Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in patients with multiple sclerosis.

Multiple Sclerosis (MS) is a neurological disorder that often begins in young adulthood. The illness causes impairment in multiple domains of functioning and can have a profound impact on a patient’s quality of life. Cognitive impairment has received increased attention over the past two decades as a common symptom of MS and is now recognized as one of the leading causes of disability among patients. Up to 65% of patients with MS experience cognitive impairment and these difficulties can occur across all stages of the illness (Amato, Zipoli, & Portaccio, 2006). The cognitive domains commonly affected in patients with MS include recent memory, working memory, processing speed, executive functioning, and visuospatial abilities (Bobholz & Rao, 2003; Rao, Leo, Bernadin, & Unverzagt, 1991a). These cognitive difficulties negatively impact employment, social relationships, and overall quality of life (Amato, Ponziani, Siracusa, & Sorbi., 2001; Rao et al., 1991b). Despite its high prevalence, cognitive dysfunction is thought to be under-diagnosed in this population. Cognitive difficulties can occur independent of physical disability and are easily missed in a routine neurological exam (Rao, 1995). Health care providers typically depend on patient self-report to identify cognitive problems. Unfortunately, patients are generally poor reporters of their own cognitive abilities. Although some studies have found a correlation between subjective reports of cognitive impairment and objective neuropsychological performance (Marrie, Chelune, Miller, Deborah, & Cohen, 2005; Randolph, Arnett, & Higginson, 2001), most studies fail to find a substantial relationship (Christodoulou et al., 2005; Maor, Olmer, Mozes, 2001; Lovera et al., 2006; Fischer et al., 1999; Middleton, Denney, Lynch, & Parmenter, 2006). Randolph et al., (2001) found that patients were equally good reporters of their cognitive functioning when compared with spouses; however, other studies indicate that caregiver perceptions of patient cognitive abilities are more accurate than the patient’s own report (Benedict et al., 2003; Benedict et al., 2004). These equivocal findings may be attributable to differing disease severity in the samples. Accuracy of patient self-perceived cognitive functioning is further complicated by confounding symptoms such as depression and fatigue. Depression is highly correlated with subjective cognitive complaints (Benedict et al., 2004; Julian, Merluzzi, & Mohr, 2007; Maor et al., 2001; Middleton et al., 2006). Researchers have found that MS patients suffering from depression over-report cognitive difficulties (Benedict et al., 2004; Carone, Benedict, Munschauer, Fishman, & Weinstock-Guttman, 2005) and subjective cognitive complaints are more strongly correlated with depression than objective neuropsychological functioning (Julian et al., 2007). Research on the relationship between depression and objective neuropsychological functioning is less consistent. A review of the neuropsychology literature in MS concluded that there is no consistent relationship between depression and cognitive functioning (Brassington & Marsh, 1998). However, more recent work has suggested that there may be some subtler effects under specific circumstances. For example, Demaree, Gaudino and DeLuca (2003) have suggested that the cognitive deficits may appear only at higher levels of depression. Arnett has suggested a more complex, bidirectional relationship between depression and cognitive function in which depression may affect effortful cognition but not automatic cognition (Arnett, Barwick, & Beeney, 2008). Fatigue is another common symptom of MS and affects up to 90% of patients with the disease (Krupp, Alvarez, LaRocca, & Scheinberg, 1988). Many patients believe that fatigue contributes to poor cognitive performance. Some studies indicate that cognitive fatigue can impair cognitive functioning in MS (Krupp & Elkins, 2000). However, most research indicates that there is not a direct association between fatigue and actual cognitive performance (Fraser & Stark, 2003; Parmenter, Denney, & Lynch, 2003; Paul, Beatty, Schneider, Blanco, & Hames, 1998). For example, Parmenter et al. (2003) examined neuropsychological performance in patients with MS during periods of high and low fatigue. Although patients perceived that they performed more poorly during “high” fatigue periods, there were no actual differences in cognitive performance that could be attributed to fatigue. Given the strong association between depression, fatigue, and perceived cognitive functioning, many researchers believe that perceptions of cognitive abilities are driven more by these comorbid symptoms than by actual cognitive performance. For example, Bruce and Arnett (2004) suggested that mildly depressed patients overestimate their memory impairment due to a depressive schema. Randolph, Arnett, & Freske (2004) also found that depression aggravated patients’ memory complaints due in part to depressive attitudes. Similarly, Middleton et al. (2006) concluded that patients’ perceptions of their cognitive functioning are more reflective of their emotional state and fatigue than their objective abilities. These findings are consistent with Beck’s (1967) cognitive theory of depression. This theory states that depression is associated with a negative, pessimistic view of oneself, the environment, and the future. This negative bias can lead people to misinterpret facts and exaggerate one’s problems, such as overestimating cognitive difficulties. If this negative bias led patients to overestimate their cognitive problems, then we would expect that treatment of depression would result in more accurate perceptions of one’s abilities. Unfortunately, the majority of studies examining the relationship between these constructs (depression, perceived abilities, neuropsychological performance) have been cross-sectional. A recent study by Julian et al. (2007) examined these constructs longitudinally. The authors found an increased association between objective and subjective assessments of cognitive impairment after successful treatment of depression. These findings suggest that depression does in fact influence patients’ abilities to accurately perceive their cognitive abilities. Although important, this study was limited in that it did not include a measure of fatigue. Given the association of fatigue with depression and subjective cognitive reports, it is unclear how this variable might have influenced these results. The purpose of the current study was to extend the findings from the Julian et al. (2007) study by examining the relationship among depression, fatigue, perceived cognitive functioning, and objective neuropsychological performance in the context of a clinical trial designed to treat depression in a sample of MS patients. The first aim of this investigation was to examine depression and fatigue as potential predictors of change in objective neuropsychological scores and subjective cognitive complaints from pre- to post-treatment. The second aim was to examine changes in depression and fatigue as predictors of patients’ accuracy in detecting cognitive impairment.