Relationship of depression to physical
Table 13.1.Relationship of depression and physical impairment Conclude D and ImpairmentTime sinceUnivariate analysis Multiple logisticimpairment StudynmeasurestrokeD versus NDD and impairmentregressionrelated I.Relationship ofD and physical impairment Robinson et al.(1983)103JHFI1114 daysr0.36NA Sinyor et al.(1986)64PECS6 week FUr0.45,NA p0.05 Ebrahim et al.(1987)14910 items,1 monthp0.01NA 0–10-point scale Eastwood (1989)87BI2–3 monthsr0.18 Ham,NA r0.33 GDS Morris (1990)88BI8.4 weeksr0.11,pNSADL impairment and associated minor D (odds ratio0.68, p0.05) Schubert et al.(1992)21BI1–4 weeksNSNA Angeleri et al.(1993)180NUDS3736 monthsr0.41,Beck strongest p0.05correlate Astrom et al.(1993)73Katz3 monthsp0.020NA Schwartz (1993)91Crichtondis90 daysr0.41,NA p0.001 Shima (1997)20Chart review1 month to No correlation D NA 3 yearsand ADL Herrmann et al.(1998)150FIM3 monthsr0.31,NA p0.0001
Ramasubbu et al.(1998)626BI7–10 daysr0.25,NA p0.0001 Paolucci et al.(1999)470BIApproximately p0.05 (odds NA 44 daysratio:1.99; CI:1.14–3.46) Kauhanen et al.(2000)76Rand physical 12 monthsp0.0001NA functioning dimension Gainotti et al.(2001)64BI1–4 monthsp0.05NA House et al.(2001)448BI1 monthp0.004NA Berg et al.(2003)100Tapping,right2 weeksr0.34,r0.26, p0.01p0.05 Desmond et al.(2003)421BI3 monthsp0.05,odds BI not significant in ratio1.815logistic regression Total83% ofstudies found significant association ofD with impaired recovery II.Effect ofD on recovery from physical impairment Parikh et al.(1990)63JHFI2 yearsD patients showed p0.01NA less functional recovery over 2 years than ND patients Herrmann et al.(1998)150FIM,Oxford 15 monthsD correlates with 3 months:NA handicap scaleFIM at 3 months r0.31, and 1 yearp0.001;1 year: r0.28, p0.001
Table 13.1.(Continued) Conclude D and ImpairmentTime sinceUnivariate analysis Multiple logisticimpairment StudynmeasurestrokeD versus NDD and impairmentregressionrelated van de Weg et al.(1999)85FIM6 weeksNo difference in14.99.0 versus NA amount change in 14.210.2 SD FIM,D versus ND Paolucci et al.(1999,470BI8341 SD daysD patients p0.05NA 2000a,b,2001)(Ham-D18) had greater frequency ofBI1 compared to ND (odds ratio:1.99; CI:1.14–3.46) Pohjasvaara et al.(2001)256RS15 monthsMajor D versus ND D at 3 months and (48% major D had RS at 15 months poor outcome (odds ratio:7.5; versus 27% ND)CI:1.6–3.8) Sturm et al.(2004)226London 2 yearsD at 2 years r0.35NA handicap correlated with scale (LHS)LHS at 2 years p0.002 Total83% ofstudies found that depression impairs recovery in ADL III.Effect oftreatment ofD on recovery
Lipsey et al.34262 daysNortriptyline 6 weeksJHFIDouble blindNortriptyline (1984)(100mg/day),n14,placebo (at 4 placebo20weeks),no ADL difference Reding et al.1645 daysTrazodone 32.6 daysBIDouble blindTrazodoneplacebo,mean (1986)(maximum BI scores improved to 38 for 200mg/day),n9,trazodone versus 20 for placebo placebo7 Gonzalez-Torrecillas 374 weeksNortriptyline 6 weeksBI and KPSOpen studynortriptylinefluoxetineno Rx et al.(1995)(maximum 75mg/(at 3–6 weeks) on BI day) Fluoxetine nortriptylinefluoxetineno Rx (maximum 20mg/(at 5 and 6 weeks) on KPS day) Dam et al.(1996)461–6 months16 fluoxetine3 monthsBI and HSSOpen labelGood recovery with fluoxetine 75% 14 maprotilinefluoxetine,36% maprotiline, 16 placebo38%placebo improved after treatment Palomaki et al.10014.3 days51 mianserin 12 monthsBI and RSDouble blindMianserinplacebo (at 2,6,12, (1999)(maximum 60mg/day)and 18mhs) 49 placebo Paolucci et al.29036 days120 fluoxetine83 daysBI and RMMIOpen labelNo difference in ADL recovery (2000b)16 maprotilinecomparing 145 D and 145 ND 9 other
