14
148
Cognitive impairment and stroke
There are numerous studies which have demonstrated cognitive impairment asso-ciated with of specific regions of cerebral infarction (Gazzaniga 2000). Although the focus of this chapter will be on the relationship between depression and cognitive impairment, it is worthwhile to review some of the recent studies which have docu-mented the frequency and severity of cognitive impairment associated with stroke.
Perhaps the most well-designed study is the one involving the Framingham cohort (Kase et al. 1998). They prospectively studied a group of 74 subjects who had suf-fered a stroke during a 13-year follow-up and compared them with 74 control sub-jects who had not suffered a stroke, but were matched for age and sex. The patients who suffered a stroke were noted to have a significantly lower mini-mental state exam (MMSE) score at prestroke baseline (i.e., 27.3 0.3, stroke and 28.1 0.2, control). Following the stroke, however, the mean MMSE in the affected group was 23.6 0.9 compared with a mean mini-mental score of 28.3 0.2 (p 0.001) in the control patients. The decline in cognitive function was correlated with large left-sided strokes as documented on CT scan. The Framingham Study also found that the Center for Epidemiological Studies – depression scale (CES-D) scores indicated significantly more depressive symptoms in the patients with stroke compared with controls. Another study by Censori et al. (1996) found that, when 110 hospitalized patients, who had suffered a first ever stroke as documented by CT scan, were exam-ined at 3 months following stroke, 5% showed dementia, as determexam-ined by the National Institute of Neurological Disorders and Stroke ARIEN criteria. Considering only patients with supratentorial lesions and with residual deficits of motor or sensory functions, the frequency of dementia was 24.6% (95% confidence interval (CI): 14.5–37.3%). A multivariate analysis identified age, the existence of diabetes, presence of aphasia, large, middle-cerebral artery infarction, and lesions of the frontal lobe, as significant independent correlates of poststroke dementia. Finally, Pohjasvaara et al. (1997) found that among 451 patients with acute stroke, cognitive
decline was present in 61.7%. In the groups aged 55–64, 65–74, and 75–85, the fre-quency of cognitive decline was 45.7%, 53.8%, and 74.1%, respectively (p 0.0008). The frequency of dementia was 18.4% using diagnostic and statistical man-ual (DSM-IV) criteria. Thus, these studies document the fact that, in the majority of patients suffering a stroke, cognitive impairment is a common consequence of stroke and probably represents the most common mental impairment associated with ischemic lesions.
Cognitive impairment and depression
The nature of the relationship between cognitive impairment and depression appears to involve a complex interaction between depression, the stroke lesion and cognitive impairment. Although one might understandably view cognitive impair-ment as a cause of depression, their relationship is clearly a more complex one.
In 1989, we hypothesized that major depression following left hemisphere lesions produces through some physiological process a greater degree of cognitive impair-ment than can be explained by the lesions alone and that this represents a post-stroke dementia of depression (Bolla-Wilson et al. 1989).
Although some investigators have found that patients with depression were no more cognitively impaired than those without depression (Eastwood et al. 1989;
Morris et al. 1990), most studies have reported that patients with major depression have a greater degree of cognitive impairment than non-depressed patients (Robinson et al. 1986; House et al. 1991; Kauhanen et al. 1999; Spalletta and Caltagirone 2003).
In our initial longitudinal study of 103 patients, we found a significant correlation between severity of cognitive impairment, as measured by the MMSE score, and severity of depression, as measured by either the Zung depression rating scale (r 0.28; p 0.01), the Hamilton depression rating scale (HDRS) (r 0.22;
p 0.02), or the present state examination (PSE) (r 0.38; p 0.02) (Robinson et al. 1983). Furthermore, the MMSE scores of patients with major depression were significantly lower (19.7 4.7 SD) than those of patients with minor depression (22.5 6.3 SD) or no depression (23.4 4.7 SD) (p 0.01).
