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EBRSR [Evidence-Based Review of Stroke Rehabilitation]

18 Post Stroke Depression

Katherine Salter PhD (cand.), Swati Mehta PhD (cand.), Sanjit Bhogal PhD, Robert Teasell MD, Norine Foley MSc, Mark Speechley PhD

(We gratefully acknowledge the contribution of Maggie Gibson PhD)

Last Updated: August 2013

Abstract

Depression is a common complication post-stroke affecting approximately one-third of patients. The presence of post-stroke depression has been associated with decreases in functional recovery, social activity and cognition. In addition, the presence of mental health disorders following stroke may be associated with increased mortality. The present review discusses the prevalence, natural history and risk factors for post-stroke depression as well as issues around its assessment and impact on rehabilitation outcomes. Strategies for the prevention and management of post-stroke depression are reviewed. Recommendations for assessment and treatment are provided based on current guidelines. A discussion of post-stroke emotionalism, its impact and treatment is also included.

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Key Points

Prevalence of Post-Stroke Depression

Depression is a common complication post-stroke affecting approximately one-third of patients.

The highest rates of incident depression are reported in the first month post stroke and, while incidence may decline over time and there may be a general trend toward improvement in symptoms, PSD may persist in a significant proportion of individuals.

Risk Factors

The risk factors associated with increased risk for post-stroke depression (PSD) include female sex, past history of depression or psychiatric illness, functional limitations, and cognitive impairment.

Despite an abundance of research, the influence of stroke location on the risk for developing post-stroke depression has not been determined.

Screening and Assessment

Detection and diagnosis of post-stroke depression is often inconsistent and compliance with guidelines for screening is poor. Identified barriers to routine screening include time pressures and concerns about screening tools.

Consequences of Post-Stroke Depression

Depression post-stroke has a negative impact on functional recovery.

There is a significant association between the presence of depression and greater social isolation.

Post-stroke depression is associated with cognitive impairment.

The presence of mental health disorders post stroke is associated with increased risk for mortality.

Pharmacological Treatment of Post-Stroke Depression

Early initiation of antidepressant therapy in non-depressed individuals is effective in preventing post-stroke depression.

Ongoing, individualized contact and support may reduce the risk for deterioration of psychological health following stroke.

Heterocyclic antidepressants improve post-stroke depression.

SSRI antidepressants are effective in the treatment of post-stroke depression. Further study is required.

Bright light therapy may be an effective adjunct to treatment with SSRI antidepressants.



Reboxetine is an effective treatment for “retarded” post-stroke depression characterized by lethargy and slowness to initiate action.

There is insufficient evidence regarding the use of venlafaxine and duloxetine for PSD. Randomized controlled trials are required.

Nefiracetam is not an effective treatment for post-stroke depression.

Methylphenidate (a psychostimulant) appears to be effective in treating symptoms of depression and has an earlier onset of action than traditional antidepressants.

Melatonin agonist may be effective in management of PSD; however, more studies need to be conducted.

Active care management in conjunction with antidepressant therapy may improve response to treatment.

The herbal medicine Free and Easy Wanderer Plus may be effective in the treatment of PSD. Further research is required.

Dietary supplementation with omega-3 fatty acids has no impact on mood post stroke.

Pharmacologic treatment of post-stroke depression is associated with improved functional recovery.

Treatment with antidepressants following stroke improves long-term survival. Further research is indicated.

Non-Pharmacological Treatment of Post-Stroke Depression

There is insufficient evidence to evaluate the use of electroconvulsive therapy as a treatment for post-stroke depression.

Use of repetitive transcranial magnetic stimulation is associated with reduced symptoms of depression.

Cognitive behavioural therapy may not effective in the treatment of post-stroke depression. Further research is required.

Psychosocial behavioural therapy may be used as an effective adjunct to treatment with antidepressants.

Music therapy and listening to music may have a positive influence on mood post stroke.

Speech therapy does not appear to improve depression post stroke.

Exercise training, whether progressive group programs, treadmill training or aerobic training, does not appear to be associated with a reduction in symptoms of depression post stroke.



Further research is required.

Ecosystem focused therapy may be an effective treatment for post-stroke depression. Further study is required.

Guidelines for Treatment of Post-Stroke Depression

Guidelines for the treatment of post stroke depression recommend screening, assessment and treatment with an appropriate antidepressant for a period of approximately 6 months.

Post-Stroke Emotionalism

In the first 6 months following stroke, post-stroke emotionalism affects approximately one-quarter of stroke survivors.

Antidepressants and SSRI antidepressants, in particular, are effective in the treatment of post-stroke emotionalism. Further study is required to determine optimum timing and duration for treatment.

Dr. Robert Teasell 801 Commissioners Road East, London, Ontario, Canada, N6C 5J1

Phone: 519.685.4000 ● Web: www.ebrsr.com ● Email: [email protected]



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Table of Contents

Abstract ....................................................................................................................... 1

Key Points .................................................................................................................... 2

Table of Contents ........................................................................................................ 5

Post-Stroke Depression ................................................................................................ 7

18.1 Introduction ............................................................................................................... 7

18.2 Prevalence and Natural History of Post-stroke Depression .......................................... 7

18.3 Risk Factors for Post-Stroke Depression ...................................................................... 9 18.3.1 Stroke Location and Depression .............................................................................................. 11

18.4 Assessment of Post-Stroke Depression...................................................................... 18

18.5 Consequences Associated with Post-Stroke Depression ............................................ 20 18.5.1 Functional Impairment and Depression Post-Stroke ............................................................... 20 18.5.2 Depression and Social Activities Post-Stroke ........................................................................... 26 18.5.3 Cognitive Impairment and Depression Post-Stroke ................................................................. 28 18.5.4 Mortality and Depression Post-Stroke ..................................................................................... 32

18.6 Prevention of Post-Stroke Depression ....................................................................... 35 18.6.1 Care Provision and the Prevention of PSD ............................................................................... 38 18.6.2 Dietary Supplementation ......................................................................................................... 41 18.6.2.1 Omega-3 Fish Oil ................................................................................................................... 41 18.6.2.2 B-Vitamins ............................................................................................................................. 42

18.7 Pharmacologic Treatment of Post-Stroke Depression ................................................ 43 18.7.1 Heterocyclic Antidepressants .................................................................................................. 44 18.7.2 Selective Serotonin Reuptake Inhibitors (SSRIs) ...................................................................... 46 18.7.2.1 Adjunctive Light Therapy ...................................................................................................... 49 18.7.3 Selective Noradrenaline Reuptake Inhibitors (NARI) ............................................................... 50 18.7.4 Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) ..................................................... 51 18.7.5 Gamma Aminobutyric Acid Compounds (GABA) ..................................................................... 52 18.7.6 Psychostimulants in the Treatment of Symptoms of Depression............................................ 53 18.7.7 Melatonin Agonist in the Treatment of Depression Post Stroke ............................................. 55 18.7.7 Care Management for Post-Stroke Depression ....................................................................... 56 18.7.8 Alternative Medicine................................................................................................................ 56

18.8 Impact of Pharmacologic Treatment of PSD on Rehabilitation Outcomes .................. 58 18.8.1 Functional Recovery Associated with Pharmacologic Treatment of Post-Stroke Depression . 58 18.8.2 Mortality and Pharmacologic Treatment of Post-stroke Depression ...................................... 59

18.9 Non-Pharmacologic Treatment of Post-Stroke Depression ........................................ 61 18.9.1 Electroconvulsive Therapy ....................................................................................................... 61 18.9.2 Repetitive Transcranial Magnetic Stimulation ......................................................................... 61 18.9.3 Cognitive Behavioural Therapy ................................................................................................ 63 18.9.3.1 Combined Therapy ................................................................................................................ 64 18.9.4 Music Therapy .......................................................................................................................... 65 18.9.5 Speech Therapy in Post-Stroke Depression ............................................................................. 67 18.9.6 Physical Activity ........................................................................................................................ 68 18.9.7 Ecosystem Focused Therapy. ................................................................................................... 72

18.10 Guidelines for Treatment of Post-Stroke Depression ............................................... 73



18.11 Post-Stroke Emotionalism ....................................................................................... 75 18.11.1 Prevalence and Natural History of Post-stroke Emotionalism............................................... 76 18.11.2 Risk Factors for Post-Stroke Emotionalism ............................................................................ 76 18.11.3 Treatment of Post-Stroke Emotionalism ............................................................................... 77

18.12 Summary ................................................................................................................ 82

References ................................................................................................................. 86



Post-Stroke Depression

18.1 Introduction

A variety of emotional and behavioural disorders may develop following cerebrovascular lesions. The DSM-IV categorizes post-stroke depression as a “mood disorder due to general medical conditions” with the specifiers of: (a) depressive features; (b) major depressive-like episodes; (c) manic features; or (d) mixed features. The two types of depressive disorders most associated with stroke are major depression and minor depression, the latter of which has been defined for research purposes by the DSM-IV criteria as a “depressed mood or loss of interest and at least 2 but fewer than 4 symptoms of major depression.”

Depression is often observed in patients with severe physical illnesses. While the endogenous features of depression are present in these patients, the interpretations of vegetative signs are not clear. There appears to be less emphasis on feelings of low self-esteem, guilt and self-blame when depression accompanies physical illness while hypochondrial concerns, lethargy and behaviour disturbances are most characteristic (Morris & Raphael 1987). Three possible explanations for the association between physical illness and depression have been sought. First, and least likely, is a coincidental relationship. The second is a negative mood reaction to the physical consequences of the stroke. The impact of the physical illness may wield its effect through the losses it causes to the individual as a major negative life event (losses to self-esteem, independence, employment, etc.). The third possible explanation is a neurotransmitter imbalance as a result of cerebral damage caused by the stroke.