Table 13.1.(Continued) After stroke n(mean days)MedicationDurationResultsDesignSignificant drug effect Robinson et al.5610 weeks16 nortriptyline12 weeksFIM and JHFIDouble blind Nortriptylinefluoxetine at 9 and (2000)23 fluoxetine12 weeks;placebofluoxetine at 17 placebo12 weeks on FIM improvement No treatment effect on JHFI improvement Wiart et al.(2000)3147.1 days16 fluoxetine 6 weeksFIMDouble blindFluoxetineplacebo (at 6 weeks) (20mg/day) 15 placebo Chemerinski et al.1010 weeks7 nortriptyline12 weeksJHFIDouble blindResponders showed significantly (2001a)better recovery over12 weeks of nortriptyline or fluoxetine compared with non-responders,no significant difference in ADL, between nortriptyline versus placebo groups Total44% ofstudies found treatment improved recovery.Responders to treatment improve more than non-responders N:number ofsubjects;D:depression;ND:no depression;KPS:Karnofsky’s performance status scale;GDS:geriatric depression scale;FU:fluoraouracil; PECS:Patient Evaluation Conference System;HSS:hemispheric stroke scale;NUDS:Northwestern University disability scale;SSS:Scandinavian stroke scale.
131 Relationship of depression to physical impairment
The relationship between severity of depression and severity of physical impairment
As indicated in Table 13.1, 83% of studies that have examined the relationship between poststroke depression and physical impairment have found that patients with depression are significantly more physically impaired than patients without depression, and furthermore that there is a direct correlation between severity of physical impairment and severity of depressive symptoms (Robinson et al. 1983;
Eastwood et al. 1989; Astrom et al. 1993). We have examined our overall acute stroke patient database to examine the relationship between severity of neurological impairment in motor function, sensory deficit, visual impairment, and the severity of depression (Table 13.2). Mean depression scores in patients with upper or lower extremity paresis were not significantly different among patients with mild to mod-erate motor impairment as compared to those with severe impairment.
Perhaps the most useful way to assess the relationship between physical impair-ment and poststroke depression is not to look at the severity of motor or sensory
Table 13.2. Severity of neurological impairment and depression
Weakness Touch-pain deficit
Mild/moderate Severe (Significance) No Yes (Significance)
Right arm or leg
n 220 79 217 22
Depression 7.9 6.3 8.7 6.2 (NS) 7.5 6.5 6.6 5.9 (NS)
ADL 5.2 4.6 7.9 5.8 (0.0001) 6.1 5.4 4.8 5.9 (NS)
Mini-mental 24.0 5.1 22.6 6.4 (0.0581) 22.5 5.7 25.1 4.1 (0.0394) Left arm or leg
n 180 116 213 26
Depression 7.6 6.4 8.8 6.0 (NS) 7.3 6.4 8.3 6.8 (NS)
ADL 5.6 5.4 6.3 4.6 (NS) 5.9 5.3 6.5 6.5 (NS)
Mini-mental 23.2 5.6 24.2 5.3 (NS) 22.7 5.7 23.5 5.5 (NS) Visual field deficit
No Yes
278 64
Depression 7.4 6.4 9.3 7.0 0.0394
ADL 5.7 5.0 7.5 5.6 0.0106
Mini-mental 23.5 5.5 24.05 6.0 0.5580
Depression: Ham-D score. Higher numbers indicate greater severity of depression (values given in mean SD).
ADL: JHFI score. Higher numbers indicate greater impairment (values given in mean SD).
Mini-mental: lower numbers indicate greater intellectual impairment (values given in mean SD).
132 Poststroke depression
impairment but to quantitate deficits in performance of daily activities. In our studies, we have used the Johns Hopkins functioning inventory (JHFI) to quantify severity of impairment in ADL. Our more recent studies have utilized the func-tional independence measure (FIM) as a more widely accepted measurement of ADL impairment. The JHFI assesses the patient’s ability to dress themselves, feed themselves, walk, find their way around, express needs, read and write, keep their room in order, and to maintain sphincter control. Although this ADL scale evalu-ates severity of impairment across a range of activities related to daily care, it is heavily dependent on limitations in physical activity.