Subsequently, other investigators have also found that cognitive impairment is significantly greater among patients with major depression compared with non-depressed patients (House et al. 1990). Kauhanen et al. (1999) examined 106 con-secutive patients with acute first ever ischemic stroke. The prevalence of major depression was 9% at 3 months and 16% at 12 months. Patients with major depres-sive disorder were significantly more impaired than the non-depressed patients (Kauhanen et al. 1999). A study by Andersen et al. (1996) examined 166 patients 1 year following acute stroke. Depression diagnosis was based on having a Hamilton depression score of 13 or greater. Fifty percent were diagnosed with depression at 149 Relationship to cognitive impairment and treatment
150 Poststroke depression
1 month and 79% within 3 months after stroke. Improvement in mood symptoms was correlated with improvement of intellectual function. The Mattis dementia rat-ing scale correlated with the Hamilton depression score in the first year followrat-ing stroke (r 0.22; p 0.005). In 53 patients, however, improvement in intellectual performance was absent and the use of antidepressant medication did not lead to a significant improvement in the Mattis dementia rating scale.
Neuropsychological testing showed that major depressed patients had signifi-cant impairments in almost all areas of cognitive function in comparison with non-depressed patients. Patients with depression were more impaired at 3 and 6 months in verbal logical thinking, comprehension, non-verbal problem solving, including picture completion and block design, verbal memory, as measured by logical memory and serial learning, visual memory, as measured by visual repro-duction, visual recognition and attention, and executive function, as measured by trail making test part A, verbal fluency, and visual constructive functions. These findings held up after patients with aphasias were removed. Thus, detailed neu-ropsychological testing revealed a significant association between major depres-sion and widespread cognitive impairment (i.e., dementia syndrome).
We have recently examined the relationship between depression diagnosis and cognitive impairment as measured by the mini-mental state in all of the patients which we have examined in our acute stroke depression studies (i.e., 357). This group included our original 103 patients and 254 new patients. The background charac-teristics of this group are shown in Table 14.1. The mean MMSE scores for these patients are shown in relationship to their depressive diagnosis in Fig. 14.1, study 1.
Patients with major depression (i.e., MMSE 19.2 7.4 SD) were significantly more cognitively impaired that those with minor depression or no mood disorder
Table 14.1. Background characteristics
Baltimore and Iowa stroke patients combined n 357
Age in years (mean SD) 61.3 (13.8)
Education in years (mean SD) 10.0 (3.9)
Gender (% male) 57.7
Race (% black) 51.0
Alcohol abuse (% positive) 16.1
Marital status (% married) 46.5
Socio-economic status
Hollingshead Class I and II 14.9
Hollingshead Class III and IV 85.1
Family history of psychiatric disorder (% with history) 10.8 Personal history of psychiatric disorder (% with history) 10.5
151 Relationship to cognitive impairment and treatment
(MMSE 23.1 5.1)(p 0.0001). Furthermore, using a score of 23 or less as indi-cating significant cognitive impairment, in the non-depressed group, 80 of 222 patients (36%) were cognitively impaired, as were 28 of 65 (43%) with minor depression versus 41 of 70 (59%) with major depression (p 0.0037). Thus, in our overall acute stroke population, cognitive impairment as measured by the MMSE was significantly more frequent in patients with major depression compared with minor depression or no depression.
In addition to the effect of depression, we have also found significant associa-tions of cognitive impairment with age, education, and race (Table 14.2). A multi-ple linear regression analysis found that major depression (p 0.0029), age (p 0.0511), and education (p 0.0001) were all independent factors associated with cognitive impairment following stroke.
In an effort to determine whether there was an interaction between severity of cognitive impairment and severity of major depression, a two-way analysis of vari-ance (ANOVA) of Hamilton depression scores was performed (Factor 1 presence or absence of major depression, Factor 2 presence or absence of cognitive impairment).
Results demonstrated the expected effect of depression, that is depressed patients had significantly higher Hamilton depression scores, but no effect of cognitive impairment (i.e., cognitively impaired patients with major depression did not have higher Hamilton scores than non-cognitively impaired patients) and no interaction
0 5 10 15 20 25 30 35
Study 1 n 357 (all acute patients)
Mini-mental state score
Study 2 n 26 (matched for lesion) Major depressed Minor depressed Non-depressed
Figure 14.1 Mini-mental scores related to depression diagnoses (i.e., major, minor, or no depression) in two studies. Study 1 included all acute stroke patients with mini-mental exams. Study 2 compared cognitive function in patients with or without major depression who were matched for lesion volume (5%) and lesion location. These studies found that major but not minor poststroke depression was associated with greater cognitive impairment than no mood disturbance. * p 0.05 compared with minor or non-depressed.