18.2 Prevalence and Natural History of Post-stroke Depression

Depression is a well-documented sequela of stroke. Based on pooled data from published prevalence studies, Robinson reported a mean prevalence of depression among in-patients in acute or rehabilitation settings of 19.3% and 18.5% for major and minor depression respectively (Table 18.1) (Robinson 2003). Among individuals in community settings, mean prevalence for major and minor depression was reported to be 14.1% and 9.1%. For patients included in outpatient studies, mean reported prevalence was 23.3% for major depression

and 15% for minor depression (Robinson 2003). Overall mean prevalence ranged from 31.8% in the community studies to 35.5% in the acute and rehabilitation hospital studies.

Table 18.1 Prevalence Studies included in Robinson (2003)

Community Studies:

Wade et al. (1987) House et al. (1991) Burvill et al. (1995) Kotila et al. (1998)

Acute & Rehabilitation Hospital Studies:

Robinson et al. (1983) Ebrahim et al. (1987) Fedoroff et al. (1991) Castillo et al. (1995) Starkstein et al. (1992) Astrom et al. (1993) Herrmann & Walesch (1993) Singh et al. (2000) Andersen et al. (1994) Gainoti et al. (1999) Folstein et al. (1977) Finklestein et al. (1982) Sinyor et al. (1986) Finset et al. (1989) Eastwood et al. (1989) Morris et al. (1990) Schubert et al. (1992) Schwartz et al. (1993)

Outpatient studies:

Pohjasvaara et al. (1998) Feibel & Springer (1982) Robinson & Price (1982) Herrmann et al. (1998) Vataja et al. (2001) Collin et al. (1987) Astrom et al. (1993) Castillo et al. (1995)



In a systematic review of prospective, observational studies of post-stroke depression, Hackett et al. reported that 33% of stroke survivors exhibit depressive symptoms at some time following stroke (acute, medium-term or long-term follow-up) (Hackett et al. 2005). This pooled estimate was based on data collected from 51 studies in population, hospital and rehabilitation-based settings. The authors stated that this is likely to be an underestimation of the frequency with which post-stroke depression occurs. Errors in estimation may be attributed to under-reporting of unusual mood, difficulties in the assessment of depression in neurologically impaired individuals and variability in the methods used to assess and define depression or “caseness” within the literature (Hackett et al. 2005). In a large, case-control study, Linden et al. (2007) reported identified depression in 34% of patients (n=149) one year post stroke compared to 13% of sex and age-matched controls (n=745). All types of depressive disorders, both major and minor, were more frequent among individuals with stroke. Major depressive disorders were most frequent among individuals with stroke who were more than 80 years of age (Linden et al. 2007). Whyte et al. reported that the risk for depression among individuals aged 65 or over, living in the community and who have experienced a stroke 2 years previously, is 6 times greater than for their stroke-free counterparts (Whyte et al. 2004). Estimates of prevalence may be affected by the time from stroke onset until assessment. Patients who are assessed during the subacute phase may be in a period of transition during which they are attempting to adjust to the consequences of stroke. Depression at this time may simply be a reflection of the difficulties associated with this transition. In fact, the highest rates of incident depression have been reported in the first month following stroke (Aben et al. 2006; Aben et al. 2003; Andersen et al. 1995; Bhogal et al. 2004; Bour et al. 2010; Morrison et al. 2005). In a study of 190 individuals with first-ever stroke, Bour et al. reported a decrease in incident cases of depression over the course of the first year following the stroke event (Bour et al. 2010). Cumulative incidence of PSD was 18.8% at 1 month and 23.1%, 26.7%, 31%, and 36.2% at 3, 6, 9 and 12 months respectively. Paolucci et al. (2005) reported that, of 1064 patients included in the DESTRO study, 36% developed depression. Eighty percent of these became depressed within the first three months of the stroke event(Paolucci et al. 2005). In that study, dysthymia (mild depression) was the most common form of depression, occurring in 80.7% of cases, whereas major depression was diagnosed in only 2.9% .While the incidence of major depression post-stroke may decrease over the first 24 months following stroke (Astrom et al. 1993; Verdelho et al. 2004), minor depression may persist or increase over the same time period (Berg et al. 2003; Burvill et al. 1995; Verdelho et al. 2004). Prevalence of PSD should not be regarded as static. While there may be a general trend toward improvement in depressive symptomatology over the first year following stroke (Ostir et al. 2011), and incidence rates may decline over time (Bour et al. 2010; Bour et al. 2011), PSD may be persistent for a significant proportion of individuals identified as depressed (Ostir et al. 2011) (Ayerbe et al. 2011; Berg et al. 2003; Farner et al. 2010). Ostir et al. (2011) examined patterns of change in depressive symptomatology in the first year following first-ever stroke in 544 individuals (Ostir et al. 2011). At the time of discharge from inpatient rehabilitation, 27.6% of patients were identified as depressed. Over the course of the following 12 months, the authors identified a general, significant trend toward recovery in terms of depressive symptomatology. However, approximately one-fifth of individuals identified as depressed at baseline remained depressed at one year; while for approximately one-third of this group, depression remained unresolved and they “moved in and out of depression” during the follow-up period (Ostir et al. 2011).



Ayerbe et al. (2011) followed individuals (n=3689) for 5 years as part of a population-based study (South London Stroke Register). Over this period, the prevalence of PSD was reported to be 33%, 28%, 32% and 31% at 3 months, 1 year, 3 years and 5 years, respectively (where depression was defined as a score >7 on the depression subscale of the Hospital Anxiety and Depression Scale). Although some cases resolved, 15-20% of individuals identified as depressed at each follow-up were new cases. In addition, as many as 55% of individuals identified as depressed at one assessment remained depressed on follow-up (Ayerbe et al. 2011). Similarly, Farner et al. (2010) reported persistent depression in more than half (55%) of the individuals identified as depressed during inpatient rehabilitation post stroke. Significant predictors of persistent depression included lower levels of pre-stroke social activity, greater severity of stroke and lower levels of function at baseline. At the same time, 35% of individuals with no significant depressive symptomatology at baseline were identified with incident depression over the 13-month follow-up period.

Conclusions regarding the prevalence and natural history of PSD At least one-third of stroke patients will experience depression. While the patterns of incidence and recovery change over time, for many individuals PSD may be persistent.

Depression is a common complication post-stroke affecting approximately one-third of patients.

The highest rates of incident depression are reported in the first month post stroke and, while incidence may decline over time and there may be a general trend toward improvement, PSD may

persist for years in a significant proportion of individuals.

18.3 Risk Factors for Post-Stroke Depression

Although post-stroke depression (PSD) is a common consequence of stroke, risk factors for the development of PSD have not been clearly delineated. In a systematic review, Hackett and Anderson (2005) included data from a total of 21 studies (Table 18.2). Of the many different variables assessed, physical disability, stroke severity and cognitive impairment were most consistently associated with depression. The authors noted that major methodological limitations within the available literature make it difficult to form a definitive conclusion. Methodological limitations cited include selection biases, poor methodology and reporting, problems in choosing variables to include as potential predictors and inadequate sample size from which to derive appropriate predictive models for depression (Hackett & Anderson 2005). In an earlier review of 9 prospective studies examining post-stroke depression, the risk factors identified most consistently as increasing an individual’s risk for post-stroke depression included a past history of depression or psychiatric illness, social isolation, functional impairment, living alone and dysphasia (Ouimet et al. 2001). Since the time of the Hackett et al. (2005) and Ouimet et al. (2001) reviews, more recent studies have confirmed the importance of severity of initial neurological deficit and physical disability as predictors of the development of depression after stroke (Bour et al. 2010; Carota et al. 2005; Christensen et al. 2009; Hackett & Anderson 2005; Hackett et al. 2005; Hackett et al. 2005; Ouimet et al. 2001); although a recent study also demonstrated a high prevalence of PSD (41%) among a group of individuals with minor ischemic stroke (NIHSS ≤5) (Altieri et al. 2012). In addition, Storor and Byrne (2006) examined post-stroke depression in the acute phase (within 14 days of stroke onset) and



identified significant associations between pre-stroke neuroticism (OR = 3.69, 95% CI 1.25 – 10.92) and a past history of mental disorders (OR = 10.26, 95% CI 3.02 – 34.86) and the presence of depressive symptoms. Both anxiety and depression at 4 months post stroke have been associated with self-reported symptoms of anxiety at the time of admission for the stroke event (Sagen et al. 2010). The potential influences of socioeconomic status (SES), age and gender on the development of depression following stroke have all been examined, with inconsistent results (Ouimet et al. 2001). Although one could predict intuitively that lower SES and increasing age are associated with the risk for PSD, this is not necessarily the case. Andersen et al. (1995) reported that SES had no influence on the risk for post-stroke depression and recent studies suggest that younger rather than older age is associated with increased risk (Andersen et al. 1995; Carota et al. 2005; Eriksson et al. 2004). Bour et al. (2010) demonstrated that older age may be associated with recurrent cases of depression (vs. transient or persistent cases, p=0.06). Given the substantially higher prevalence of depression among women when compared to men in the general population (Ouimet et al. 2001; Salokangas et al. 2002; Wilhelm & Parker 1994), a higher prevalence of PSD among women might be expected. While the results from some studies support the association between female sex and PSD (Desmond et al. 2003; Eriksson et al. 2004; Ouimet et al. 2001;

Paolucci et al. 2005; Paradiso & Robinson 1998; Poynter et al. 2009), others do not (Berg et al. 2003; Ouimet et al. 2001; Poynter et al. 2009; Spalletta et al. 2005; Whyte et al. 2004). In part, sex-based differences could be attributed to response bias created by the greater tendency for women to remember and report symptoms of depression (Wilhelm & Parker 1994). In addition, certain assessment tools may include items that exacerbate gender-based response biases such as “sadness” or “crying” that may be connected to gender-bound role behaviour (Salokangas et al. 2002). However, there may be real differences between men and women in terms of the relative importance of risk factors for PSD. Among men, physical impairment may be a more influential risk factor for depression (Berg et al. 2003; Paradiso & Robinson 1998), while among women, previous history of psychiatric disorder may be more important (Paradiso & Robinson 1998). As in the evaluation of any potential risk factor, conflicting findings could be the result of variations in subject sampling, assessment techniques, definitions of depression, or time passed since stroke onset (Paradiso & Robinson 1998; Rigler 1999). As part of the DESTRO study, a multicentre observational study of depression in stroke, Paolucci et al. (2005) identified female sex (OR=1.49), previous stroke (OR = 1.55), previous depression (OR=3.97) and severe disability (Modified Rankin Scale score >3, OR = 2.70) as

factors likely to facilitate the development of depression following stroke. The risk for post-stroke depression was found to increase exponentially in individuals with more than one risk factor. This ranged from 25% in males with one previous stroke episode, mild disability but no previous psychiatric episodes to 89.1% in women with previous stroke, previous depression and moderate to moderate/severe disability (Paolucci et al. 2005). This information could be used as the basis for a simple decision-tree, used to guide a selective screening process directed at those individuals at most risk for developing PSD.