As shown in Table 13.1, most studies have found that the severity of impairment in ADL scores is significantly greater in depressed compared with non-depressed patients. Furthermore, some studies have found a statistically significant correla-tion between severity of impairment in ADL and severity of depressive symptoms.
Even when multiple regression or logistic regression analyses have been used to look for independent effects of severity of impairment on depressive disorder, sig-nificant relationships have been reported.
Figure 13.1 shows the mean correlation coefficient between the JHFI score and the summed total scores on the Zung, Hamilton, and present state examination (PSE) at 5-time points during 2 years following acute stroke. During the first 6 months following stroke, there was an increase in the mean correlation between severity of impairment and severity of depression. However, at 1- and 2-year post-stroke, the strength of the correlation declined.
In addition to this cross sectional look at the relationship between impairment and depression, we have also examined the predictive relationship between ADL and depression scores over the first 2 years following stroke. If severity of physical impairment was causing depression through a psychological response (e.g., grief
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7
In-hospital 3 6 12 24
Correlation coefficient
Months
Figure 13.1 Correlation coefficients between ADL (JHFI) scores and depression scores over the first 2 years following stroke. The correlations increased in strength during the first 6-month poststroke and then declined for the next 18 months. The correlation, however, remained statistically significant, throughout the first 2 years following an acute stroke.
133 Relationship of depression to physical impairment
secondary to loss of previous lifestyle), one would predict that in-hospital severity of impairment in ADL would predict depression at 3 or 6 months. Similarly, if severity of depression was influencing patients’ physical recovery from stroke, one would predict depression in-hospital would be related to ADL impairment at 3 or 6 months. Our data, in fact, supported both explanations as shown in Fig. 13.2. We found that in-hospital measures of depression using either the PSE Hamilton or Zung depression scores correlated significantly with ADL as measured by the JHFI score at 3 months following stroke. Also both the PSE and the Hamilton depres-sion (Ham-D) scores assessed at the time of the in-patient evaluation correlated significantly with measures of ADL at 6-month follow-up. On the other hand, ADL scores (JHFI scores in-hospital were significantly correlated with depression scores at both 3- and 6-month follow-up (Fig. 13.2). These findings suggest that the most physically impaired patients remain the most depressed at follow-up and the most depressed patients remained the most physically impaired at follow-up.
Our finding, however, raises the question of why the relationship between physical impairment and depression may be a dynamic one. It is possible that the strength of the correlation increased for the first 6 months (see Fig. 13.1) because the most severely impaired patients became more depressed over the first 6 months.
As shown in our previous analysis, however, part of this increased correlation could
0 0.1 0.2 0.3 0.4 0.5 0.6
ADL scores at 3 months
ADL scores at 6 months
Depression scores at 3 months
Depression scores at 6 months
Correlation coefficient
In-hospital depression scores In-hospital ADL scores
PSE Zung Hamilton p 0.05
Figure 13.2 Correlation coefficients between depression and ADL impairment over the first 6 months following stroke. There were significant correlations between in-hospital depression or ADL scores and depression or impairment scores at 3- or 6-month follow-up. Note that in-hospital depression appears to weaken in its relationship to follow-up ADL scores over time while in-hospital ADL scores show increasing correspondence with follow-up depression scores. This may suggest that the most physically impaired patients remain the most depressed over the first 6 months following stroke.
134 Poststroke depression
represent a failure of depressed patients to recover in their ADL during the initial poststroke period when much of the physical recovery would be expected to take place. A third possible explanation for the increased correspondence between depres-sion and ADL impairment is that both depresdepres-sion and physical impairment are related to another factor. For example, patients who have the greatest degree of cog-nitive impairment might not be able to participate in stroke rehabilitation and might become the most depressed patients. Although the available data suggest that physical impairment influences depression and vice versa. Multiple regression analyses by Eastwood et al. (1989), Morris et al. (1990), and ourselves (unpublished data) have shown that the relationship between depression and impairment in ADL is independent of the severity in cognitive impairment, social function, age, educa-tion, or other background characteristics.
The effect of depression on recovery in ADL
Examining the effect of depression on recovery in ADL is a complicated task because there are so many variables which have been demonstrated to effect phys-ical recovery from stroke (Table 13.1). The factors which have been shown to influ-ence recovery include baseline neurological deficits, early intervention care, presinflu-ence of a stroke unit, type of infarct, and the use of physiotherapy (Dove et al. 1984).
The effect of depression cannot be evaluated unless all of these as well as other fac-tors are either comparable across groups or controlled.