152 Poststroke depression
between the two. This finding indicates that severity of depression cannot account for the existence of cognitive impairment in those with poststroke major depression.
Effects of depression versus effects of lesion
To separate the effect of stroke from the effect of depression on cognitive impair-ment, we examined 13 pairs of patients who were matched for lesion size and loca-tion, but one patient of the pair had major depression, while the other was non-depressed (Starkstein et al. 1988). Patients were matched for lesion location if both of their lesions involved, either totally or partially, the same regions as those defined by Levine and Grek (1984). There were no significant group differences in background characteristics such as age, gender, years of education, or socio-economic status. Depressed patients, however, had significantly lower mini-mental scores than non-depressed patients (Fig. 14.1). Of the 13 pairs of patients, 10 had lower MMSE scores than their respective lesion-matched controls, two had the same scores and only one depressed patient had less cognitive impairment than their non-depressed lesion-matched control (p 0.001).
Table 14.2. Background characteristics in relationship to depression and cognitive impairment
In-hospital
Not depressed Major depression cognitive impairment cognitive impairment
No Yes No Yes p
n 179 108 29 41
Age in years (mean SD) 61.1 (14.2) 64.0 (11.6) 57.2 (15.6) 57.9 (14.9) 0.0240a,b Education in years (mean SD) 11.1 (3.6) 8.3 (4.1) 11.2 (2.8) 9.0 (3.2) 0.0001a
Gender (% male) 57.0 63.9 48.3 51.2 0.3216
Race (% African–American) 40.8 72.2 27.6 56.1 0.0001a
Alcohol abuse (% positive) 15.6 11.1 20.7 26.8 0.0644
Marital status (% married) 50.3 40.7 58.6 36.6 0.1217
Socio-economic status (%)
Hollingshead Class I and II 46.8 18.0 31.0 12.2
Hollingshead Class III and IV 53.2 82.0 69.0 87.8 0.3623
Family history of psychiatric 11.9 6.5 6.9 20.0 0.1017
disorder (% with history)
Personal history of psychiatric 9.0 3.7 20.7 26.8 0.0001b
disorder (% with history)
aCognitive impaired versus non-cognitive impaired.
bMajor depression versus not depressed.
This study demonstrated that the greater degree of cognitive impairment among patients with major depression compared to non-depressed patients could not be explained by the effect of the ischemic lesion. Our second study which dis-tinguished between the effects of depression and the effects of brain injury admin-istered a battery of neuropsychological tests to assess cognitive function among 53 patients with single stroke lesions of the right or left hemisphere who had no lan-guage disturbance except mild anomia (Bolla-Wilson et al. 1989).
The neuropsychological examination included orientation, language, remote memory, verbal memory, visual memory, recognition, visual perceptual ability, visual constructional ability, executive motor function, and frontal lobe functions.
Patients were grouped according to the hemisphere in which their lesion was located and by the presence or absence of major depression. There were no significant dif-ferences between the depressed and non-depressed groups in terms of their back-ground characteristics including age, socio-economic status, years of education, gender, race, handedness, or time since stroke. Similarly, there were no significant differences in neurological findings with 85% of patients being hemiparetic and 50%
having a hemisensory deficit. Visual field deficits, hemi-anopsia or quadrant anopsia, were found in one patient with a left hemisphere lesion and five patients with a right hemisphere lesion, none of whom were depressed. In these patients, all testing mate-rials were presented to the non-affected visual field. CT scan analysis found that there were no significant differences between the depressed and non-depressed groups in the frequency of cortical compared with subcortical lesions. The mean lesion vol-umes for the patients with left hemisphere lesions with major depression (n 10) was 2.0 2.0% of brain volume, and without depression (n 16) was 5.3 1.0%, while in patients with right hemisphere lesions with major depression (n 8) was 3.5 2.0% and without depression (n 19) was (6.8 6.0%). The anterior lesion borders as a percent of the overall anterior posterior distance for the four groups were 30.4 6.0%, 37.9 20.0%, 45.9 17.0%, and 40.5 22.0%, respectively.
