orzz 01894 s04.025810.000 “Te Jou oF Neots av Mien Disease Copyright © 104 by Wits & Wiking Vol 12, No. 4 Group Differences in the Relationship Between Apathy and Depression ROBERT S. MARIN, M.D,, SEKIP FIRINCIOGULLARI, M.S, aND RUTH C, BIEDRZYCKI, M.ED! The purpose of this study was to evaluate the discriminability of apathy and depression by ‘dotermining whether the relationship of these two dimensions of behavior varies in different diagnostic groups. Using the authors’ Apathy Evaluation Scale and the Hamilton Rating Seale for Depression, we rated 123 subjects, mean age 72 years, who met research criteria for healthy elderly controls, left or right hemisphere stroke, probable Alzheimer’s disease, and ‘major depression. Elevated apathy scores unassociated with elevated depression were most frequent in Alzheimer's disease and right hemisphere stroke, and also occurred in a small ‘mumnber of left. hemisphere stroke and normal subjects, In major depression, apathy was associated with high depression scores, although a substantial number of major depressives showed elevated depression without elevated apathy. In left hemisphere stroke, probable Alaheimer’s disease, and major depression, there were significant positive correlations be- tween apathy and depression. The slope of the regression of apathy on depression was greatest in probable Alzheimer’s disease and major depression. These results indicate that the relationship between apathy and depression differs across diagnostic groups and, thus, support the discriminabilty of apathy and depression. Although apathy occurs in a variety of neuropsychiat- rie disorders, it is usually considered a symptom of depression. The evidence supporting the association of apathy with depression is substantial (Friedman et al., 1963; Grinker et al, 1961; Overall, 1963; Schulterbrandt et al,, 1974), Apathy also may be a symptom of delirium or dementia. However, there is considerable clinical evidence (Marin, 1991) that apathy occurs as a syn- drome itself in a variety of other disorders. ‘We recently developed (Marin et al., 1991) an apathy scale to validate the hypothesis that apathy and depres- sion are discriminable dimensions of behavior. Based on a functional analysis of apathetic behavior, apathy was defined as lack of motivation and operationalized as simultaneous decrease in the behavioral, cognitive, ‘and emotional concomitants of goal-directed behavior. ‘The seale's reliability and validity were evaluated in a sample of elderly patients who met research criteria for left or right hemispheric infarction, probable Alzhei- ™er's disease, major depression, and healthy elderly controls, Evidence was presented (Marin et al., 1991, 1993) that in the combined sample the scale has validity for discriminating groups according to mean apathy levels and for discriminating apathy from depression by psychometric criteria and behavioral outcomes. ‘A limitation of these results is that they do not indi- cate whether the relationship between apathy and de- —TFrom the Department of Psychiatry, University of Ptsburgt School of Medicine. Send sepia request to Dr. Marin at Western Pett ttt a ci i Tia Se, srg Fen This study was supported in pare by grants from NIMH (MII41830) and NIA (Academic Award AGOO235), 235, J Nero Ment Dis 182:235-239, 1994 pression differs between diagnostic groups. Answering this question is a first step in investigating the ways in which the mechanisms or management of apathy may vary between groups. For this article, we evaluated the relationship of apathy and depression in each group by comparing the mean levels of apathy and depression, by using regression and correlation techniques, and by ‘examining variability within each diagnostic group us- ing cross-abulations of subjects’ apathy and depres- sion scores. Regression and correlation methods exam- ine the statistical relationship between variables. The cross-tabulation approach has the advantage that the cells thus defined can be related to syndromal catego- ries used by clinicians. In particular, to distinguish syn- dromes of apathy and depression (Marin, 1991) in terms of cross-tabular data, apathy would be defined by clini- cally significant apathy in the absence of elevated de- pression. The syndrome of depression would be charac- terized by elevated depression with or without elevation of apathy. Based on clinical observations and published findings, we expected to find that patients with an apathy syndrome, é.c., high apathy and low depression, were associated primarily with right hemi- sphere stroke and probable Alzheimer's disease. Methods Subject selection criteria and the sources of subjects have been described previously (Marin et al., 1991). In brief, subjects were 55 to 85 years old and met research criteria for healthy controls, single infarctions of the left or right cerebral hemisphere, probable Alzheimer's disease (McKhann et al., 1984), or major depression236 MARIN et al. (unipolar, nonpsychotic; Spitzer et al, 1975). Subjects with psychiatric disorders other than those of interest. to this study or with medical and neurological disorders likely to affect central nervous system function were excluded. All subjects were ambulatory, although some required a cane or walker and had restricted