In an effort to control for all of these factors, we studied 25 patients who had either major or minor depression following an acute stroke and some impairment in their ADL score (JHFI score 0) compared with 38 non-depressed patients who had a comparable degree of physical impairment at the time of their initial evaluation fol-lowing acute stroke (Parikh et al. 1990). Patients were included only if they had sur-vived 2 years since stroke without subsequent stroke or other significant medical illnesses that would have effected their recovery in daily activities. Background char-acteristics are shown in Table 13.3 including their baseline neurological findings.
There were no statistically significant differences in demographic characteristics of the depressed (major and minor depression combined) and non-depressed patients.
Similarly there were no significant intergroup differences in neurological findings or in the severity of intellectual impairment or social impairment. Furthermore, all patients received acute care on the same specialized stroke unit and there were no sig-nificant differences in the mean time from stroke to receipt of medical care.
Repeated measures analysis of variance (ANOVA) of ADL scores (i.e., Johns Hopkins functioning inventory or JHFI scores) comparing depressed and non-depressed patients in-hospital and at 2-year follow-up showed a significant group-by-time interaction (i.e., change in JHFI scores over time were significantly different
135 Relationship of depression to physical impairment
for depressed and non-depressed groups, p 0.05) (Fig. 13.3). Repeated measures ANOVA of major versus minor depression, however, did not show any significant differences in the ADL recovery curves for these two kinds of depression. Although the two groups were not significantly different in terms of their JHFI scores in-hospital, post hoc analysis revealed statistically significantly lower (i.e., less impairment in ADL) scores for the non-depressed patients compared with the depressed group at 2-year follow-up (p 0.01).
Table 13.3. In-hospital characteristics of the depressed and non-depressed groupsa
Depressedb(n 25) Non-depressed (n 38)
Age, year (mean SD) 56 12 61 19
Sex (% male) 42 66
Race (% black) 59 56
Marital status (%)
Married 50 49
Widowed 16 21
Other 34 30
Socioeconomic status (Hollingshead class) (%)
I–III 13 21
IV–V 87 79
History of CVA (%) 14 16
MMSE (mean SD) 21.1 60 22.0 6.0
Social ties checklist (mean SD) 4.3 2.0 4.3 1.9
Social functioning examination (mean SD) 0.27 .20 0.20 0.13
Time from stroke to interview (days SD) 11 12 9 6
Stroke type
Thromboembolism 20 31
Intracerebral hemorrhage 5 7
Neurological examination findings
Hemiparesis–monoparesis, moderate to severe 10 13
Sensory deficit, moderate to severe 9 14
Visual field deficit, hemianopsia or quadrantanopsia 5 6 Aphasia
Broca’s 2 1
Wernicke’s 0 1
Global 2 1
Other 5 3
CVA: cerebrovascular accident.
aThere were no significant differences in any of the variables between the two groups.
bMajor and minor depression combined.
136 Poststroke depression
A factor analysis of the 10 items in the JHFI revealed that there were three dis-tinct factors being measured by the JHFI score. Factor 1 included six items related to physical impairment: ability to walk, dress, eat, write, find one’s way around and perform routine tasks. Factor 2 included three items related to comprehension and expression of language: comprehension of spoken and written language, and the ability to express one’s needs. Factor 3 was one item related to sphincter control.
Analysis of each factor independently indicated that there was a significant time-by-group interaction for Factor 1 (i.e., physical impairment) and Factor 2 (i.e., lan-guage impairment) but not for Factor 3.
A multiple regression analysis of ADL scores at 2-year follow-up examining the effects of in-hospital depression scores, 2-year depression scores, in-hospital ADL scores, intellectual impairment scores in-hospital and at follow-up, social func-tioning scores in-hospital and at follow-up, and lesion location (i.e., proximity to the frontal pole) demonstrated that in-hospital depression scores were independ-ently and positively correlated with JHFI scores at 2 years (r 0.42, p 0.05) (i.e., the lower the in-hospital depression score the less the impairment in ADL 2 years later). The only other significant correlate of ADL scores at 2-year follow-up was the in-hospital JHFI score (r 0.40, p 0.05). Interestingly, in-hospital ADL scores did not correlate significantly with depression scores at 2 years. This suggests that the most severely impaired patients at the time of the acute stroke were not the most severely depressed patients by 2-year follow-up.