Table 18.2 Studies included in the review by Hackett and Anderson (2005)

Kotila et al. (1998) Appelros & Viitanen (2004)

Sharpe et al. (1994) Aben et al. (2002)

Andersen et al. (1995) Berg et al. (2001)

Desmond et al. (2003) Eriksson et al. (2004)

Hayee et a. (2001) Hosking et al. (2000)

Pohjasvaara et al. (1998) Sing et al. (2000)

Astrom et al. (1993) Bacher et al. (1990)

King et al. (2002) Morris et al. (1991)

Ng et al. (1995) Paolucci et al. (1999) Spalletta et al. (2002) Verdelho et al. (2004) Weimar et al. (2002)



In a report from the Auckland Regional Community Stroke Study (Hackett & Anderson 2006), the authors described an attempt to create a simple, predictive tool for the identification of individuals most at risk for abnormal mood. Unfortunately, the resulting model, which included female gender, age, more

than two co-morbid conditions, prior treatment for depression and requiring “much help” (based on baseline Barthel Index score) could correctly identify mood status, assessed on the General Health Questionnaire at 6 months, in only 54% of patients. Of the factors included in the model, only two were significant predictors of mood; prior treatment for depression (OR = 2.4, 95% CI 1.34 – 3.43) and requiring “much help” with activities of daily living (OR = 2.35, 95% CI 1.33 – 4.14) (Hackett & Anderson 2006). The ability of the model to predict risk for depression might be increased by the inclusion of other factors such as fatigue and performance of instrumental activities of daily living. However, van de Port et al. (2007) demonstrated that use of these two predictors (prior treatment for depression and requiring much help with ADLs) in a multivariate model could correctly classify depression in 76% of patients 3 years post stroke.

Conclusions regarding risk factors for post-stroke depression Commonly identified risk factors include female sex, previous history of depression, functional limitations and cognitive impairment. Prior treatment of depression and the need for assistance with activities of daily living may be the factors most predictive of risk.

The risk factors associated with increased risk for post-stroke depression (PSD) include female sex, past history of depression or psychiatric illness, functional limitations, and cognitive impairment.

18.3.1 Stroke Location and Depression The association between the brain lesion as a result of stroke and post-stroke depression has been the topic of much research. While it has been suggested that lesion location may account for up to 50% of the variance in the development of PSD (Robinson et al. 1986), the complex association between lesion location and the susceptibility to post-stroke depression is not well understood (Ghika-Schmid & Bogousslavsky 1997). The John Hopkins Group (Lipsey et al. 1983; Robinson et al. 1987; Robinson et al. 1986; Robinson & Price 1982; Robinson et al. 1983; Robinson et al. 1984; Robinson & Szetela 1981) carried out a series of studies exploring the relationship of post-stroke depression to the location of the lesion within the brain itself. They found that in a selected group of stroke patients, similar to those admitted to a stroke rehabilitation unit, depression appeared to be more frequent in patients with left hemispheric lesions (Robinson et al. 1987; Robinson et al. 1986; Robinson & Price 1982; Robinson & Szetela 1981). Among

Table 18.3 Studies included in the review by Singh et al. (1998)

Author, Year Hemispheric lesion localization

Robinson et al. (1984) Sinyor et al. (1986)

Starkstein et al. (1987) Starkstein et al. (1988)

Starkstein et al. (1988)* Dam et al. (1989)

Sharpe et al. (1990) Stern et al. (1991)

Schwartz et al. (1993) Anderson et al. (1995) Hermann et al. (1995) Morris et al. (1996a) Morris et al. (1996b)

L>R L=R L>R L>R

L<R L=R L=R L<R L=R L=R L>R L=R



these patients, the severity of depression correlated inversely with the distance of the lesion from the frontal poles (Robinson 1986; Robinson et al. 1987; Robinson & Price 1982; Robinson et al. 1983; Robinson et al. 1984; Robinson & Szetela 1981; Starkstein et al. 1987). Patients with subcortical, cerebellar or brainstem lesions had much shorter-lasting depressions than patients with cortical lesions (Starkstein et al. 1987; Starkstein et al. 1988). There have been a number of systematic reviews and meta-analyses examining the evidence with regard to the possible relationship between lesion location and PSD. Singh et al. (1998) conducted a critical appraisal on the importance of lesion location in post-stroke depression. The authors systematically selected 26 original articles that examined lesion location and post-stroke depression. Thirteen of the 26 articles satisfied inclusion criterion (Table 18.3). Six of those studies found no significant difference in depression between right and left hemisphere lesions. Two studies found that right-sided lesions were more likely to be associated with depression and 4 studies found that left-sided lesions were more likely to be associated with post-stroke depression. Only one study matched patients with and without depression for lesion location and size to identify non-lesion risk factors. The authors noted that all of the studies reviewed were methodologically flawed. None of the studies were comparable with respect to sample, timing and analysis of CT scan and psychiatric evaluation. Consequently, Singh et al. were unable to make any definitive conclusions concerning stroke lesion location and the risk for depression (Singh et al. 1998). Carson et al. (2000) undertook a systematic review examining the association between post-stroke depression and lesion location. All reports on the association of post-stroke depression with location of brain lesions were included in the review. In total 48 reports were included for review (Table 18.4). The authors of the review identified 38 reports that found no significant difference in risk of depression between lesion sites; 2 reported an increased risk of post-stroke depression with left-sided lesions; 7 reported increased risk with right-sided lesions; and one report demonstrated an association between depression and lesions in the right parietal region or the left frontal region. However, 4 studies were observed to be from the same samples of patients and were treated as one report. Thus 35 reports were analyzed. When data from all reports were pooled, lesion location was not associated with depression. The null effect remained regardless of whether a fixed-effect model (0.95, 95% CI 0.83-1.03) or a random-effect model (0.95, 95% CI 0.83-1.10) had been used. Based on the results generated by their systematic review, the authors concluded that the risk of post-stroke depression was not affected by location of the brain lesion. Carson et al. (2000) identified several sources of bias that may have led to the different results of the individual studies. The main source of bias appears to be the heterogeneity of study patients. There was evidence to suggest that patients selected from the community, but not those selected from

Table 18.4 Lesion Location & Post-Stroke Depression in Carson et al. (2000) Systematic Review

Robinson et al. 1983 MacHale et al. 1998

House et al. 1990 Andersen et al. 1995 Schwartz et al. 1993 Gainotti et al. 1999

Ng et al. 1995 Collins et al. 1987 Wade et al. 1987 Burvill et al. 1996

Gordon et al. 1991 Agrell et al. 1994

Eastwood et al. 1989 Grasso et al. 1994 Feibel et al. 1982 Kase et al. 1998

Iacobani et al. 1995

Gonzalez-Torrecillas et al. 1995a, 1995b

Hibbard et al. 1992 Morris et al. 1990, 1996

Nagaraja et al. 1997 Herrmann et al. 1995

Pohjasvannra et al. 1998 Van Rooijen et al. 1990

Bacher et al. 1990 Folstein et al. 1977

Finkelstein et al. 1982 Kotila et al. 1987

Ebrahim et al. 1987 Malec et al. 1990

Agarwal et al. 1987 Astrom et al. 1993



hospitals or rehabilitation units, experience an increased risk of depression with right-sided lesions. The exclusion of aphasic patients that usually occurs in reports that follow patients from hospitals and rehabilitation units may have accounted for this finding. Furthermore, differences among individual studies were most apparent when carried out in the first 28 days of stroke; these were studies most often conducted in inpatient units. Studies examining lesion location and post-stroke depression are summarized in Table 18.5.

Table 18.5 Stroke Location and Depression

Author, Year Country

PEDro Score

Methods

Outcomes

Folstein et al. (1977) USA

20 stroke patients admitted 30 days after stroke onset and 10 orthopaedically disabled patients admitted at the same time were assessed for depression via the Hamilton Rating Scale, Visual Analogue Mood Scale, Present State Exam, Mini-Mental State Exam and Activities of Daily Living.

Patients with right hemisphere stroke seemed to be particularly vulnerable and displayed a syndrome of irritability, loss of interest and difficulty in concentration in addition to depression of mood.

Robinson & Szetela (1981) USA

18 patients with left hemispheric stroke were compared to 11 patients with traumatic brain injury for frequency and severity of depression using a visual analog mood scale, the Zung Self Rating Depression Scale and the Hamilton Depression Rating Scale.

More than 60% of the stroke patients had clinically significant depression compared with about 20% of the trauma patients, although both groups were comparable in impairment in activities of daily living and global cognitive function. Two groups had similar-sized lesion, but areas of ischemic injury were more anterior than the traumatic lesion. Severity of depression was directly correlated with the closeness of the lesion to the frontal poles.

Robinson et al. (1983) USA

103 stroke patients capable of undergoing psychiatric interview and not exhibiting decreased consciousness and /or aphasia with severe comprehension deficits were evaluated for mood disorders. No stroke patients wishing treatment from clinic were excluded and there was no selection bias or age limitation except that the referrals tended to be from lower socio-economic classes who did not have other sources of private medical care. All examinations were done in late morning or early afternoon to avoid effects of diurnal mood variation. Depression was assessed using the Zung Self Rating Depression Scale, Hamilton Depression Scale, the Present State Examination and the General Health Questionnaire.