mobility. Rating Instruments ‘The content, development, reliability, and validity of ourapathy scale have been presented previously (Marin et al, 1991). In brief, self-, informant-, and clinician- rated versions of the scale were developed, each con- sisting of the same 18 items. The apathy rating is based. on assessment of the subject's thoughts, emotions, and activities during the previous 4 weeks. Items are re- coded as necessary so that a higher score represents a higher level of apathy. Apathy data reported here refer only to the clinician version of the scale, since its reliability and validity were somewhat stronger than the other two versions. We rated depression using the YPitem version of the Hamilton Rating Scale for De- pression (HRSD; Hamilton, 1967). Procedure Subjects and, for Alzheimer's disease subjects, family members gave written informed consent. Subjects were paid $10 per hour for their efforts. To define apathy subgroups, subjects were divided {into two groups, using as a criterion an apathy score (clinician version) 2 standard deviations above the mean for healthy controls. This criterion seemed rea- sonable since, in our experience, subjects at this level of apathy demonstrate minimal, but clinically recogniz- able, apathy. Depression ratings represent total scores using the first 17 items of the HRSD. An initial attempt to define an intermediate level of apathy that was be- ‘tween 1 and 2 standard deviations above the mean of, normal subjects yielded too few subjects in the interme- diate level. Three levels of depression were defined initially (HRSD scores <8, 8 to 15, and > 15). However, a review of videotape recordings indicated that several subjects who were clinically apathetic and not de- pressed fell into the high apathy/moderate depression cell. Using a HRSD criteria of 10 or less did provide appropriate classification of these subjects. Therefore, the HRSD criteria for depression levels were changed to 0 to 10 for low, and > 10 for high depression. Like the high apathy category, this high depression rating identified patients with at least mild, but clinically rec ognizable, depression. ‘Apathy and depression ratings used in this paper are the average scores for the two raters (R, 8. M. and R. €.B,) except for 17 subjects who were seen by only 1 of the raters, Statistical Analyses To evaluate the cross-tabulations, chi-square analy- sses were used to evaluate the association between apa- thy and depression scores for each diagnostic group. We also performed chi-square tests to compare the five diagnostic groups for the overall frequency of high ver- sus low apathy (regardless of depression score) and for the frequency of patients with high apathy and low depression, i.e., for patients who would be character- ized clinically as showing an apathy syndrome. The relationship of apathy and depression was also com- pared for each pair of groups with respect to correla~ tion coefficients and the slope of apathy on depression following procedures recommended by Cohen and Co- hen (1975) and Kleinbaum (1988). Results As described previously (Marin et al., 1991), there were significant between-group differences in educa- tion and income (Table 1). However, these variables ‘were uncorrelated with apathy scores and did not have a significant effect on mean apathy levels in analyses of covariance. The mean age of the left hemisphere stroke patients was slightly lower than the other groups. There was a clear predominance of women in the major depression subjects. Table 2 shows the summary statistics for each group's Mini-Mental State Examination (Folstein et al., 1975), apathy, and depression ratings, Correlation coef- ficients (Pearson's product-moment correlation) be- tween apathy and depression and the slope for the regression of apathy on depression are included. Figure 1 shows box and whisker plots which highlight group differences in the relationship between apathy and de- pression, As described previously (Marin et al., 1991), ‘mean apathy scores were significantly higher than well, elderly scores in right hemisphere stroke, probable Alz- TABLE 1 Demographic Characteristios Sex age Eductlon Income Tota MP (ean) “(mean)” (ean) Weil ideriy aia ne eeroa ean Left Hemisphere Soke 18 10 8 661 242, Right Hemisphere Stoke 22 1210 701 21 LT Probable Alzheimer's Disease eww me 29 28 Malor Depression so 327 78 22 18 ‘Total 12349 74 “age: F= 5.19, df= 4118, p = 02; education: F = 830, df= 1 < 0001; income: F = 6.96 df» 4116, p <.0001. Education: 1 years, 2 = completed highschool, =>12,years 4 = graduated college, 5 = af least some graduate training: income: | = <$10,000 annual ‘income; 2 = $10,000~<820,00, 8 = $20,000-c890,000; 4 » $90,000- $40,000; 5 = 840,000.RELATIONSHIP OF APATHY AND DEPRESSION 237 TABLE 2 Descriptive Statistics for Mini-Mental State Examination, Apathy, and Depress Correlation of Sope for ‘Athy and Regression of HAM Dopresson ‘pally on Men SD Panoon Depreston Well Eldery coerce cn eros on) 36 (NS) ‘Left Hemiephere Stroke 99 635849 C08) 8 (04) Right Hemisphere Stroke 84860 20.NS) 33 (NS) Probable Altheimer's Disease uo ba 49 BACON) 119.