0 2 4 6 8 10
0 Years (poststroke)
ADL (JHFI) scores
2
Non-depression (n 38)
Depression (n 25) p 0.01
Figure 13.3 JHFI scores among patients with an acute in-hospital diagnosis of poststroke major or minor depression or no mood disorder. Higher scores (mean SEM shown) indicate greater impairment. There was a significant group-by-time interaction, demonstrating that depressed patients had less recovery in terms of ADL than non-depressed patients (modified from Parikh et al. Arch Neurol 47:785–789, copyright © 1990 American Medical Association. All rights reserved.).
137 Relationship of depression to physical impairment
Depressive diagnoses at 2-year follow-up revealed no significant intergroup dif-ferences in the frequency or severity of depression. This suggests that the significantly poorer physical recovery in patients with major or minor depression was related to the initial period of depression and not to depressive status at 2-year follow-up.
We also examined other factors which might influence recovery of ADL at 2-year follow-up including lesion location (hemisphere or structure), lesion volume, nature of the ischemic lesion, the existence of aphasia, and the amount of rehabil-itation therapy. We also examined the frequency of purely subcortical, purely cor-tical, and mixed cortical subcortical lesions in the depressed compared with the non-depressed group. There were no significant differences between groups in any of these factors (e.g., total lesion volume for depressed patients was 6.2 5.25% of total brain volume versus 5.3 3.7 for non-depressed patients, p NS). Similarly, thromboembolic versus hemorrhagic infarcts and lacunar versus non-lacunar infarcts did not explain the differences in recovery between the depressed and non-depressed groups. Finally, the effect of physical, occupational, or speech therapy after hospitalization did not differentiate the depressed and non-depressed groups (e.g., 55% of the depressed and 50% of the non-depressed patients had post-hospital rehabilitation therapy).
Pohjasvaara et al. (2001) reported on the relationship between depressive disor-der at 3 months following ischemic stroke and outcome 15 months later in a group of 256 patients who were examined for depression among a consecutive group of 486 patients with stroke aged 55–85 years. Diagnostic and Statistical Manual, 2nd ed., revised (DSM-II-R) major depression was diagnosed in 66 (25.8%) and minor depression in 32 (12.5%) of 256 patients 3 months following stroke. Patients with Beck depression inventory scores of 10 or greater or with a diagnosis of major depression had significantly greater frequency of poor functional outcome as meas-ured by the Rankin scale (RS) or the Barthel index (BI) (i.e., depressed patients with RS II or BI 17 was 48% compared to non-depressed with RS II or BI 17, 27%). A logistic regression analysis demonstrated that the diagnosis of depression as defined by Beck score of 10 or greater was significantly and independently asso-ciated with an RS II (odds ratio: 2.5; 95% confidence interval (CI): 1.6–3.8).
However, an RS II at 3 months was not independently associated with (Beck depression scale 10 or greater at 15 months. Thus depression at 3 months appeared to be a better predictor of functional physical outcome at 15 months than physical outcome was a predictor of depression at 15 months.
Herrmann et al. (1998) examined 150 patients at 3 months and 136 patients at 1-year poststroke. Depressive symptoms as measured by the Zung depression scale and the Montgomery Asberg depression rating scale at 3 months following stroke were significantly correlated with ADL as measured by the FIM (r 0.31, p 0.0001) and the Oxford handicap scale (r 0.41, p 0.0001) and at 1 year
(r 0.28, p 0.001, FIM; r 0.35, p 0.0001, Oxford handicap scale). Thus, severity of depression at 3 months was significantly associated with greater degree of impairment at 1-year follow-up.
Paolucci et al. (1999) reported that among 470 patients who were a mean of 44 days following stroke, multiple regression analyses failed to show an association between impairment of ADL as measured by the BI or the River mead mobility index (RMMI) and severity of depression as measured by the Ham-D scale. The only significant association with depression was a poor rehabilitation response (i.e., with less change in the BI than no depression) during the course of 83 41-day treatment in a rehabilitation hospital (odds ratio: 1.99; CI: 1.1–4.46). It should be noted, however, that all of the 129 patients with depression with Ham-D scores greater than 18 (i.e., the definition of depression), received either fluoxetine (n 118) or amitriptyline (n 11). Thus, treatment likely influenced the lack of a longitudinal association between depression and impairment in ADLs.
van de Weg et al. (1999) examined 85 patients admitted to a rehabilitation hospi-tal 3–6 weeks following stroke with follow-up 6 months later. Thirty patients (35%) were diagnosed with major depression based on a clinical interview and DSM, 3rd ed., revised (DSM-III-R) criteria. FIM scores at admission were significantly lower (more impaired) in the depressed compared with the non-depressed patients (n 55). At 6 months follow-up, however, there was a 14.9 9.0-point improve-ment for the depressed patients and 14.4 10.2 for the non-depressed patients (p NS). Thus, the rate of recovery in ADLs in the depressed patients was equiva-lent to the rate of recovery in the non-depressed patients. At both admission and at follow-up, however, the depressed patients were more impaired than the non-depressed patients.