Nearly 50% of patients had clinically significant depression and one fourth had symptom clusters typically found in major depression disorders. Lesion location was found to be most important in determining the frequency and severity of depression. Functional physical impairment, intellectual impairment, quality of social support and age contributed to or modified depression. Distance of lesion on CAT scan from the frontal pole in patients with left anterior infarcts was significantly associated with severity of depression at 3 and 6 months post-stroke. Intellectual functioning and functional physical impairment in-hospital were significantly correlated with severity of depression and social functioning scores at 3 and 6 months post-stroke. Authors concluded patients developing depression during the first 6 months post-stroke might be responding to severity of their impairment whereas patients who develop depression during acute post-stroke may have a neuroanatomical and neurophysiological basis for the relationship.


http://www.ncbi.nlm.nih.gov/pubmed/591971







Sinyor et al. (1996) Canada

Depression was assessed in 16 stroke patients with localized right hemisphere lesions and 19 with localized left hemisphere lesions. All psychological tests were administered between 10 a.m. and 3 p.m. to control for diurnal variations in mood. All patients underwent computerized tomography of the brain. Measures of depression used were the Zung Depression Scale, Beck Hopelessness Scale, Hopkins Symptom Checklist and the Composite Depression Index.

Ratings of mild, moderate or severe depression as assessed by the Zung Depression scale were 17%, 23% and 9% respectively. There was a significant positive relationship between the Zung Depression Scale scores and the most posterior point location of the lesion in right hemisphere patients. In left hemisphere patients, severity of depression tended to be greater with increasing proximity of the lesion to the frontal pole.

Ebrahim et al. (1987) UK

149 acute stroke survivors underwent mood assessment using the General Health Questionnaire.

The prevalence of depression was 23% for the study sample. No difference in depression was found between right and left hemisphere strokes. Affective illness was strongly associated with functional ability. Only 15% of those with high depression scores were receiving antidepressant drugs.

Eastwood et al. (1989) Canada

Case-control study of 87 stroke patients conducted over 18-months. Depression was assessed using the Schedule for Affective Disorders and Schizophrenia (SDAS), the Zung Self-Rating Depression, the Geriatric Depression Scale and the Hamilton Rating Scale.

Depression affected 50% of the patients. Previous psychiatric disorder and previous cerebrovascular accident appeared to be important risk factors. There were hemispheric differences with both site-of-lesion and reactive depression viewpoints confirmed.

Aström et al. (1993) Sweden

Major depression, functional ability and social networks were repeatedly assessed for 3 years in a population-based cohort of 80 acute stroke patients. Cerebral atrophy and brain lesion parameters were determined from CT scans. Patients were diagnosed with depression according to DSM-III criteria.

At discharge, depression was noted to be significantly more frequent in those patients with left hemisphere lesions. By 3 months post-stroke there was a significant increase in the frequency of depression among patients with right hemispheric lesions. Lesion location in the left anterior hemisphere was significantly associated with depression with a rate 3 times higher than that with lesions in the right hemisphere. However, after 3 months this was no longer significant and after 3 years, depression occurred more often in right than in left hemisphere lesions.

Herrmann et al. (1995) Germany

47 patients with single demarcated unilateral lesions were selected for study. Clinical examination, CT scan examination and psychiatric assessment were performed within a 2-month period after the acute stroke. Depression was assessed according to the Cornell Depression Scale, the Montgomery-Asberg Depression Rating Scale and modified DSM-III-R criteria.

No significant differences in depression scores noted between patients with left and right hemisphere lesions. No correlation was noted between the severity of depression and the anteriority and the volume of the lesion or brain atrophy. Major depression was exhibited in 9 patients with left hemispheric strokes all involving the basal ganglia. None of the patients with right hemispheric strokes exhibited a major depression.

Morris et al. (1996)a Australia

44 first-ever stroke patients with single lesions on CT were examined for the presence of post-stroke depression, severity of depression and its relationship to lesion location.

Patients with left hemisphere prefrontal or basal ganglia structures had a significantly higher frequency of depressive disorder than other left hemispheric lesions or those with right hemispheric lesions.

Morris et al. (1996)b

First time stroke patients were selected from the Stroke Data Bank for study who had completed the Centre for

47 (24%) of the 193 patients studied were depressed. Lesion size or location was not
















USA

Epidemiology Studies-Depression (CES-D) scale during their in-patient stay 7-10 days post-stroke; they had a single lesion visible on CT scan within the cerebral hemispheres; the CT scan lesion corresponded to the clinical neurological finding. 193 patients from the Stroke Data Bank were included for study.

associated with depression; however, among patients with comparable small-sized lesions, depression was more frequent among those with left hemispheric stroke than those with right hemispheric stroke. Among patients with small lesions, those with hemispheric lesions had a significantly higher frequency of depression than right hemispheric lesions. Patients with predominantly left cortical lesions had a higher rate of depression than right cortical lesions. The difference in the rate of depression was greatest, albeit non-significantly, between left and right posterior cortical lesions.

MacHale et al. (1998) UK

55 patients with a single lesion on CT were assessed for depression 6 months post stroke by the DSM-IV.

26% of patients met DSM-IV criteria for an anxiety or depressive disorder with 20% being depressed. Depression was significantly associated with larger lesions involving the right cerebral hemisphere.

Sato et al. (1999) USA

3371 patients were assessed to determine the relationship between MRI infarcts in the basal ganglia and non-basal-ganglia areas, potential functional consequences of the lesion and depressive symptomatology. Depression was assessed using the Centre for Epidemiology Studies Depression Scale.

The Centre for Epidemiology Studies Depression Scale scores were independently associated with non-basal-ganglia lesions but not independently associated with basal ganglia lesions. Hemispheric location and the size of the basal ganglia lesion were found to have no relation to depression levels when adjustments for deficits in cognitive and physical functions were made.

Kim & Choi-Kwon (2000) Korea

Prospectively studied 148 patients with single, unilateral stroke for the presence of post-stroke depression and post stroke emotional incontinence at 2 to 4 months post stroke. Depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders IV criteria and the Beck Depression Inventory.

27 (18%) of patients exhibited post-stroke depression and 50 (34%) exhibited emotional incontinence. The frequency of post-stroke depression and emotional incontinence was not associated with the nature, laterality or size of the lesion. Post-stroke depression was related to motor dysfunction and location (anterior versus posterior cortex) of the lesion with location being the strongest predictor of post-stroke depression. The prevalence of post-stroke depression was 75% in the frontal anterior cerebral artery territory, 50% in the temporal lobe, 30% in the frontal-middle cerebral artery territory and 13% in the medulla and none in the cerebellum.

Aben et al. (2006) Netherlands

190 patients with first infarct were followed for a period of 1 year. CT was performed during the acute admission. 75 patients also received MRI. Depression was assessed at 1, 3, 6, 9 and 12 months post stroke using self-rated scales. Diagnosis of depression was based on interview (DSM-IV criteria).

1-year cumulative incidence of depression was 38.7%. Incidence rates were greatest in the first month following stroke and decreased throughout the year. No significant association could be found between side of lesion, frontal involvement and development of depression. No relationship between generalized vascular damage and risk for depression could be established. On regression analysis, neuroticism & level of handicap were significant risk factors for PSD. A positive family history for psychiatric










disorders was associated with a trend toward increased risk.

Santos et al. (2009) Switzerland

An autopsy series of 41 stroke patients, 20 of whom had been diagnosed with PSD. Clinical diagnosis of depression had been established using the DSM-IV. In addition, overall cognitive status was assessed using the Clinical Dementia Rating Scale (CDR). Macroinfarct site was recorded and cortical microinfarcts and lacunes were assessed in 10 sections per area using a semi-quantitative scale. Total scores for each of these lesion types were obtained by adding scores for each area.

There was no significant association between macroinfarct site and PSD. The presence of small vascular lesions was related to PSD for both thalamic and basal ganglia lacunes bilaterally and for deep white matter lesions in the right hemisphere. Examination of lacune scores revealed a significant positive correlation between basal ganglia and thalamic lacunes and PSD (p=0.002). Severity scores for white matter lesions were also related to PSD (p=0.03). The total brain lacune score (thalamic + basal ganglia + deep white matter) was significantly associated with the occurrence of PSD (p<0.0001) accounting for 25% of the variance.

Nishiyama et al. (2010) Japan

Examined the relationship between lesion location and the presence of depressive symptoms one month following stroke in 134 patients. Depression was assessed using the Zung Self-rating Depression Scale (ZSDS). All patients received an MRI scan or CT to determine lesion location.

At 1-month, incidence of depression in this group was 34.3%. Hypertension and a high level of education were recorded more frequently in the group of individuals without depression. Lenticulocapsular lesions were recorded more often in the depressed group. On multivariate logistic regression, the presence of hypertension, higher education level and lenticulocapsular lesions were all significant predictors of PSD at one-month post stroke. A lesion in the lenticulocapsular area was associated with significantly increased odds for PSD (OR=3.92, 95% CI 1.-1-15.68, p=0.048).

Chatterjee et al. (2010) UK

Identified individuals with major depression (satisfied DSM-IV criteria + MADRS scores >17; n=33) for comparison with control participants (no major or minor depressive symptoms, no treatment for depression within 6 months and MADRS scores ≤6; n=70). CT scans performed acutely were assessed for chronic changes and a rating scale for while matter changes applied.

When compared to participants in the control group, CT scans of individuals with major depression were more likely to be abnormal (91% vs. 71%, OR = 4.0, 95% CI 1-18) and more likely to show discrete lesions (OR = 3.1, 95% CI 1.1-9.2) of less than 1.5 cm (OR = 3.2, 95% CI 1.0 – 11.2). There were more subcortical lesions (including brainstem) identified in individuals with depression vs. control group (p=0.04) and overall white matter change (WMC) scores were higher in the depressed group vs. controls (p=0.013), demonstrating increased white matter changes in the basal ganglia (p=0.019) and frontal areas (p=0.043) in particular.