In order to compare across various neuropsychological domains, individual scores were converted to standardized Z-scores and are shown in Fig. 14.2. The sum Z-scores demonstrate that there was a significantly greater impairment among patients with left hemisphere lesions and major depression compared to patients with left hemisphere lesions without depression or compared to those with right hemisphere lesions with or without depression (p 0.01). Analysis of individual tests of neuropsychological function indicated that patients with left hemisphere lesions and major depression were more impaired in orientation, language, visual perceptual constructional tasks, executive motor function, and frontal lobe func-tions compared to patients with left hemisphere lesions but no depression.
Among patients with right hemisphere lesions, however, there were no significant differences between patients with major depression and those who were non-depressed 153 Relationship to cognitive impairment and treatment
154 Poststroke depression
in any of the nine cognitive domains. Thus cognitive impairment associated with major depression occurred only among patients with left hemisphere lesions and involved impairments in right hemisphere function and frontal lobe function.
Kauhanen et al. (1999) reported similar findings. Patients with first ever stroke and major depression were found to be significantly more impaired than non-depressed patients (n 46 at 3 months and n 53 at 12 months) in verbal and visual memory, non-verbal problem solving, executive function and visuocon-structional tasks at both time points. Although this study did not examine the effect of hemispheric side of injury and they found that both major and minor depression were associated with cognitive impairment, the impairment tended to be more severe in patients with major depression, particularly among patients with dysphasia and major depression (n 7) at 12 months.
Spalleta et al. (2002) examined 153 patients with first ever stroke lesions of the right (n 87) or left (n 66) hemisphere who were less than 1 year poststroke.
The presence of major depression was based on the structured clinical interview
Cognitive domain Depressed (n 10)
Non-depressed (n 16)
Depressed (n 8) Non-depressed (n 19) Orientation
Language Remote memory
Verbal memory Visual memory Recognition memory
Executive motor Frontal lobe
functioning Visuoperception Visuoconstruction
R i g h t
h e m i s p h e r e L
e f t
h e m i s p h e r e
2
Z-scores Z-scores
10 1 p 0.05 4 3 2 1 0 1
p 0.01
2 3 4 5
Figure 14.2 The results of neuropsychological testing in patients with major depression (depressed) or no mood disturbance (non-depressed) following a single lesion of the left or right hemisphere. Scores in each cognitive domain were converted to Z-scores so that comparisons could be made across domains. A more positive Z-score indicates a greater degree of impairment. Note that among patients with left hemisphere strokes, patients with major depression were more impaired than the non-depressed in every cognitive domain. Five of these domains reached statistical significance, indicated by asterisks.
None of the domains reached significance in the patients with right hemisphere stroke.
155 Relationship to cognitive impairment and treatment
for DSM-IV (SCID) and the severity of cognitive impairment was based on the MMSE. Sixty-two (41%) of the patients had a major depression (32 right lesions, 30 left lesions) while 26 (17%) had a minor depression (17 right, 9 left lesions).
Patients with left hemisphere lesion and major depression were found to be signifi-cantly more impaired than non-depressed patients with left hemisphere lesions (mini-mental 12.3 9.0 for major depressed versus 18.9 8.5 non-depressed) p 0.001) (Fig. 14.3). Similarly, patients with left hemisphere lesions were signifi-cantly more cognitively impaired than patients with right hemisphere lesions even though they both had major depressive disorder (12.3 9.0 SD versus 23.7 7.1 SD) (p 0.0001). There was no effect of minor depression or side of injury on cognitive function. A series of stepwise multiple regression analyses examining the effects of Hamilton depression score, number of brain regions affected by the stroke, trait anger inventory, age, Hamilton anxiety scale, Barthel Index, diabetes mellitus, and age revealed that among patients with left hemisphere lesions the strongest correlate of mini-mental score was HDRS (r 0.34) (p 0.001). Numbers of areas of brain injury and the anger trait/anger expression inventory also were independ-ently associated with mini-mental score. Among patients with right hemisphere lesions, only education level was significantly associated with severity of cognitive impairment (r 0.24) (p 0.025).