Effect of treatment on recovery in physical impairment
The final area of investigation which has generated a surprising number of studies has involved the assessment of antidepressant medications and their effects on recovery from physical impairment or ADL impairment. The first study to demon-strate a positive effect of treatment of depression on recovery in ADLs was reported by Reding et al. (1986). During a 6-week double-blind treatment trial, 16 patients who had a positive dexamethasone suppression test (DST) showed greater improve-ment in their ADL scores as measured by the BI when they received double-blind treatment with trazodone (n 7) (dose: 50–200 mg/day) as compared with placebo (Table 13.2). Although grouping the patients based on the clinical diagnosis of major or dysthymic depressive disorder did not show a statistically significant effect of trazodone, there was a trend for actively treated depressed patients to improve their BI scores more than depressed patients treated with placebo.
138 Poststroke depression
In an open label study, Gonzalez-Torrecillas (1995) compared 26 poststroke depressed patients treated with fluoxetine (20–40 mg/day), 11 poststroke depressed patients treated with nortriptyline (25–100 mg/day), and 11 poststroke depressed patients given no treatment. Patients began treatment 4-week poststroke and the treatment trial lasted 6 weeks. Both neurological function as measured by the Orgogozo scale and ADL as measured by the BI showed significantly greater improve-ment in patients treated with either nortriptyline or fluoxetine compared with placebo (p 0.005) for both scales (Table 13.1).
Dam et al. (1996) reported on 52 severely hemiplegic subjects treated with fluox-etine (n 16), maprotiline (n 14), or placebo (n 16) in an open label design.
Patients were in a rehabilitation program between 1 and 6 months following stroke and the duration of treatment was 3 months. There were no significant differences prior to treatment in their BI scores or in their graded neurological scale (HSS) (Adams et al. 1987). There were no significant differences between groups in either the BI or HSS score. Based on cluster analysis, patients were divided into those with good recovery and those with poor recovery. The patients treated with fluoxetine had 12 of 16 patients (75%) in the good recovery group at the end of the 3-month protocol compared to 5 of 14 patients (36%) treated with maprotiline and 6 of 16 patients (38%) treated with placebo (p 0.05 fluoxetine versus maprotiline and placebo). In contrast to these positive findings with antidepressant medications, Paolucci et al. (2001) performed a case-controlled study in 290 stroke in-patients matched for age1 year and interval between stroke and admission (3 days).
Of the 145 depressed patients, 120 received fluoxetine (10–20 mg/day), 16 mapro-tiline (10–20 mg/day), and 9 received other antidepressants (amitriptyline or mianserin). Patients were treated in an open label study and were in a rehabilita-tion program. The durarehabilita-tion of treatment was 83 41 days. The patients with poststroke depression compared to patients without depression showed the same course of recovery with both showing improvement in BI and Rankin scores. The only significant finding was patients with poststroke depression were less likely to have a high response on the Rankin scale compared with non-depressed patients (24.6% versus 15.1%, p 0.05).
In our 12-week treatment study comparing nortriptyline, fluoxetine and placebo, using double-blind methodology, we found no significant difference in ADL as measured by the FIM. The FIM is an 18-item 72-point scale with lower numbers indicating greater impairment. The FIM consists of six domains including self-care, sphincter control, mobility, locomotion, communication, and social cognition. On the FIM, however, there was significantly less recovery in the fluoxetine treated group compared with the nortriptyline or placebo group (Robinson et al. 2000).
Other double-blind treatment studies which have measured change in ADL have also failed to show a difference between active and placebo treatment.
139 Relationship of depression to physical impairment
140 Poststroke depression
Wiart et al. (2000) showed a significant time effect but no significant group effect on ADL as measured by the FIM. The study by Fruehwald (2003) found no signif-icant difference in a double-blind-randomized treatment study of 26 patients treated with fluoxetine (20 mg/day) or placebo for 12 weeks. During the 12 weeks of treat-ment there were no significant differences in improvetreat-ment in the SSS or Barthel scales, however, at 18-month follow-up the fluoxetine treated group showed a greater degree of recovery than the placebo treated group.