Tang et al. (2011) China

591 individuals admitted to an acute stroke were assessed by a psychiatrist for depression at 3 months post stroke. MRIs were obtained during the acute period (99.8% during the first week following the stroke event).

Of the 591 individuals assessed, 75 were identified as having PSD at 3-month assessment; 14.7% of these had a history of previous depression. Frontal subcortical infarcts were more common in individuals with depression vs. those without (p=0.03). On multivariate regression analysis, presence of frontal subcortical infarcts, female gender, previous history of depression and social network were all identified as significant, independent risk










factors for PSD.

Discussion Based on the results of a meta-analysis conducted by Bhogal et al. (2004), there appears to be some evidence that depression following stroke may be related to the anatomical site of brain damage, although the nature of this anatomic relationship is not completely clear (Figure 18.1). The correlation of major depression to the proximity of the lesion to the frontal pole has been confirmed by Sinyor et al. (1986) and Eastwood (1989). Right hemispheric lesions failed to demonstrate a similar relationship with depression. Interestingly, in one study, patients who had both an anxiety disorder and a major depression showed a significantly higher frequency of cortical lesions, while patients with major depression only had a significantly higher frequency of subcortical (basal ganglia) stroke (Starkstein et al. 1987). A number of authors (Chatterjee et al. 2010; Santos et al. 2009; Tang et al. 2010) have since demonstrated that accumulation of lacunar infarcts within the basal ganglia, thalamus and deep white matter are all associated the presence of depression following stroke suggesting that older individuals with cerebral small vessel disease may be at greater risk for PSD. It has been speculated that the role of the brain lesion in the development of post-stroke depression is mediated by the depletion of catecholamines believed to play a major role in the etiology of depression (Robinson 1986). It has been suggested that when cerebral catecholoaminergic neurons are injured, they markedly reduce neurotransmitter production during the regenerative process causing a decline in neurotransmitter availability, not only in the injured area, but also throughout the cerebrum.

Figure 18.1 Odds Ratio of Post-Stroke Depression and Affected Hemisphere



The region close to the frontal pole has been reported to have the greatest concentration of catecholaminergic fibres. This was thought to correspond to the observation that injuries to the frontal region of the cortex produce the greatest vulnerability to post-stroke mood disorder. Three groups were unable to replicate the interhemispheric differences found by the John Hopkins’ group (Eastwood et al. 1989; Ebrahim et al. 1987; Sinyor et al. 1986). Robinson et al. (1983) failed to confirm their previously established interhemispheric differences when looking at a larger number of patients (Robinson et al. 1983). Folstein et al. (1977) found that patients with right-sided lesions were more likely to suffer psychological symptoms of irritability, loss of interest, difficulty in concentrating, subjective memory loss and depressed mood when compared to controls or patients with left hemispheric lesions. Aben et al. (2006), attempted to replicate the finding that left-sided strokes and/or anterior strokes are associated with an increased risk for PSD. The findings could support neither this hypothesis nor the hypothesis that post-stroke depression results from generalized vascular damage (Aben et al. 2006). Finally, the two large systematic reviews by Singh et al. and Carson et al. referred to previously, failed to find a relationship between the stroke lesion site and depression (Carson et al. 2000; Singh et al. 1998). As important as the contribution of Robinson and his group is to our understanding of post-stroke depression, there are potential weaknesses in their research in part related to selection biases in the patient population, which might account for why their findings have not been consistently replicated. These weaknesses were outlined in two studies (Ebrahim 1990; Malec et al. 1990). The site and size of the brain lesion in stroke does not appear to be strongly correlated with depression although the data is not consistent and it continues to be difficult to determine whether positive findings can be accounted for by the clinical consequences of the stroke or the neurophysiological changes that may lead to depression. Recent reports have suggested that psychosocial risk factors including age, sex and functional impairment or previous history of psychiatric disturbance are greater contributors to the development of PSD than lesion location (Aben et al. 2006; Berg et al. 2003; Carota et al. 2005; Singh et al. 2000).

Conclusion Regarding Stroke Location and Depression There remains a wide diversity of findings in studies looking at the relationships between stroke location and depression. Not all studies have confirmed this relationship and meta-analyses have failed to establish a definitive relationship between the site of the brain lesion and depression.

Despite an abundance of research, the influence of stroke location on the risk for developing post-stroke depression has not been determined.

18.4 Assessment of Post-Stroke Depression

The detection of depression is not always consistent. Given the fluctuation in the incidence of depression post stroke, timing of assessment may be an important factor in screening and diagnosis, particularly during the initial post-stroke transition phase (see section 18.2). Apart from timing, the standards against which depression is assessed are also important. At present, the criteria provided by the DSM-IV are the gold standard against which diagnosis is made and form the basis for the evaluation of assessment tools. According to the DSM-IV-TR, both major and minor depression may be distinguished from a “Mood Disorder due to a General Medical Condition” when the mood disturbance is judged to be a direct



consequence of a medical condition such as stroke. Major and minor depression following stroke, or PSD, may be classified as Mood Disorder due to Stroke with major-depressive-like episode or with depressive features, respectively (Salter et al. 2007). The primary concern with the use of the DSM in the diagnosis and assessment of post-stroke depression is that the diagnostic criteria provided includes vegetative symptoms of depression such as psychomotor retardation, fatigue, sleep and appetite disturbances, which, in themselves, may be a consequence of the stroke event. Gainotti et al. (1997) reported distinct differences between functional depression and post-stroke depression and demonstrated that the motivated or reactive aspects of depression are more prevalent in PSD. However, it has also been suggested that the DSM criteria for depression are equally valid among psychiatric and stroke patients. For example, Spalletta et al. (2005) reported that vegetative symptoms appearing in the DSM-IV were as discriminative of the presence of major and minor depression in a group of stroke patients as the psychological and cognitive criteria. More recently, Cumming et al. (2010) demonstrated that the experience of depression in individuals with stroke is similar, though not identical, to age and sex-matched controls without stroke. Depressed individuals in the control group were significantly more likely than individuals with PSD to report symptoms of anhedonia (p=0.002) and disturbed sleep (p=0.008). There were, however, no difference in scores on either the somatic or psychological factors of depression between the depressed controls and PSD groups (Cumming et al. 2010). Self-report Assessment Lincoln et al. (2003) noted that there was poor agreement between psychiatric diagnosis and self-report questionnaires. It has been reported that, in terms of screening or classifying patients on the basis of depressive symptomatology, rating scales are quite sensitive, but lack specificity (Aben et al. 2002; Lincoln et al. 2003; Schramke et al. 1998), perhaps due to the inclusion of somatic symptoms. Dam et al. (1989) suggested that discrepancies in diagnosis between psychiatric interviews and self-report scales could be explained by an indifference to symptoms, typical in patients with right-hemisphere stroke, which would be more pronounced when relying on self-report to assess depression. Schramke et al. (1998) reported that patients with left hemisphere lesions were assessed as experiencing greater levels of distress than patients with right hemisphere lesions on the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hamilton Rating Scale for Depression (HRSD). However, this difference between groups reached significance only on assessments made with the CES-D, a self-report measure (Schramke et al. 1998). Self-report measures rely on the assumption that the individuals being evaluated are sufficiently self-aware to provide an accurate self-assessment and report. As Lincoln et al. (2003) pointed out, this is not necessarily true of individuals who have experienced a stroke, who may either minimize or exaggerate changes. Schubert et al. (1992) carried out a chart review of 15 stroke patients on a medical ward. Charts were examined for detection of depression by the rehabilitation team. Chart evaluation revealed no notation of depression or mention of possible depressed mood by the rehabilitation team. Assessment of these patients using the Beck Depression Inventory identified 50% of the patients as mildly depressed. Review of the psychiatric charts revealed that 68% of patients were had received some psychiatric diagnosis: 26% were diagnosed with major depression and 42% with adjustment disorder with depressed mood. Screening for Depression Although, formal screening for post-stroke depression may be superior to simple observation and is included among the recommendations appearing in current guidelines (see section 18.10), reported compliance is low. The UK National Clinical Guidelines for Stroke recommend screening for depression within the first month of a stroke event; however, the National Sentinel Audit for the years 2001 – 2002 revealed a compliance rate of only 50% (Bowen et al. 2005). When hospitals with psychologist input



were examined separately, the rate of compliance was 60%. An examination of reasons for non-compliance was based on survey responses received from 75 healthcare professionals affiliated with 16 stroke units in the UK (Hart & Morris 2008). These suggested that while compliance for screening was low, attitudes toward the practice were positive. While nurses most often performed the screening, neither the profession of the individual responsible for this task nor the availability of psychologist input had an effect on compliance. Identified barriers to screening included time pressures and concerns about screening tests, while being knowledgeable about screening, having screening in the job role and belief in the value of screening were identified as facilitators (Hart & Morris 2008).

Detection and diagnosis of post-stroke depression is often inconsistent. Compliance with guidelines for screening is poor. Identified barriers to routine screening include time pressures and concerns

about screening tools.

18.5 Consequences Associated with Post-Stroke Depression

18.5.1 Functional Impairment and Depression Post-Stroke The relationship between functional deficits and depression is an ongoing topic for debate. The degree to which functional ability influences depression or depression impacts functional ability is uncertain. However, post-stroke depression has been associated with rate of recovery and success of rehabilitation. Individual studies examining the impact of PSD on functional limitations are summarized in Table 18.6.

Table 18.6 Functional Ability and Depression Post-Stroke


PEDro Score

Methods

Outcomes


103 stroke patients capable of undergoing psychiatric interview and not exhibiting decreased consciousness and /or aphasia with severe comprehension deficits were evaluated for mood disorder. No stroke patient wishing treatment from the clinic was excluded and there was no selection bias or age limitation except that the referrals tended to be from lower socio-economic classes who did not have other sources of private medical care. All examinations were done in late morning or early afternoon to avoid effects of diurnal mood variation. Depression was assessed using the Zung Self Rating Depression Scale, Hamilton Depression Scale, the Present State Examination and the General Health Questionnaire.

