The relationship between depressive symptoms and ...

COGNITIVE NEUROPSYCHIATRY, 2003, 8 (3), 161±171

The relationship between depressive symptoms and cognitive dysfunction in multiple sclerosis Heath A. Demaree Case Western Reserve University, Cleveland, Ohio, USA

Elizabeth Gaudino Kessler Medical Research Rehabilitation and Education Corporation, West Orange, New Jersey, USA

John DeLuca Kessler Medical Research Rehabilitation and Education Corporation, West Orange and UMDNJ-New Jersey Medical School Newark, New Jersey, USA Introduction. Although it has been well established that otherwise healthy persons with depression experience various neuropsychological deficits, such a relationship has not been robustly supported in the initial investigations using the multiple sclerosis (MS) population. The relative inability to discover a significant relationship between depression and cognitive dysfunction may be due to methodological difficulties in previous studies (e.g., use of correlational analysis; use of neuropsychological measures that are generally not affected by depression). Methods. The present study examined a control group and 17 MS subjects who reported relatively low (BDI 9) or high (BDI 16) depression levels on a variety of neurocognitive measures that were (i.e., PASAT, Digit Span Backward subtest of the WAIS-R, and a modified version of the Buschke Selective Reminding Test; SRT) or were not (i.e., Similarities, Vocabulary, and Digit Span Forward subtests of the WAIS-R) hypothesised to be associated with depression symptomatology. Results. These results support our hypotheses that depressed individuals with MS evidence greater neuropsychological dysfunction relative to their nondepressed counterparts. Conclusion. Findings are discussed in terms of the specific cognitive impairments evidenced by depressed subjects with MS. This research may have significant implications with regard to the expected effects of antidepressant and cognitive therapies on neuropsychological functioning in MS.

Correspondence should be addressed to Dr John DeLuca, Neuropsychology Laboratory, Kessler Medical Research Rehabilitation and Education Corporation, 1199 Pleasant Valley Way, West Orange, NJ 07052, USA; e-mail: [email protected] # 2003 Psychology Press Ltd http://www.tandf.co.uk/journals/pp/13546805.html DOI:10.1080/13546800244000265

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Compared to the relatively robust research supporting cognitive deficits in healthy depressed persons (Breslow, Kocsis, & Belkin, 1980; Deptula & Yozawitz, 1984; Fischer, Sweet, & Pfaelzer-Smith, 1986; Savard, Rey, & Post, 1980; Shipley et al., 1981; Sternberg & Jarvik, 1976; Watson, Davis, & Gassen, 1978), researchers have only recently begun to support a significant relationship between depression symptomatology and cognitive functioning within the multiple sclerosis (MS) population. Several studies have failed to find a significant relationship between cognitive impairment and depression in persons with MS (DeLuca, Barbieri, & Johnson, 1994; Grafman et al., 1991; Minden et al., 1990; Rao, Leo, & St. Aubin-Faubert, 1989). For example, Schiffer and Caine (1991) examined nine patients with major depression using a battery of neuropsychological measures both before and after treatment for depression. These investigators, using a strict p = .02 criterion based on their multiple comparisons, found that cognitive dysfunction was unrelated to depression level. However, non-MS literature suggests that depression is only related to ``effortful'' cognitive tasks (i.e. requiring information manipulation), as opposed to more ``passive'' tests (such as the Grooved Pegboard; Fischer et al., 1994). In fact, closer examination of the Schiffer and Caine (1991) data reveal that nondepressed MS patients outperformed depressed MS patients on letter fluency (p = .05) and delayed word list recall (p = .02), two effortful tasks. Like Schiffer and Caine (1991), other investigators may not have detected a significant relationship between depression and cognitive dysfunction due to their selection of analytic method. Specifically, Grafman et al. (1991), Rao, Leo et al. (1989); DeLuca et al. (1994); and Minden et al. (1990) correlated Beck Depression Inventory (BDI) scores with effortful cognitive task performances. Using correlational analyses, significant relationships between depression and cognitive abilities were not observed. However, non-MS research suggests that this relationship is not linear and that a threshold level of depression may be necessary before dysfunction is evidenced (Hartlage et al., 1993). Subjects with ``minimum'' depression levels (BDI = 9±16; Spreen & Strauss, 1988) are highly variable in neuropsychological performance, thereby drastically reducing the sensitivity of a correlational analysis when assessing for significance (Crews, Harrison, & Rhodes, 1999). Thus, the use of two distinct groups (i.e., low vs. high depression) may be a better method to detect neuropsychological differences with regard to depression symptomatology in subjects with MS. More recently, researchers (Arnett et al., 1999-a) have increased the sensitivity of their work by using two distinct groups with different depression levels (low and high). One research study has recently supported the notion that depression symptomatology is related to cognitive dysfunction within the MS population. As suggested above, Arnett et al. (1999-a) studied two groups of MS subjectsÐ depressed and nondepressed. These researchers determined that depressed subjects were significantly impaired on a highly effortful working memory task