House et al. (1990) found that patients with major depression (n 10), or any other DSM-III axis I diagnosis (n 27) at 1 month poststroke, were significantly
0 10 20 30
Mini-mental state score
Morris et al. 1990
Downhill et al. 1994
Spalletta et al. 2002 n 9 n 7 n 22 n 20 n 73 n 98 n 30 n 32 n 27 n 38
Major Non-depressed Major Non-depressed Major Non-depressed n 24 n 24
Right
Left p 0.001
Figure 14.3 MMSE scores following acute stroke in three studies among patients with major or no mood disturbance grouped according to the hemisphere of ischemia. In all three studies, there was a significant difference between patients with major depression following left hemisphere stroke and non-depressed patients with similar lesions ( * p 0.001). Major depression following right hemisphere lesions did not lead to the same phenomenon.
156 Poststroke depression
more cognitively impaired as measured by the MMSE than patients with no axis I diagnosis (n 52; p 0.006). Patients with major depression had the lowest MMSE scores. In addition, for patients with left hemisphere lesions there was a significant correlation between MMSE scores and the severity of depression as measured by the Beck depression inventory (BDI) or the PSE (BDI, r 0.55; PSE r 0.43;
p 0.003). For patients with right hemisphere lesions these correlations were weaker or NS (BDI r 0.08; p NS; PSE r 0.39; p 0.04). At 6-month fol-low-up, the correlation between BDI score and MMSE was significant for patients with left hemisphere lesions (r 0.21 but NS for patients with right hemisphere lesions r 0.06).
Morris et al. (1990) also found a significant association between major depression and cognitive impairment at 2–3 months following acute stroke among patients with left hemisphere lesions. Patients with left hemisphere lesions and major depression (n 9) had a mean MMSE of 16.6 8.6 while non-depressed patients with left hemisphere lesions (n 24) had a mean MMSE of 23.0 7.0 (p 0.03). There were no significant differences in the mental scores between 7 patients with major depression following right hemisphere lesions (25.7 2.3) and 24 non-depressed patients with right hemisphere lesions (25.1 4.0) (Fig. 14.3).
In summary, several studies have demonstrated that during the first year follow-ing stroke, major depression is associated with a greater degree of cognitive impair-ment than could be explained based on the size or location of the stroke lesion. The degree of cognitive impairment among patients with major depression and left hemisphere stroke was also significantly greater than among patients with major depression and right hemisphere strokes or patients with minor depression or no mood disturbance. This phenomenon was also confirmed using detailed neuro-psychological testing which showed that a significant number of neuropsycholog-ical domains were significantly affected by major depressive disorder following a left hemisphere stroke.
Longitudinal course of cognitive impairment and depression
In our original 2-year longitudinal study of 103 patients (see Table 8.1 for popula-tion characteristics), we found that the mean correlapopula-tion coefficient between the severity of depression and the MMSE score declined from0.34 (p 0.01) dur-ing acute hospitalization to0.18 at 3 months (p NS). By 6-month follow-up, however, the correlation had increased to0.31 (p 0.01). At 1- and 2-year follow-up, however, the correlations were not significant. Thus, in our initial follow-up study, the strength of the relationship between depression and cogni-tive impairment appeared to decline over time. As mentioned previously, House et al. (1990) found a similar phenomenon. The correlation between the BDI and
the MMSE score for 76 patients at 1 month poststroke was r 0.34 (p 0.001).
At 6 months poststroke, for 107 patients, the correlation was r 0.24 (p 0.006) while at 12 months, for 88 patients, the correlation had fallen to r 0.09 (p NS). These data suggest that the relationship between depression and cognitive impairment declines with time following stroke.