Nearly 50% of patients had clinically significant depression and one fourth had symptom clusters found in major depression disorders. Functional physical impairment, intellectual impairment, quality of social support and age contribute to or modify depression. Functional physical impairments in-hospital was significantly correlated with severity of depression and social functioning scores at 3 and 6 months post-stroke. The authors concluded patients developing depression during the first 6 months post-stroke may be responding to severity of their impairment whereas patients who develop depression during acute post-stroke may have a neuroanatomical and neurophysiological basis for their relationship.

Sinyor et al. (1986) USA

64 patients screened from 166 consecutive stroke admissions to a rehabilitation hospital. Patients were assessed in hospital and 6 weeks post discharge using the Zung Self-Rating Depression Scale, the Beck Hopelessness Scale, Hopkins Symptom Checklist, Composite Depression Index, Nurses’ Rating Scale,

Moderate to severe depression was identified in 22% of patients; mild depression in 25%. Depression scores were not correlated with functional status scores on discharge, change in functional status over the rehabilitation stay or with length of stay. When comparing depressed







Coping Scale and Health Locus of control Scale. Functional Status was assessed using the Patient Evaluation Conference System.

patients to nondepressed patients, depressed patients had lower functional status scores. Both groups of patients improved significantly over time and there were no significant differences between groups regarding the degree of improvement.

Ebrahim et al. (1987) UK

149 acute stroke survivors underwent mood assessment using the General Health Questionnaire.

Found that the prevalence of depression was 23% for study sample. Affective illness was strongly associated with functional ability. Only 15% of those with high depression scores were receiving antidepressant drugs.


Refer to Robinson et al. (1983). All follow-up patients with major depression scores in-hospital improved by 2 years, with a significant reduction in mean depression scores and improvement in ADLs. There was no significant improvement in mean depression scores or ADL for dysthymic patients. 34% of patients not depressed in hospital had developed major or minor depression by 2 years with their mean depression scores significantly elevated.

Bacher et al. (1990) Canada

48 stroke patients were followed for 12-months in order to identify the course of post-stroke depression among rehabilitation patients and the relationship of depression with physical and cognitive impairment. Patients with known history of psychiatric illness and or stroke, dementia or comprehension disorders were excluded. Depression was assessed using the Zung Self Rating Scale; clinical depression defined as a score > 50 & moderate to severe > 60.

By 12 months more than half the patients were clinically depressed. Functional level improved for all patients, but was higher for non-depressed patients.

Parikh et al. (1990) USA

36 patients with acute thrombotic or hemorrhagic stroke were followed for 2 years.

In hospital all patients had comparable scores on all measures; however, rate of recovery was different with depressed patients being more impaired at 2 years. Among patients with major depression, the difference in impairment recovery was present even after depression had subsided.

Morris et al. (1992) USA

49 in-patients with stroke initially at 2-months after stroke and then again 14-months post-stroke were studied to examine the effect of clinical depression on recovery from stroke.

At initial assessment, 41% of patients were depressed. There were no significant differences in demographic, clinical, stroke or lesion characteristics. Depressed patients improved less than non-depressed patients in functional status and cognitive functioning. Mean recovery of ADLs was not different between the two groups. Depressed patients tended to deteriorate over time on ADLs.

Sharpe et al. (1994) UK

60 stroke survivors 3 – 5 years post stroke were interviewed.

Presence of depression was associated with physical and cognitive impairment, increased age, institutionalization, absence of close relationships and large brain lesion. When controlling for the effects of all other variables, the association between depression and physical function (functional dependence)






http://psycnet.apa.org/psycinfo/1991-10939-001







remained significant.

Loong et al. (1995) Singapore

Prospective study assessing the outcomes of rehabilitation (mood & physical recovery) for patients with post-stroke depression. Patients assessed to have rehabilitative potential were admitted to the rehabilitation unit and all those with severe motor deficits or comprehension deficits were not admitted if there was a shortage of beds. Patients with aphasia, dementia or delusion were excluded. Depression was assessed using the DSM-III-R criteria and patients were also scored on the Hamilton Rating Scale for Depression.

From a sample of 52 patients, 55% were assessed as depressed. Patients less functionally impaired on discharge were less likely to be depressed. Patients less depressed were also found to be less likely to be depressed at time of discharge. Patients who were more depressed on admission were more likely to be functionally impaired on discharge. The association between depression and functional impairment was found to be strong and accounted for 48% of the variance.

Herrmann et al. (1998) Canada

Of 436 consecutive admissions to a regional stroke center, 150 were available for assessment at 3 months and 136 at one year post stroke. Patients were assessed via the Montgomery Asberg Depression Rating Scale (MADRS), the Zung Self-rating Depression Scale (ZSDS), the FIM and the Oxford Handicap Scale

At 3 months, marked symptoms of depression were assessed in 22% of patients using the SDS and 27% using the MADRS. Depression was significantly associated with FIM scores and OHS scores both at 3 months (p<0.0001 & p<0.0001, respectively) and at one year (p<0.001 & p<0.0001, respectively).

Pohjasvaara et al. (1998) Finland

277 stroke patients were assessed at 3 – 4 months post stroke using the MADRS, the Beck Depression Inventory, the Zung Self-Rating Anxiety Scale and the SCL-90. Physical function was assessed using the Barthel Index (BI).

On logistic regression, dependence in ADLs was associated with the diagnosis of major depression (OR = 2.9) or depression (OR= 1.8).

Kotila et al. (1999) Finland

Post-stroke depression and functional outcome was examined in 594 patients in four different districts. Depression was defined by a Beck’s depression inventory (BDI) score of > 10.

47% of the 321 surviving patients were depressed at 3 months and 47.3% of 311 surviving patients were depressed at 12 months. Depressed patients needed more help on activities of daily living than did non-depressed patients. 68.9% of depressed patients were in institutional care compared to 57.6% of non-depressed patients.

Paolucci et al. (1999) Italy

470 patients assessed for post-stroke depression and to evaluate its impact on individual physiotherapy session of about 60 minutes session for 6 week based on Bobath’s therapeutic exercises.

Post-stroke depression was identified in 27.4% of study patients. Depression was observed to be a significant independent predictor of low response on Activities of Daily Living despite treatment.

Van de Weg et al. (1999) Netherlands

85 stroke patients admitted consecutively to rehabilitation 3 – 6 weeks following stroke were assessed for depression using the DSM-III criteria. Depressed patients were compared to non-depressed patients in terms of admission and follow-up (6 months) FIM scores and scores on the Rehabilitation Activities Profile (RAP).

Prevalence of PSD in this sample was 35%. Depressed patients had significantly lower scores on both the FIM and RAP than non-depressed patients (p=0.001 and p=0.02, respectively). The same pattern was observed at follow-up (p=0.05 & p=0.03 for FIM and RAP scores, respectively). There was no significant difference between depressed and non-depressed patients in improvement in functional ability from admission to follow-up. Depressed patients who were taking antidepressants experienced 30% better improvement than depressed patients whose depression was untreated.

Gillen et al. (2001)

243 patients admitted consecutively for to an acute inpatient stroke rehabilitation program were screened,

Patients with higher FIM efficiency scores were younger (p<0.01), less cognitively impaired











USA following admission, using the Geriatric Depression Scale (GDS) and Cognistat. The FIM was administered at admission and at discharge.

(p<0.05) and had lower scores on the GDS (p<0.05). Patients with higher GDS scores had lower FIM scores both at admission and at discharge (p<0.01). On multivariate analysis, controlling for admission FIM, GDS scores at admission were significantly associated with FIM efficiency (FIM change/length of stay; p<0.05). However, depressed patients did not experience longer lengths of stay than non-depressed patients.

Pohjasvaara et al. (1998) Finland

486 stroke patients were assessed 3 months following stroke and again at 15 months (n=390). 390 patients completed the Beck Depression Inventory at 3 months and 276 at 15 months.

Patients with major depression or classified as depressed using the Beck Depression Inventory were more likely to have poor functional outcome (dependence) at 15 months assessed on the Barthel Index and Rankin Scale.

Nannetti et al. (2005) Italy

117 patients admitted consecutively for inpatient stroke rehabilitation approximately 2 weeks following a stroke event were assessed for the presence of depression. Patients with and without post-stroke depression were assessed for motor and functional recovery at admission to and discharge from rehabilitation. Patients were also assessed at 3 months following the stroke event.

41.9% of patients were diagnosed with post-stroke depression. Over the period of rehabilitation, patients with and without depression made significant motor and functional recovery (p<0.001). Motor recovery was significantly greater at all assessment times for patients without post-stroke depression p<0.05). Functional recovery was greater for non depressed patients at 3 month follow-up only, although there was a non-significant trend toward higher scores among the non-depressed at admission and discharge assessments. From discharge to follow-up, post-stroke depression was the only significant predictor of functional recovery. Among patients without depression, recovery was 2.4 times greater when compared to those patients with post-stroke depression.

Cully et al. (2005) USA

Charts were reviewed from the consecutive admissions of 509 older adults to inpatient rehabilitation. Patients were split into two groups; stroke (n=207) and nonstroke (n=302). Patients received assessment for depression within 3 days of admission using the Geriatric Depression Scale. Functional ability was assessed using FIM scores at admission.

31.8% of stroke patients and 31.5% of nonstroke patients were identified as depressed. In all patients, depression was significantly associated with self-care (p<0.01), mobility (p<0.01), communication/social ability (p<0.05) and sphincter control (p<0.01) as assessed on 4 FIM domains. Only FIM sphincter control scores demonstrated a significant interaction between depression and diagnostic group. The presence of depression was significantly associated with functional ability, but its impact did not differ between groups of stroke vs. nonstroke patients.

Paolucci et al. (2006) Italy

Clinical & demographic features of 1,074 stroke patients enrolled in a multicenter observational study were compared in groups with vs. without PSD. Impact of PSD on disability and quality of life was examined using Barthel Index, Modified Rankin scale and SF-36 scores.