We have conducted three studies which have examined the effect of treatment or remission of depression on recovery in ADL (Chemerinski et al. 2001a, b; Narushima et al. 2003). Our first study examined 21 patients who had major or minor depres-sion following acute stroke and who had remisdepres-sion of depresdepres-sion defined as50%
reduction in Ham-D score by 3- or 6-month follow-up. Non-remission was a50%
reduction in Ham-D score at the same follow-up interval. The remission group (n 21) had an initial JHFI score of 8.3 5.9 (SD) while the non-remission group (n 34) had an initial JHFI score of 8.0 5.0 (SD) (Fig. 13.4). Repeated measures ANOVA revealed a significant group-by-time interaction with the patients in remis-sion having improved significantly more than the non-remisremis-sion patients. A factor analysis of the JHFI revealed three distinct factors (Parikh et al. 1990): Factor 1 included six motor items, ability to walk, dress, eat, write, find one’s way around a familiar setting and ability to perform routine tasks; Factor 2 included three language items, comprehension of spoken and written language and ability to express one’s needs; and Factor 3 included only sphincter control. A repeated measures ANOVA for each factor revealed a significant group-by-time interaction for Factor 1
0 1 2 3 4 5 6 7 8 9
JHFI initial JHFI follow-up
ADL (JHFI) scores
Non-remission (n 34) p 0.038 Remission (n 21)
Figure 13.4 ADL scores, as measured by the JHFI, in depressed patients during the acute poststroke evaluation and at 3- or 6-month follow-up. Patients who had remission of their depression sometime between initial evaluation and follow-up showed significantly better recovery in their ADLs than patients who remained depressed (reprinted with permission from Chemerinski et al. Stroke (2001b) 32:113–117).
(p 0.03) but not Factor 2 (p 0.6) or Factor 3 (p 0.5). There were no significant differences between the remission and non-remission groups in age, race, marital status, years of education, time since stroke or the percent of patients receiving anti-depressant therapy (mood improvement 19%, no mood improvement 20%). There were no significant differences between groups in cognitive impairment as measured by the mini-mental state examination (MMSE), lesion volume, cortical or subcorti-cal lesion location, number with motor deficits, sensory deficits, visual field deficits, aphasia, apraxia, neglect or the number who had received physical therapy. There was, however, a significantly higher percentage of women in the non-remission group (p 0.01). When we reanalyzed the data using only male patients, however, there remained a significant group-by-time interaction indicating that the improve-ment in remitted patients was not due to male/female differences in ADL recovery.
There were also no significant differences in the amount of recovery between patients with major versus minor depression. JHFI scores for the remitted major depression patients went from 4.7 3.5 to 3.7 2.9 (SD) while the minor depression patients went from 5.7 5.2 to 2.4 2.4 (p NS).
Our second study examined the effect of treatment of depression on recovery of ADL comparing 10 patients with a first ever stroke who had major or minor depression who responded to nortriptyline or placebo in a double-blind study and had a score 0 on the JHFI with 10 patients who met the same criteria but who failed to respond to treatment. There were no significant differences between the two groups in age, gender, race, handedness, marital status, years of education, time since stroke, socioeconomic status or personal or family history of mood dis-order or history of alcohol abuse. Seven out of 10 patients in the remission group had received active nortriptyline in a double-blind treatment trial while only one of 10 non-remitted patients had received nortriptyline. There were no significant differences between responders and non-responders in hemisphere of injury, vol-ume of lesion, cortical versus subcortical lesion location, initial neurological deficits, or the percent of patients assigned to physical rehabilitation programs.
We then compared trajectories (i.e., the mean slope of the line between 0 and 100 mg of nortriptyline) of JHFI scores among patients whose depression had responded and those who had not. The mean JHFI score trajectory over the 6–9-week study period in the remission group was 0.58 0.35 (SD) while in the non-improvement group, the mean value was 0.08 0.52 (SD) (a negative number indicated continued improvement in JHFI scores) (Fig. 13.5).