We examined this phenomenon in all of our acute stroke patients who were seen for at least one follow-up during the first 2 years poststroke (n 140). Longitudinal data obtained at the 3-, 6-, 12-, and 24-month follow-ups were analyzed for the rela-tionship between depression and cognitive impairment (Downhill and Robinson 1994). ANOVA of MMSE scores, comparing major depressed and non-depressed (including or excluding minor depressions) patients in-hospital or at the 3-, 6-, 12-, and 24-month follow-ups demonstrated a significant effect of major depression at the initial in-hospital evaluation (Fig. 14.3) and at 3- and 6-month follow-ups (in-hospital MMSE score 17.3 8.1 for depressed versus 24.1 5.6 for non-depressed patients; p 0.01; 3 months MMSE scores 18.5 9.9 for depressed versus 24.8 5.0 for non-depressed; p 0.01; 6 months MMSE scores 20.2 9.7 for depressed versus 24.7 5.7 for non-depressed; p 0.1.
Since the association between depression and cognitive impairment was strongest in patients with left hemisphere lesions, patients were grouped according to the side of their lesion. Patients with a diagnosis of major depression and a left hemi-sphere lesion were more cognitively impaired than non-depressed patients or patients with major depression and a right hemisphere lesion in-hospital (p 0.01) and at the 3 (p 0.006) and 6 (p 0.03) month follow-ups (Fig. 14.4 bottom panel). The composition of the major depression and non-depressed groups, however, was slightly different at each time point (i.e., at each follow-up, any patient with a diagnosis of major depression was included regardless of whether they had been depressed at a previous evaluation).
This analysis could have “diluted” the effect, if there was something different about patients who had cognitive impairment with major depression in the imme-diate poststroke period as compared to patients with late-onset major depression.
Therefore, we examined the longitudinal course of cognitive impairment in patients with in-hospital major depression regardless of their diagnosis at follow-up (i.e., groups were composed of the same patients at each follow-up time point). There was a significant effect of in-hospital diagnosis of major depression and left hemi-sphere stroke on cognitive performance at the initial, 6 month (p 0.03), and 12 month (p 0.02) follow-up periods (Fig. 14.4 top panel). There was no significant effect of major depression on cognitive performance at 2 years poststroke and there was no significant effect among patients with right hemisphere stroke at any poststroke time period. These data suggested that in-hospital major depression after a left hemisphere lesion is different than other major depressions and when it 157 Relationship to cognitive impairment and treatment
158 Poststroke depression
L not depressed at initial evaluation L depressed at initial evaluation
R not depressed at initial evaluation R depressed at initial evaluation
L not depressed at each evaluation L depressed at each evaluation
R not depressed at each evaluation R depressed at each evaluation 0
5 10 15 20 25 30
0 3 6 12 24
Months since stroke
MMSE score
p 0.05 0
5 10 15 20 25 30
0 3 6 12 24
Months since stroke
MMSE score
p 0.05
Figure 14.4 MMSE scores of patients grouped according to hemisphere of stroke (Left (L) or Right (R)) with major depression (depressed) or no mood disorder (not depressed) (patients with minor depression excluded) at the in-hospital evaluation and over 2-year follow-up. The top panel shows the scores of patients who were depressed at the in-hospital evaluation and the scores of those same patients (independent of whether they remained
depressed) at each follow-up. The bottom panel shows the scores of all patients with major depression or no mood disorder at each follow-up (independent of their diagnosis at prior evaluation). Cognitive function is significantly more impaired in patients with major depression following left, but not right, hemisphere stroke. The greater cognitive impairment lasted for about 1 year (data from Downhill and Robinson, 1994).
159 Relationship to cognitive impairment and treatment
resolves (within the first year following stroke) major depression is no longer asso-ciated with cognitive dysfunction.
Finally, we examined the relationship between in-hospital findings and cogni-tive function at either 3- or the 6-month follow-up. This study utilized the original group of 103 patients who were evaluated over 2 years following acute stroke.