By the end of study selection (34 – 38 weeks post stroke) 36% of patients had developed depression – 22.18% had demonstrated depression by one month. Patients with PSD demonstrated significantly greater functional impairments both at baseline and at follow-up visits. Patients with no PSD and those with early onset PSD demonstrated significant







improvement in BI scores during follow-up (both p<0.001).

Van de Port et al. (2006) Netherlands

Prospective cohort study of 205 patients with first-ever stroke (mean age 57 years). Mobility status of patients was assessed at 1 & 3 years post stroke via the Rivermead Mobility Index. Data was examined to determine factors predictive of deterioration in mobility status.

Decline in mobility status was demonstrated in 21% of patients. On multivariate logistic regression, level of activity, cognitive impairment, fatigue and depression 1 year post stroke were significant predictors of mobility decline between 1 & 3 years (AUC = 0.80).

Saxena et al. (2007) Singapore

6-month prospective cohort study of 141 stroke patients admitted to two rehabilitation hospitals. Patients were assessed on admission and again at 6 months post stroke. Functional recovery was assessed using the Barthel Index.

Linear regression demonstrated that greater change in BI scores from rehabilitation admission to 6 months was associated with better mood status at baseline and greater improvement in depressive symptoms (p=0.02 and p<0.001, respectively). Other significant predictors of functional recovery included baseline neurological status, neurological improvement, baseline functional status and age.

Hama et al. (2007) Japan

237 stroke patients admitted to a rehabilitation hospital were assessed using the FIM, the Zung Self-rating Depression Scale (ZSDS), the Apathy Scale and the Neuropsychiatric Inventory (NPI).

Depression was recorded in 31.6% of patients (ZSDS) or 40.2% (NPI). On linear regression analysis, cognitive status and apathy were significantly associated with functional status (FIM scores), but depression scores (ZSDS) were not.

Goodwin & Devanand (2008) USA

Data from the Midlife Development in the United States Study (MIDUS) were analysed to determine the relationship between stroke, depression and functional outcome in community-dwelling individuals.

Of the 3,032 participants (aged 25-74 years), only 24 (0.8%) reported having a stroke within the past 12 months. Participants with stroke were significantly older than those without. Stroke and depression were both independently associated with impairment in physical functioning (adjusted for sociodemographic and personality characteristics). In addition, having both depression and stroke at the same time was associated with greater limitations than either condition alone.

West et al. (2010) UK

As part of the Stroke Outcomes Study, physical function and psychological symptoms were assessed at baseline (2-6 weeks post stroke) and 9, 13, 26 and 52 weeks. Symptom trajectories were analysed and logistic regression was used to model poor functional outcome.

Most psychological distress occurred within the first weeks of stroke. In general, individuals with more psychological symptoms had poor initial physical function. At one year, individuals with more psychological symptoms had poor outcomes. On logistic regression, patients at greatest risk for poor physical outcome were those who were older, had more severe disability early after stroke and had persistent psychological symptoms over the first 26 weeks following stroke.

Donnellan et al. (2010) Ireland

107 patients with stroke were assessed one-month and 1 year following the stroke event. Depression was assessed using the Hospital Anxiety and Depression Scale (HADS). Probable depression was identified with a cut-off score on the depression scale of ≥8. Previous history of depression was determined using a single, self-report question.

Prevalence of depression was 35% at one month and 36% at one year. 22% of individuals identified with depression at 1 month continued to experience symptoms at 1 year. There was a significant association between depression and functional outcome at both assessment points (r=-0.29, p<0.01 and r=-0.19, p<0.05 at 1 month










and 1 year, respectively) such that greater depression was associated with poorer function. Presence of depression was also associated with poorer HRQOL at one month and one year assessment points (r=0.-56, p<0.001 and r=-0.41, p<0.001).

Feigin et al. (2010) Australia

As part of the Auckland Stroke Outcomes Study (ASTRO), 418 5-year stroke survivors were included in an analysis of association between functional outcomes and potential predictors such as depression. Depression was assessed using the Geriatric Depression Scale (GDS). A score ≥5 was used to indicate depression. The Barthel Index score ≤19 was used to indicate dependency.

At 5 years, 29.6% of survivors reported symptoms suggestive of depression. Depression was independently associated with greater odds for dependency (OR = 4.58, 95% CI 2.48-8.46) as well as reduced IADL activity (Frenchay Activities Index; OR = -4.55, 95% CI -6.29 to -2.81) and lower levels of participation (London Handicap Scale; OR = -7.48, 95% CI -11.06 to -3.9)

Willey et al. (2010) USA

In the Northern Manhattan Stroke Study (NOMASS), a single question was used to identify the presence of “depressed mood” within 7 – 10 days post stroke (n=340). Patients were followed every 6 months for 2 years and every year up to 5 years following enrolment. Disability was assessed using the Barthel Index and categorized as no disability (BI ≥95), moderate (BI 60 – 95) or severe (BI <60).

At 7 – 10 days post stroke, 40.9% of individuals reported feeling depressed. Analysis adjusted for sociodemographic variables, stroke severity, diabetes, physical inactivity and CAD, there was significant association between depressed mood and functional ability such that the presence of depressed mood was associated with greater odds of severe disability at 1 and 2 years (when compared to no disability) (OR=2.91, 95% CI 1.07-7.91 and OR=3.72, 95% CI 1.29-10.71). Depressed mood was not associated with moderate disability when compared to no disability on any of the analyses.

Schmid et al. (2011) USA

Secondary data analysis from the Activate-Initiate-Monitor (AIM) study to examine the association between depression and functional outcomes. Participants were categorized as depressed vs. non-depressed (determined at study entry via structured clinical interview). Change in depression was assessed by change in PHQ-9 scores. Improvement was defined as a decreased in PHQ-9 scores from baseline to 12 weeks of at least 50% (or a score of less than 10 at 12 weeks). Functional status was assessed using the mRS. Participants scoring 0-2 were considered independent.

Participants who were classified as dependent at 12 weeks had significantly greater baseline depression scores than individuals classified as independent (p=0.026). Depressed individuals who met the criteria for improvement over the 12-week period were more often independent at 12 weeks (p=0.012) than those who did not improve. Independent predictors of 12-week function in the depressed group were medical co-morbidity, stroke severity and depression severity. In the non-depressed group, baseline depression was not independently associated with dependency at 12-weeks.

Brown et al. (2012) Sweden

181 individuals with stroke were assessed at discharge from hospital, then again at 3 months and 12 months post stroke using the Barthel Index and CES-D. Presence of depression was defined as CES-D score ≥16. On the Barthel Index, scores of ≤60 were indicative of lower levels of independence.

At all three assessment points, individuals who were identified as depressed using the CES-D had lower BI scores than individuals who were not depressed – although these differences reached statistical significance at discharge and 3 months only (p<0.05). At all three assessment points, individuals with lower levels of independence in function had significantly higher CES-D scores than individuals who were considered independent on the Barthel Index (p<0.05). Regression analysis demonstrated that, at all three time periods, function as assessed on the Barthel Index was significantly







associated with depression accounting for 6-11% of the variance.

Discussion Depression post stroke is associated with functional ability and may have a negative impact on recovery. Although patients with post-stroke depression may experience significant recovery, functional ability may remain at a lower level than non-depressed patients, despite rehabilitation interventions. Goodwin and Devanand (2008) demonstrated that co-occurrence of stroke and depression is associated with greater physical limitations than either condition on its own. Physical impairment and post-stroke depression appear to act upon each other, and each influences the recovery of the other. Van de Port et al. (2006) recently published the results of a prospective cohort study (n=205), which demonstrated that mobility decline was experienced by 21% of participants between 1 and 3 years post stroke. Significant predictors of this decline in mobility status were level of activity, cognitive problems, fatigue and depression. Given that the relationship between depression and physical impairment may be reciprocal, depression may contribute to a progressive deterioration in mobility, which may in turn contribute to increased feelings of depression. Since depression is a treatable condition, which impacts both function and functional recovery, it should be taken into account in the evaluation and treatment of all stroke patients (Ramasubbu 1998). Although it is difficult to determine whether depression is a significant independent factor in the development of dependency, improvement in depressive symptomatology has been associated with reduced odds for dependency at 3 months post stroke (Schmid et al. 2011). As Ramasubbu et al. (1998) pointed out, early recognition and treatment of depression may “optimize rehabilitation potential” and reduce “significant human and financial costs associated with post-stroke functional impairment”.

Conclusion Regarding Functional Impairment and Depression Depression may have a significant and negative impact on functional ability following stroke. Early identification and treatment of post-stroke depression may serve to enhance functional recovery.

Depression post-stroke has a negative impact on functional recovery.

18.5.2 Depression and Social Activities Post-Stroke

Individual studies examining the association between social isolation and participation and the experience of post-stroke depression are presented in Table 18.7.

Table 18.7 Depression and Social Activities Post Stroke


PEDro Score

Methods

Outcomes



Labi et al. (1980) USA

121 stroke survivors and 141 controls with a minimum score of 20 on the Kenny self-care evaluation were tested on three parameters of social function – socialization in the home, socialization outside the home and hobbies and interests – to determine social reintegration of long-term survivors of completed stroke survivors.

A significant proportion of survivors manifested social disability, despite complete physical recovery. Most of the disability could not be accounted for by age, physical impairment or specific neurological deficits. The greatest social functioning impairments were seen in women and those of higher educational background.

Feibel & Springer (1982) USA

91 stroke patients were assessed for physical independence in activities of daily living and mobility using the Katz Index and depression by nurses’ observation, patient’s mood, behaviour, somatic complaints and number of social activities.

Incidence of depression was 26% 6 months after stroke. Depression was significantly correlated with failure to resume premorbid social activities. Depressed patients lost a mean of 67% of their previous activities. Depression status was not significantly correlated to age, sex, marital status or side of brain involvement.


103 stroke patients capable of undergoing psychiatric interview and not exhibiting decreased consciousness and /or aphasia with severe comprehension deficits were evaluated for mood disorder at 6 months. No stroke patient wishing treatment from clinic was excluded and there was no selection bias or age limitation except that the referrals tended to be from lower socio-economic classes who did not have other sources of private medical care. All examinations were done in late morning or early afternoon to avoid effects of diurnal mood variation. Depression was assessed using the Zung Self Rating Depression Scale, Hamilton Depression Scale, the Present State Examination and the General Health Questionnaire.