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relative to their nondepressed counterparts. No group differences, however, were found on a relatively passive working memory task (Arnett et al., 1999-a). Follow-up research by Arnett and colleagues suggest that, relative to nondepressed MS patients, depressed persons with MS exhibit slowed informationprocessing speed on capacity-demanding attentional measures and at least one executive task (the Tower of London) (Arnett et al., 1999-b; Arnett, Higgonson, & Randolph, 2001). In addition, although not designed to investigate this relationship, a study by Fischer (1988) revealed that BDI scores were inversely related to Wechsler Memory Scale-Revised (WMS-R) performance among MS patients. Last, Gilchrist and Creed (1994) found that depressed MS patients performed significantly worse on the Rey Auditory Verbal Learning test and Raven's Progressive Matrices relative to their nondepressed counterparts. However, because the depressed group was also found to be significantly older than the nondepressed group, these results should be interpreted with caution. Interestingly, a meta-analysis performed by Thornton and Raz (1997) found a significant relationship between depression and working memory measures, such as the PASAT. While only one known study has reported a significant relationship between depression and effortful cognitive processing (Arnett et al., 1999-a), the increased statistical power of the meta-analysis may have been helpful in discovering this relationship. The present study was designed to assess how depression symptomatology is related to cognitive dysfunction. However, in contrast to most previous research, the current investigation will use two distinct groups of MS patientsÐpersons with relatively low and high levels of depression. Increased group differences with regard to depression symptomatology should help counteract the nonlinear relationship between depression and effortful cognitive. Research using the present sample (DeLuca et al., 1994) demonstrated that MS patients as a group performed significantly worse than healthy controls on the PASAT and Digit Span Backwards tests, and required significantly more trials than controls to learn a list of words (from the Buschke Selective Reminding Test). In the present reanalysis, the goal was to determine if MS subjects with a relatively high level of depression symptomatology evidenced greater cognitive impairment than their low depression counterparts as well as healthy controls.

METHODS Subjects The multiple sclerosis (MS) group consisted of 25 subjects with diagnosis of clinically definite multiple sclerosis (MS) based on the criteria by Poser et al. (1983), and were at least one month post exacerbation. Participants with MS were recruited from the outpatient MS clinics at the University of Medicine and Dentistry of New Jersey (UMDNJ) and the Kessler Institute for Rehabilitation,

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as well as volunteers from local MS chapters. All MS subjects were evaluated by a neurologist and/or physiatrist who works with MS patients. Data from two of the subjects were excluded because they were unable to meet verbal learning requirements (described in the verbal learning section). The remaining 23 MS subjects consisted of 10 chronic-progressive, 8 relapsing-remitting, 4 relapsingprogressive, and 1 subject who experienced a stable course of the disease. The mean age of the MS group was 44.1 years (SD = 7.6, range 31±54) and mean years of education was 14.0 (SD = 1.9, range 11±18). The duration of MS since diagnosis ranged from 1 to 24 years, with a mean of 9.0 years (SD = 6.8). Kurtzke's Expanded Disability Status Scores (EDSS; Kurtzke, 1994) ranged from 2.0 to 8.0 with a mean of 5.7 (SD = 2.0). Healthy controls were 23 individuals recruited from among hospital staff and family members of MS subjects. The mean age of the control group was 41.0 years (SD = 8.6, range 25±56) and mean education was 15.1 years (SD = 2.1, range 12±19). The MS and control groups were statistically similar with regard to age and education level. All subjects signed IRB-approved informed consent forms prior to testing and were paid for their participation. MS and control subjects were excluded if they reported a history of chronic medical disorders (other than MS), alcohol or drug abuse, history of bipolar disorder, psychotic disorder or other significant psychiatric disorder, history of moderate-severe head injury, or were over the age of 68. Subjects in the ``MS low-BDI'' and ``MS high-BDI'' groups (see below for group descriptions) did not significantly differ in age, fatigue, or EDSS scores (see Table 1). However, the MS low-BDI group had significantly fewer years of education as compared to the control group.