Findings obtained during the initial in-hospital evaluation were correlated with outcome at 3- and 6-month follow-ups (Fig. 14.5). In-hospital depression scores were weakly correlated with MMSE scores at the 3-month follow-up. None of the three measures of depression at the in-hospital evaluation were significantly cor-related with MMSE scores at the 6-month follow-up. Thus, depression was only weakly predictive of cognitive impairment at follow-up. Alternatively, MMSE scores at the in-hospital evaluation were not significantly correlated with depres-sion scores at 3-month follow-up. At the 6-month follow-up, however, there were significant correlations between in-hospital MMSE scores and depression scores at follow-up (Fig. 14.5). Thus, cognitive impairment at the time of acute stroke was moderately predictive of depression at 6-month follow-up.
In conclusion, the relationship between cognitive impairment and depression appeared to be as complex as the relationship between physical impairment and
0 0.1 0.2 0.3 0.4 0.5
MMSE score 3 months
MMSE score 6 months
Depressed score 3 months
Depressed score 6 months
Correlation coefficient
In-hospital depression scores In-hospital MMSE scores PSE Zung Hamilton p 0.05
Figure 14.5 Correlation coefficients between in-hospital measures of depression or cognitive impairment and the corresponding measures in the same patients at 3- and 6-month follow-up. Note that in-hospital depression showed declining correlation with cognitive impairment over time while in-hospital mini-mental scores increased in their relationship to depression at follow-up. This may reflect that depressions with cognitive impairment lasted longer than depression without cognitive impairment or that patients with cognitive impairment become more depressed over time.
160 Poststroke depression
depression. During the first year poststroke, the most severely cognitively impaired patients remained depressed and the most depressed patients showed the smallest amount of recovery in their cognitive functions.
Effect of antidepressant treatment on cognitive function
Perhaps the most important data which addresses the question about whether cog-nitive impairment produces depression or depression produces cogcog-nitive impair-ment is treatimpair-ment outcome. Prior double-blind treatimpair-ment studies (Lipsey et al.
1984; Andersen et al. 1994; Robinson et al. 2000; Fruehwald et al. 2003) have all found that patients treated with active antidepressant medication had no greater improvement in their cognitive function than patients treated with placebo, in spite of the fact that active treatment significantly improved mood. This observa-tion led Andersen to suggest that cognitive impairment may lead to depressive dis-order (Andersen et al. 1996).
We recently performed a merged analysis of patients from our prior treatment studies to examine whether successful treatment of depression would lead to improved cognitive function (Kimura et al. 2000). Patients from the Lipsey et al.
(1984) treatment study (Baltimore) as well as the Robinson et al. study (2000) (Iowa) were included if they had completed the treatment study and had received either nortriptyline (n 21) or placebo (n 26). Background characteristics are shown in Table 14.3. The only significant intergroup difference was a significantly higher frequency of family history of psychiatric disorder in the nortriptyline group than the placebo group (p 0.006). There were no significant differences in stroke type, lesion location, or neurological deficit. Repeated measures ANOVA of the MMSE scores showed no significant group effect or group by time interaction. We next examined treatment effects among patients who did or did not respond to treatment.
Responders (n 24), major depression (n 15), minor depression (n 9), had a
Table 14.3. Comparison of Ham-D and MMSE scores for nortriptyline and placebo groups
Ham-D MMSE
Dose Nortriptyline (n) Placebo (n) *p Nortriptyline (n) Placebo (n) *p 0 mg 17.38 4.30 (21) 17.92 3.95 (26) 0.655 23.62 1.24 (21) 24.39 1.02 (26) 0.632 50 mg 12.81 3.86 (21) 13.27 4.79 (26) 0.723 24.95 1.10 (20) 24.76 1.07 (25) 0.903 75 mg 8.38 5.74 (21) 13.12 7.70 (26) 0.024 25.20 1.09 (20) 25.17 1.02 (23) 0.986 100 mg 5.33 6.24 (18) 11.08 7.81 (26) 0.013 26.47 1.14 (17) 25.44 1.14 (25) 0.540 Values are mean SD. Total n of each group decreased because of missing data.
* Unpaired t-test.
Reprinted with permission from Kimura et al. (2000).