The major question which arises from these two studies is what mechanism associated with remission of depression leads to improvement in ADLs and sec-ondly, why have double-blind treatment trials comparing antidepressant treat-ment with placebo generally failed to show a significant improvetreat-ment in ADL associated with active antidepressant treatment. I believe the answer to the second 141 Relationship of depression to physical impairment
142 Poststroke depression
question is related to the size of the treatment effect. When patients who responded to active treatment are mixed with those who failed to respond, one would expect a smaller treatment effect than if only patients who responded to treatment were compared to patients who failed to respond to treatment. We examined this hypothesis in our treatment studies and found that the effect size increases from 0.3 to 0.9 when active versus placebo treatment is compared and when responders versus non-responders are compared (Kimura et al. 2000). With an effect size of 0.3, it would take 175 patients to demonstrate a statistically significant difference at the p 0.05 level between two groups while an effect size of 0.9 would require treatment groups of only 20 or more to show a statistically significant difference with an 80% probability.
The second question about why improvement in depression leads to improved recovery in ADL remains uncertain. It is possible that the improvement in ADL func-tion is mediated by changes in neurochemistry or neurophysiology related to remis-sion of depresremis-sion (Drevets et al. 1992; Mayberg et al. 1995). On the other hand, patients who are no longer depressed may be more motivated to participate in reha-bilitation activities and may devote more energy and motivation to their recovery.
Perhaps our most provocative recent study examining physical recovery from stroke utilized data from our prior treatment study (Robinson et al. 2000). We com-pared 34 patients who received antidepressant treatment during the first month fol-lowing stroke compared to 28 patients who received antidepressant treatment begun after the first month following stroke (Narushima and Robinson 2003). Patients
0 2 4 6 8 10
0 50 75 100
JHFI scores
mg Non-remission
(n 10) Remission p 0.006 (n 10)
Figure 13.5 ADL as measured by the JHFI during the course of a double-blind treatment trial with nortriptyline. Data from two studies were merged and patients whose depression remitted while taking nortriptyline showed significantly better recovery in ADLs at a nortriptyline dose of 100 mg. Patients received 50 mg at weeks 2–3, 75 mg at weeks 4–6, and 100 mg at weeks 6–9 (reprinted with permission from Chemerinski et al.
J Nerv Ment Dis(2001a) 189:421–425).
143 Relationship of depression to physical impairment
were treated for 12 weeks and recovery in ADLs was assessed at 12- and 24-month follow-up. The doses of nortriptyline were 25 mg/day for week 1, 50 mg/day for weeks 2–3, 75 mg/day for weeks 4–6, and 100 mg/day for weeks 6–12. Doses of fluoxetine were 10 mg/day for weeks 0–3, 20 mg/day for weeks 4–6, 30 mg/day for weeks 7–9, and 40 mg/day for weeks 10–12. ADLs were assessed using the FIM (Ottenbacher et al.
1994). The early treatment group was 19 25 (SD) days poststroke compared to the later treatment patients who were 140 28 (SD) days following stroke. Due to dropouts, death and medical complications, 22 of the 34 early treatment patients and 15 of the 28 late treatment patients completed the 24-month follow-up. There were no significant differences between the early and late treatment patients in their back-ground characteristics, or the total number of therapy hours received.
At the 3-month evaluation, there was a significant group-by-treatment interaction using either intention-to-treat analysis (p 0.03 with the last observation carried forward) or efficacy analysis (p 0.03). The early treatment group improved more quickly than the late treatment group during this first 3 months (Fig. 13.6). During the 3–24-month follow-up, there was a significant group-by-time interaction using either efficacy analysis or intention-to-treat analysis (p 0.03) (Fig. 13.6). The early treatment group continued to show gradual improvement in ADL scores during the 21 months of follow-up while the late treatment group began to show gradual dete-rioration between 12- and 24-month follow-up. During the 3–24-month follow-up period, there was no significant group-by-treatment effect on the severity of depres-sive symptoms as measured by the Ham-D score (intention to treat, p 0.6; efficacy, p 0.6). Thus, the late treatment group did not develop more depression than the early treatment group. Since the deterioration in ADL seen in the later treatment
45 50 55 60 65 70
6 12 24
Time since stroke (months)
FIM scores
Late
Early Intention to treat, p 0.02;
efficacy, p 0.02
Figure 13.6 Recovery in ADL as measured by the FIM over 2 years of follow-up. All patients were treated for 12 weeks in a double-blind study with fluoxetine or nortriptyline. Patients who received treatment within 1 month after stroke (early) improved significantly more than those who received treatment after the first month poststroke (late). FIM scores were measured at the same times following stroke to control for group differences in time since stroke when the 3-month treatment was given (reprinted with permission from Narushima et al. J Nerv Ment Dis (2003) 191(10):645–652).