Procedure Depressive symptoms. All subjects completed the Beck Depression Inventory (BDI; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961) to assess severity of depression symptomatology. MS subjects were divided at the 33rd and 66th percentiles to obtain groups with low depressive symptoms scores (BDI 9; N = 9) and high depressive symptom scores (BDI 16; N = 8). Thus, subjects TABLE 1 Demographic and disease severity means and SEMs for MS and control subjects Variable Age Education EDSS Fatigue (FSS total)

MS High BDI (N = 8) 41.1 13.7 6.0 158.8

MS Low BDI (N = 9)

(2.8) (0.5) (0.9) (6.6)

Significantly differs from controls, Tukey p < .05.

45.8 13.4 4.3 151.5

(2.5) (0.6)a (0.8) (8.5)

Controls (N = 23) 41.0 (2.7) 15.1 (0.6)


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with ``minimum depression'' (BDI = 10±15; Spreen & Strauss, 1988; N = 6) were excluded in order to eliminate those with the greatest likelihood of having highly variable neuropsychological test performances. Healthy controls exhibited a limited range of BDI scores (range = 0±13; N = 23). Fatigue. All subjects completed the Fatigue Severity Scale (FSS; Krupp, Sliwinski, Masur, & Friedberg, 1989). The FSS assesses the impact of fatigue on activities of daily living. Total scores on this measure range from 1 to 7 with > 4 indicating pathologic fatigue.

Neuropsychological tests Verbal learning. Verbal learning and memory were assessed using a modified version of the Selective Reminding Test (SRT) (Buschke, 1973; DeLuca et al., 1994; DeLuca, Gaudino, Diamond, Christodoulou, & Engel, 1998). In the present usage, this open-trial SRT referred to a verbal list-learning task in which the subject was asked for free recall of a list of 10 semantically related words (items of clothing) over a maximum of 15 trials (2 of the original 25 MS subjects were unable to acquire all the words within 15 trials, and the data from these subjects was excluded from this study's analyses. The BDI scores for these individuals is not known). On trials 2 through 15, the subject was reminded only of words that were missed on the preceding trial, but was required to again recall all the words on the list during the next trial. In contrast to the standard SRT procedure, the present SRT procedure required that subjects continue the list learning until a criterion of 100% accuracy (reciting all 10 words) on two consecutive trials was achieved. The advantage of the open-trial SRT method over the traditional SRT procedure is that it provides the opportunity for the MS and control groups to be equated on learning or acquisition of the verbal material (DeLuca et al., 1994, 1998; Demaree, Gaudino, DeLuca, & Ricker, 2000) before testing recall and recognition. Ensuring that all subjects reach the same level of mastery of the to-be-learned information allows for a more accurate quantification of whether performance differences are due to deficits in acquisition or in the retrieval of information (see DeLuca et al., 1994, 1998; Demaree et al., 2000). Verbal recall and recognition. Delayed free recall and recognition trials were administered 30 minutes after reaching criterion. Subjects were first asked to recall as many words from the SRT task as possible without the benefit of cueing (i.e., free recall). Recognition memory was assessed by asking subjects to identify the original 10 items from among a list of 20 words presented aurally. The dependent variable for recall was the number of items freely recalled without cues and the dependent variable for the recognition was the number of correct hits.