¢01) ‘Major Depression 81 mht 854 C000) 1.06 (001), “ABS F= 18.86, df= 4118, p < 0001; HAMD: P= 4890, f= 4,118, p <.000L, MMS: = 20.7, df= 4,16, p <.0001 helmer’s disease, and major depression. Figure 1 also shows that these elevated scores were associated with low depression scores in probable Alzheimer’s disease, with high depression scores in major depression, and intermediate scores in right hemisphere stroke. Despite heterogeneity between groups in the relative levels and ranges of scores (Figure 1), there were significant cor- relations (Table 2) between apathy and depression (ma- Jor depression r = .64, p < 001; probable Alzheimer's disease 7 = .54, p = .01; left hemisphere stroke r = .49, p = 04), Correlations were nonsignificant for healthy controls and for right hemisphere stroke. The test for the significance of these correlation coefficients are tests of the hypothesis of no difference from zero. How- ever, we were also interested in whether the correlation coefficients of these groups differed from each other. ‘Comparing the correlation coefficients for each pairing of groups (Cohen and Cohen, 1975), the only pairings that reached significance (p <.05) were major depres- sion versus normnal (Z = —1.81, two-tailed test) and ‘major depression versus right hemisphere stroke (Z = 1.86, two-tailed). For each pairing of groups, we also tested (Kleinbaum, 1988) for the difference in slopes. of the regression of apathy on depression (Table 2). ‘These tests were nonsignificant except for the compari- caco r Tym Be a1. Boxplt of apathy and depression scores. Figure shows and whisker plots for apathy scores (Ap) and depression scores (Dp) {or each diagnostic group. Left HS and right TS are left and ight hemisphere stroke groups, respectively, Alzheimer's = probable Al Iheimer’s disease; Mia. Depres. = major depression. Vertical axis = Z score for entire sample, Medium score is Identified by an asterisk Inside the box. The length of the box isthe interquartile range (IQR) ‘computed computed from Tukey's hinges. Values more tha 1-519R from the end of the box, but less than three IQRs, a labeled as outliers ("0") son of normal subjects with probable Alzheimer's dis- ease (¢ = ~1.78, p < .05) and with major depression (t= ~181, p <.06), and of right hemisphere stroke with major depression (t = 1.70, p< .06). Table 3 presents the ctoss-tabulation results. Chi-square for test of the hypothesis of no relationship between apa- thy and depression in the total sample was 4.73, df = 1, p = .03. Chi-square for the test of the hypothesis of no difference between groups in frequency of patients with high apathy (low or high depression) was highly significant (1! = 29.96, df= 4, p <.0001), due to the rates of elevated apathy in the Alzheimer's disease (73% 16/ 22) and major depression (53%; 16/30) groups. Elevated apathy scores were also found in 7% (2/81) of normal subjects, 22% (4/18) of left hemisphere stroke, and 32% (7722) of right hemisphere stroke. Chisquare for the hypothesis of no difference be- tween groups in the rate of an apathy syndrome (high apathy, low depression) was 31.41, df = 4, p < .0001), ‘The highest frequency of an apathy syndrome occurred in Alzheimer's disease (65%; 12/22 subjects), followed by right hemisphere stroke, which showed a rate of 23% (5/22). Two of 18 (11%) left: hemisphere stroke subjects showed apathy syndromes. Their apathy scores were 44 and 52, Of the stroke patients with high apathy, HRSD scores were 10 or less for all but four, of whom only one (right hemisphere stroke) met crite- ria for major depression. In major depression, all subjects were, of course, in the high depression group, with 14 having low apathy ‘and 16 having high apathy. If we had used more con- ventional clinical cutoff of 17 or more on the HRSD, 20/80 major depression subjects would have been in the high depression groups, 14/20 of whom would have been in the high depression high apathy subgroup. Chi- square tests for the hypothesis of no association be- tween apathy and depression were nonsignificant for each diagnostic group. Discussion ‘These findings suggest that the relationship between apathy and depression varies according to the diagnosis,238 MARIN et al ‘TABLES Gross-labulation of Apathy and Depression “Asai : Taithanihes “Rig hana ahem or Total spe Wa any stroke rake ‘iseae pression lo efi iii bm ra Wi Depressiont to we 2 % 2 Rn 2 8s 6 RB oo Hi % 4 30 2 2 7 2 o 4 uo 6 Total Bw m2 wo wT 66 “16 “Apathy: Lo = Apathy Evaluation Seale sore < 9 Hi ‘Depression: Lo = Hamilton Rating Scale for Depression score < Ui; Hi in question. In Alzheimer’s disease, there is a clear dif- ference in the levels of apathy and depression scores, despite the fact that there is a significant correlation between apathy and depression scores. In right hemi- sphere stroke, despite similar levels of apathy and de- pression, there is no significant correlation between ‘apathy and depression. In left hemisphere stroke and major depression, the levels of apathy and depression are both elevated and their correlation is moderately high, although only about half of subjects with elevated depression show elevated apathy. Rubin et al. (1987a) also found that a small number of normal controls may show apathy. Its possible that in some this is a sign of impending clinical disturbance. However, personality factors (Neugarten et al, 1968), sensory loss, life events, role