 76(4): 469 - 475. [Abstract] [Full Text] [PDF]
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 Other articles noted: 25 Jul 03 to 7 Nov 03 Evid. Based Nurs., January 1, 2004; 7(1): e1 - 1. [Full Text] [PDF]
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 Treatment for Depression Helps Fatigue in Multiple Sclerosis Journal Watch Neurology, November 7, 2003; 2003(1107): 12 - 12. [Full Text]
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