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Information processing. Auditory information-processing speed and efficiency was assessed using the Paced Auditory Serial Addition Test (PASAT; Gronwall, 1977). In the standardised, published PASAT procedure (Brittain, LaMarche, Reeder, Roth, & Boll, 1991), a series of 50 numbers between 1 and 9 were presented by tape recorder for each trial. The subject was instructed to add the number just heard to the immediately preceding number, so that the second number was added to the first, the third to the second, and so on, and to indicate the sum aloud. Subjects completed four consecutive trials of the PASAT, beginning with the slowest presentation rate (2.4 second interstimulus interval; ISI) and ending with the fastest presentation rate (1.2 s ISI). Other neuropsychological measures. All subjects completed selected standard neuropsychological tests. The WAIS-R Vocabulary and Similarities subtests (Wechsler, 1981) were used as indications of estimated premorbid general cognitive functioning. Measures of attention included: the WAIS-R Digit Span Forward and Digit Span Backward subtests (Wechsler, 1981).

Statistical analyses Research on the present sample (DeLuca et al., 1994) demonstrated that MS patients as a group performed significantly worse than healthy controls on the PASAT and Digit Span Backward tests, and required significantly more trials than controls to learn a list of words (from the Buschke Selective Reminding Test). In the present analysis, the goal was to determine if MS subjects with a relatively high level of depression symptomatology evidenced greater cognitive impairment than both their low-depression counterparts as well as healthy controls. One-way ANOVA was used to analyse group differences on all demographic and neuropsychological measures, with the exception of the PASAT data. A 364 (group by trial) mixed factorial ANOVA was used to compare group performance across trials. Post-hoc comparisons were made using the Tukey test.

Results Mean performances on all cognitive tests are summarised in Table 2. On the open-trial SRT verbal learning test, significant group differences on the number of trials required to reach criterion was observed, F(2, 37) = 18.1, p < .001. Univariate comparisons revealed that all groups significantly differed from each other (Tukey p < .05), with the MS high-BDI group requiring the most trials to reach criterion and healthy controls requiring the fewest trials. No significant group differences were found between groups with regard to free recall, F(2, 37) = .56, p > .05, or recognition, F(2, 37) = .72, p > .05, indicating that all groups performed comparably on recall and recognition measures after learning equivalent amounts of information.


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TABLE 2 Results of neuropsychological tests for MS subjects with relatively high BDI scores, relatively low BDI scores, and controls MS highBDI mean (SEM) (N = 8)

Test variable SRT Trials to Criterion SRT Free Recall 30 min SRT Recognition 30 min WAIS-R Digit Span Forward WAIS-R Digit Span Backward WAIS-R Vocabulary WAIS-R Similarities

10.1 9.3 9.8 7.1 5.8 9.1 9.6

(0.9)b (0.2) (0.1) (0.5) (0.4)a (0.4)a (0.6)a

MS lowBDI mean (SEM) (N = 9) 7.0 9.6 9.7 9.0 7.5 10.5 10.3

(0.8)a (0.1) (0.1) (0.6) (0.9) (0.8) (0.5)

Control mean (SEM) (N = 23) 4.9 9.7 9.9 8.8 8.6 12.5 12.0

(0.3) (0.1) (0.04) (0.4) (0.5) (0.5) (0.4)

p-value .000 .255 .323 .136 .041 .003 .015

a

Significantly differs from controls, Tukey p < .05. b Significantly differs from controls and MS low BDI, Tukey p < .05.

Performance on the PASAT is illustrated in Figure 1. A 364 ANOVA comparing groups on PASAT performance revealed a significant main effect of group, F(2, 37) = 6.44, p = .004. Specifically, post-hoc Tukey tests indicated that MS high-BDI group was significantly impaired relative to the control and MS low-BDI group on Trial 1. No significant differences were found between control and MS low-BDI groups on Trial 1. Tukey tests also revealed that, on PASAT trials 2 through 4, both MS groups performed worse than controls. A significant main effect of Trial was found, F(3, 37) = 11.63, p < .05). This, coupled with a nonsignificant interaction effect, indicates that performance among all groups declined as the PASAT ISI interval was reduced. On other neuropsychological measures, MS subjects with relatively high levels of depression performed significantly worse than controls on the WAIS-R

Figure 1. Performance on the Paced Auditory Serial Addition Test.

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Vocabulary, Similarities, and Digit Span Backward subtests (see Table 2). However, on these measures, they did not differ from MS subjects with relatively low levels of depression. No significant differences were found on the Digit Span Forward portion of the WAIS-R across groups.