161 Relationship to cognitive impairment and treatment
greater than 50% reduction in Hamilton depression scores and no longer met crite-rion for major or minor depression and non-responders (n 23), major depression (n 18), minor depression (n 5) had less than 50% reduction in Hamilton rating scale for depression (Ham-D) scores. The responder group included 16 patients treated with nortriptyline and 9 with placebo. The non-responder group included 5 patients treated with nortriptyline and 18 with placebo. There were no significant differences between the responder group and treatment failure group in their base-line Hamilton depression scores (18.3 4.2 responder versus 17.0 3.9 non-responder). There were also no significant differences between the two groups in their demographic characteristics, lesion variables or neurological findings.
Repeated measures, ANOVA of mini-mental scores demonstrated a significant group by dose interaction (p 0.005) (i.e., cognitive function in the responder group recovered more than the treatment failure group) (Fig. 14.6). Planned comparisons revealed that the responders had significantly less impaired mini-mental scores than the non-responders at nortriptyline doses of 75 mg (p 0.036) and 100 mg (p 0.024). Although some placebo patients (n 8) were in the responder group, there were significantly more nortriptyline-treated patients in this group than in the non-responder group (p 0.0032). If only nortriptyline-treated patients were used
21 22 23 24 25 26 27 28 29
0 50 mg 75 mg 100 mg
Dose of nortriptyline
MMSE score
Responders Non-responders
Figure 14.6 Change of MMSE scores in patients with poststroke depression who did or did not respond to treatment with nortriptyline or placebo in a double-blind study. The data from two studies was merged based on dose of nortriptyline (i.e., 6-week trial in one and a 9-week trial in the other). Repeated measures ANOVA showed a group by dose interaction (F3, 108 4.45, p 0.005) with significantly better MMSE scores in the responder group at doses of 75 ( p 0.036) and 100 mg ( p 0.024) (reprinted from Kimura et al. (2000) with permission).
in the treatment response group and only placebo patients in the treatment failure group, there was still a significant group by time interaction (p 0.036). This finding indicates that the failure to demonstrate cognitive improvement in prior studies was not the result of either a nortriptyline drug effect such as sedation or anticholinergic effects or because the cognitive impairment was due entirely to the brain lesion.
As we have previously found that cognitive impairment was associated with major but not minor depression, we examined whether the phenomenon of cogni-tive improvement with treatment response would occur in patients only with major depression. Among patients with major depression (n 33), responders (n 15) showed significantly greater improvement in cognitive function than non-responders (n 18) (p 0.0087). Among patients with minor depression (nine responders and five non-responders) repeated measures ANOVA of mini-mental scores showed no significant group effect, time effect, or group by time interaction.
This study, using double-blind placebo-controlled methodology, demonstrated for the first time that successful treatment of depression in patients with poststroke major depression produces a significant improvement in cognitive function. The areas of cognitive function on the MMSE that showed significant improvement were attention, concentration and recall. This finding supports our proposal that poststroke major depression with cognitive impairment represents a reversible dementia of depression.
One might logically wonder why improved cognitive function associated with mood improvement was not noted in prior treatment studies. The answer to this question is related to effect size. Nortriptyline treatment of depression as demon-strated in the present study produced a mean change of 12.1 points on the Ham-D or a 69.5% decline compared with a 36.8% (6.8 points) decline in the placebo group. The effect size was 0.71. This effect size is much larger than the effect of nor-triptyline on mini-mental scores (i.e., 9.6%, 1.8 points for active treatment and 5.6%, 1.3 points for placebo treatment) with an effect size of 0.16. It would take a group size of 598 patients to demonstrate a significant effect of nortriptyline on cognitive function with an 80% probability. By dividing patients on the basis of response to treatment, the effect on the mini-mental score was 17.2% (3.0 points) for responders and 1.3% (0.14 points) for non-responders for an effect size of 0.96.
This allowed a significant difference to be detected with a group size of only 47.
Another significant finding from this study was that improved cognitive function was related to mood improvement and not to the use of nortriptyline itself. Appro-ximately one-third of the patients responding to treatment were taking placebo and showed the same cognitive improvements as those taking nortriptyline. The fact that mood improvement with placebo was associated with the same cognitive 162 Poststroke depression