change, and other soc environmental factors also need to be considered in evaluating the significance of lack of motivation (Marin, 1990). The association of apathy with right hemisphere damage is well recognized (Gainotti, 1972; Robinson et al., 1984), although its clinical and neurological corre- lates have been studied to a limited degree (Heilman et al., 1978; Morrow et al., 1981; Robinson et al, 1984) outside of the context of neglect (Heilman et al., 1985), An association of left hemisphere stroke with apathy is less familiar, but has been reported by Gainotti (1972), who found indifference or inappropriate joking in 11% of 80 left hemisphere-damaged stroke subjects. An association of apathy with left: hemisphere stroke ‘was confirmed by Robinson (in press) using a prelimi- nary version of our apathy scale, Our results indicate that apathy occurs frequently as a distinct syndrome in Alzheimer’s disease. The associ- ation of apathy with Alzheimer's disease has been rec- ognized for some time (Reisberg, 1983; Sjogren et al., 1952; Sourander and Sjogren, 1970), The course of apa- thy and related symptoms has been described by sev- ceral groups of investigators (Burns et al., 1990; Deven- and et al., 1992; Petry et al., 1988, 1989; Rubin et al., 41087a, 1987b) studying Alzheimer’s disease. Depending, on the stage of illness, they have reported (Burns et al., 1990; Petry et al., 1989; Rubin et al., 1987b) apathy pathy valuation Seale score > 88 10, and related symptoms in 20% to 88% of patients. These results suggest that a syndrome of apathy can be recog- nized in Alzheimer’s disease and evaluated for its use in understanding such clinical variables as clinical course, family burden, and neurobiological predictors of behav- {oral disturbances. ‘The results of this study highlight the fact that for clinical purposes there are appreciable differences in the presentation of patients depending upon the promi- nence of apathy and depression, In major depression, elevated apathy is strongly associated with elevated depression scores. However, at least 30% of major de- pression subjects showed depression (HRSD > 16) without elevated apathy scores. It would be of interest to determine whether the presence or absence of apa- thy has implications regarding pathophysiology, clint- cal course, or response to treatment. In other disorders, there are individuals who present, a syndrome of motivational loss that is unassociated with depression. Such individuals may be characterized as presenting an apathy syndrome (Main, 1991). The significance of such apathy may be evaluated in rela- tionship to many socioenvironmental, psychological, functional, and biological variables. The reward or in- centive characteristies of living environments may be of importance for institutionalized or isolated individuals (Moos, 1981; Schulz, 1976). Role loss, funetional capac- ity, sensory impairment, and a variety of medical states may contribute to the development of apathy (Marin, 1990), Lesions involving the frontal lobe (Miller et al, 1991; Stuss and Benson, 1984), amygdala and temporal Jobe (Burns et al., 1990; Lilly et al, 1983), basal ganglia (Albert et al, 1974; Cummings and Benson, 1984), and parietal lobe (Gainotti, 1972; Heilman et al., 1985; Rob- inson et al,, 1984) may contribute to the development of apathy in Alzheimer's disease, stroke, and other dis- orders associated with apathy. In neurochemical terms, diminished dopaminergic funetion is hypothesized to be the common denominator producing apathy in neu- ropsychiatric disorders (Marin, 1991). Changes in sero- tonergic function (Hoehn-Sarie et al, 1990) may modu-[RELATIONSHIP OF APATHY AND DEPRESSION 239 late dopaminergic systems to produce apathy, Each of these possibilities has implications for treating patients with apathy. Conclusions Recognizing the syndrome of apathy and differentiat- ing it from depression is of importance in managing patients with a variety of clinical disorders. In this study, we evaluated the relationship between apathy ‘and depression using group means, correlation and re- gression techniques, and cross-tabulation of subjects’ scores on apathy and depression scales. Our results| indicate that the relationship between apathy and de- pression varies between diagnostic groups. They also support the suggestion that apathy and depression are clinically distinct, neuropsychiatric syndromes. In this sample, the syndrome of apathy was most common in probable Alzheimer’s disease and right. hemisphere stroke. In major depression and left hemisphere stroke, apathy was associated with elevated depression rat- ings. Although the mean apathy levels were similar, the frequency of an apathy syndrome was higher in right hemisphere stroke than in left hemisphere stroke. In ‘major depression, apathy is generally, but not always, associated with marked elevation of depression scores. ‘Comparing groups in terms of the correlation coetfti- cients and the relative slopes of the regression of apa- thy on depression highlights that despite the low range of depression scores in Alzheimer’s disease, there is a close relationship of apathy and depression in Alzhel- ‘mer’s disease, as well as in major depression. 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