DISCUSSION The present study was designed to better determine whether depression in multiple sclerosis (MS) is associated with neuropsychological impairment. The present design was atypical of most previous research in this area because it incorporated two groups of MS subjects with distinct levels of depression (high and low), thereby increasing sensitivity when assessing for a relationship between depression and cognitive functioning. The results: (1) add to the mounting literature that persons with MS experience learning and processing speed deficits; and (2) suggest that depression is associated with an increased severity of these impairments. However, given the relatively small sample size in this study, results should be interpreted with caution. Moreover, it should be recognised that the two MS groups differed on the estimates of premorbid intellectual abilities, with the MS high-BDI group scoring significantly lower on the WAIS-R Vocabulary and Similarities subsets. While group differences may have been influenced by this factor, it is unlikely to have played a major role. For instance, note that education levelÐanother indicator of premorbid abilityÐ also differed between groups but in the opposite direction. Such data once again indicate the preliminary nature of the present results due to the small sample size, and outline the need for replication. Both MS groups (regardless of depression level) required significantly more trials to reach the SRT learning criterion, suggesting that persons with MS experience learning deficits. Interestingly, after controlling for acquisition by using the open-trial SRT paradigm, all groups achieved statistically similar recall and recognition scores. Taken together, these findings support the notion that persons with MS (regardless of depression level) experience primarily learning rather than recall deficits (DeLuca et al., 1994, 1998; Demaree et al., 2000; Gaudino, Chiaravalloti, DeLuca, & Diamond, 2001). Moreover, the control group significantly outperformed both MS groups on trials 2±4 (trials with 2.0±1.2 second interstimulus intervals) of the PASAT. These PASAT results suggest that persons with MS have slowed information-processing speed. However, there is a clear indication that depression may augment the severity of learning and processing speed deficits in MS. First, relative to the MS lowBDI group, the MS high-BDI group required significantly more trials to reach the learning criteria. These SRT data indicate that persons with MS who are also depressed experience a greater level of learning impairment. Second, while both MS groups were significantly impaired on trials 2±4 of the PASAT, the MS lowBDI group (unlike their high-BDI counterparts) performed in the normal range


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on the slower 2.4 second PASAT. These 2.4 second PASAT data suggest that depressed persons with MS experience slowed information processing beyond that which may be attributable to MS alone. In sum, rather than being unrelated to neuropsychological performance at all, depression in MS may in fact be related to severity of cognitive impairment. Depression is frequently the first and most noticeable affective change during MS onset (Rao et al., 1993) and the present study suggests that the amelioration of depression may lead to improved neuropsychological functioning. While this has not been directly investigated in MS, other research has found that the pharmacological treatment of depression may improve neuropsychological test performance in other populations (e.g., Wilson & Staton, 1984). The present study also has implications for the neurocognitive rehabilitation of persons with MS. Specifically, prior research has found that impaired information processing speed leads to acquisition deficits in the MS population (Demaree, DeLuca, Gaudino, & Diamond, 1999). Thus, providing more time for the MS patient to process and acquire stimuli (e.g., increasing the interstimulus interval between words on a word list) may improve later recall. Given the present study's findings, this may be a particularly important rehabilitation strategy for persons with MS who also experience significant depression symptomatology. While the present study suggests that depression level is associated with neuropsychological functioning in MS, it is interesting to note that others have found that a highly correlated component of depressionÐapathyÐis intimately related to cognition in neurological populations. Specifically, apathy level has been found to be a sensitive indicator of cognitive dysfunction in persons with cerebrovascular lesions, Alzheimer's disease, HIV-1, and parasupranuclear palsy (Castellon, Hinkin, Wood, & Yarema, 1998; Litvan, Mega, Cummings, & Fairbanks, 1996; Mega, Cummings, Fiorello, & Gornbein, 1996; Starkstein, Federoff, Price, Leiguarda, & Robinson, 1993). While the amelioration of depression has been suggested as a means to improve cognitive functioning in MS, a closer examination of the specific affective components (e.g., apathy) related to cognitive ability in MS appears immediately warranted. This was not possible in the present study because a relatively heterogeneous measure of depression symptomatology was used (the BDI). Such research may lead to a more effective approach towards improving emotional and cognitive functioning in persons with multiple sclerosis (MS). Manuscript received 31 July 2002 Revised manuscript received 3 October 2002

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