Intellectual functioning and functional physical impairment in-hospital were significantly correlated with severity of depression and social functioning scores at 3 and 6 months post-stroke. Patients developing depression during the first 6 months post-stroke may be responding to severity of their impairment whereas patients who develop depression during the acute post-stroke period may have a neuroanatomical and neurophysiological basis for their relationship.

Andersen et al. (1995) Denmark

285 patients with stroke admitted to hospital or referred a hospital-based outpatient clinic were included. Patients were assessed at 7 days, 1 month, 6 months and 1 year post-stroke. In addition a study nurse visited patients at home at 2 – 3 months post stroke to complete the Beck Depression Inventory. Patients who were identified as possible cases were referred for assessment using the Hamilton Rating Scale for Depression.

1-year incidence of PSD was reported to be 41%. Most cases developed in the first month post stroke. The presence of PSD was associated with social distress in the 6 months preceding stroke (p<0.01), few social activities at home visits and a decrease in the social activities index scores at one month and at one year (p<0.001 & p<0.05, respectively).

Sienkiewicz-Jarosz et al. (2010) Poland

242 individuals with stroke were evaluated 3 months following the stroke event. Assessments included NIHSS, Rankin Scale, BI, MMSE, the Boston Diagnostic Aphasia Examination and a self-report of frequency and satisfaction with social contact. Depressive symptomatology was assessed using the Geriatric Depression Scale (GDS). A cut-off score of >5 was used to indicate probable depression.

Individuals with a GDS score >5 reported fewer positive assessments of family relationships (p=0.03) and less satisfaction with the frequency of contact with family members (p=0.0004). In addition, more individuals with depression reported seeing friend only rarely or occasionally (p=0.002), and they reported less satisfaction with frequency of contact (p<0.01). 66.2% of individuals with GDS score >5 reported reduction of social contacts following stroke (vs. 31.4% in the non-depressed group).

Baseman et al. (2010) USA

Individuals with stroke (6 months prior to enrolment) were assessed via mailed survey. Assessments included in the survey documents were a demographic questionnaire (including a single-item to measure impression of overall recovery), the subjective index of physical and social outcome (SIPSO) and the centre for epidemiologic studies depression scale (CES-D). CES-D scores >10 were

Depression was significantly, and inversely, correlated with social integration (r=-.74. p=0.01), function (r=-0.33, p=0.026) and perceived overall stroke recovery (r=-0.49, p=0.001). In a linear regression model, these three factors could account for 62% of the variance in social integration; although, only













considered indicative of depression. Final number of participants = 48 (310 invited to participate).

functional ability and depression were significant predictors.

Hinojosa et al. (2011) USA

77 individuals with stroke were enrolled in a longitudinal study at discharge from inpatient care for stroke. Social isolation was assessed using a connectedness-isolation scale. Participation was assessed using the FAI. The GDS was used to assess depression – scores less than 10 were considered normal.

Approximately 60% of participants experienced no change in their sense of connectedness or isolation over the first year post stroke. Approximately 7% of individuals who reported connectedness at one month were isolated at 6 months and remained isolated for the duration of the study. On multivariate regression analysis, depression was significantly associated with social isolation such that increased symptomatology was associated with increased odds for social isolation (OR = 1.11, 95% CI, 1.04-1.20).

Discussion Although there may be a tendency for individuals who were isolated prior to stroke to remain isolated (Hinojosa et al. 2011), depression is associated with reduced social activity and integration (Andersen et al. 1995; Baseman et al. 2010; Hinojosa et al. 2011; Sienkiewicz-Jarosz et al. 2010). Sienkiewicz-Jarosz et al. (2010) reported that approximately 2/3 of individuals with stroke who experienced symptoms of depression reported a reduction in social contact. These individuals also expressed a significantly greater reduction in both frequency and satisfaction with contacts with both friends and family than non-depressed individuals with stroke. The effects of stroke may alter how patients perceive themselves, their capabilities and self-image (Labi et al. 1980). These perceptions are associated with depression (Feibel & Springer 1982) and are also associated with social withdrawal, which may in turn, further exacerbate depression after stroke. Andersen et al. (1995) demonstrated that social factors explained only 3% of the variance in mood; however, even after intensive intervention for depression, social function among depressed stroke survivors was still significantly lower than among non-depressed stroke survivors during the first year following the stroke event. The significant relationship identified between lower social function prior to stroke and depression (Andersen et al. 1995) highlights the difficulty in separating the risk factors for post-stroke depression from its consequences.

Conclusion Regarding Depression and Social Activities Post-Stroke Depression is significantly associated with poorer social integration and increased isolation post-stroke.

There is a significant association between the presence of depression and greater social isolation.

18.5.3 Cognitive Impairment and Depression Post-Stroke

It has been assumed by some that cognitive impairments associated with stroke contribute to post-stroke depressive disorders. However, the reciprocal relationship may also apply. Observational studies have suggested that depressive disorders can contribute to cognitive impairment in post-stroke patients. Individual studies examining the association between cognitive impairment and post-stroke depression are summarized in Table 18.8.




Table. 18.8 Cognitive Impairment and Depression


PEDro Score

Methods

Outcomes


184 patients with ischemic lesions of the left cerebral hemisphere were examined for depression and intellectual impairment. All examinations were done in late morning or early afternoon to avoid effects of diurnal mood variation. Depression was assessed using the Zung Self Rating Depression Scale, Hamilton Depression Scale, the Present State Examination and the General Health Questionnaire.

After 6 months, non-depressed patients had significantly less cognitive impairment than depressed patients who showed no improvement. Both depression and lesion volume were significantly and independently related to cognitive impairment.

Bacher et al. (1990) Canada

48 stroke patients were followed for 12-months in order to identify the course of post-stroke depression among rehabilitation patients and the relationship of depression with physical and cognitive impairment. Patients with a known history of psychiatric illness, stroke, dementia and/or comprehension disorders were excluded. Depression was assessed using the Zung Self Rating Scale with clinical depression assigned a score > 50 and moderate to severe > 60.

At 12 months more than half the patients were clinically depressed. Depressed patients experienced a slight deterioration in cognitive functioning.


This study followed 49 patients over 14 months to assess the effects of clinical depression on stroke recovery. The diagnosis of depression was made according to the DSM-III.

41% of the study sample was depressed at initial assessment. At follow-up, depressed patients improved less than non-depressed patients in functional status and cognitive impairment.

Andersen et al. (1995) Denmark

285 patients with stroke admitted to hospital or referred a hospital-based outpatient clinic were included. Patient were assessed at 7 days, 1 month, 6 months and 1 year post-stroke. In addition a study nurse visited patients at home at 2 – 3 months post stroke to complete the Beck Depression Inventory. Patients who were identified as possible cases were referred for assessment using the Hamilton Rating Scale for Depression.

1-year incidence of PSD was reported to be 41%. Most cases developed in the first month post stroke. The presence of PSD was associated with more cognitive impairment at one month post stroke as assessed on the Brief Cognitive Rating Scale (BCRS) (p<0.001). Multivariate regression demonstrated that intellectual impairment at one month on the BCRS accounted for 33% of the variance in scores on the Hamilton Rating Scale for Depression (p<0.001).

House et al. (2001) UK

448 stroke in-patients were seen 1 month post-stroke and reassessed at 12 and 24 months. Mood symptoms were assessed via the Present State Examination and the General Health Questionnaire.

22.3% of patients met ICD-10 criteria for major depression; 19.1% met criteria for probable caseness on the GHQ-28. Depression was significantly associated with lower BI scores. A non-significant trend was identified such that post-stroke depression was associated with lower scores on the MMSE (p<0.06).

Dam (2001) Denmark

99 stroke patients, 7 years post stroke, and 28 control patients participated. Assessments included Research Diagnostic Criteria, the Hamilton Rating Scale for Depression, the Beck Depression Inventory, Raven Matrices, MMSE and 5 word pair learning. Subjects were questioned regarding changes in concentration, memory, fatigue, mood and irritability.

No differences were reported between depressed and non-depressed stroke patients on the MMSE, Raven Matrices A+B and Word Pair Learning. However, stroke survivors who were depressed reported significantly more concentration (p=0.006) and memory difficulties (p=0.01) than non-depressed survivors.



http://psycnet.apa.org/psycinfo/1991-10939-001






Spalletta et al. (2002) Italy

153 individuals who had experienced first-ever stroke within the past year and were admitted to a specialized rehabilitation facility were included. Patients were assessed using the SCID interview for the DSM-IV, the Hamilton Rating Scale for Depression, the Hamilton Anxiety Rating Scale, the Stait Trait Anger Expression Inventory, the Barthel Index (BI) and the Mini-Mental State Examination (MMSE). Patients were assessed on day 7 and 14 of their rehabilitation admission.

41% of patients were diagnosed with major depression and a further 17% with minor depression. Patients with left hemispheric stroke and major depression were more cognitively impaired than patients in all other groups (left vs. right stroke, major vs. minor or no depression). This association persisted even when controlling for lesion location (p=0.0008). MMSE & HDRS scores were correlated among patients with left hemisphere stroke only (p<0.0001). Higher depression severity, higher anger-state severity and higher number of regions affected by stroke predicted lower cognitive level in patients with left-sided stroke. In patients with right-sided stroke, the presence of depression was not predictive of cognitive impairment.

Verdelho et al. (2004) France

202 patients admitted consecutively for acute stroke were included. Patients were assessed periodically over a 3-year period (1, 6, 12, 24 & 36 months). Depression was assessed via the Cambridge Mental Disorders for the Elderly examination and the Montgomery Asberg Depression Rating Scale. Dementia was assessed via the MMSE and the Mattis Dementia Rating Scale.

At the 6-month assessment there was a greater proportion of patients with depressive symptomatology among patients who were suffering from dementia (p=0.006). At 12, 24 & 36 month this association was reported as a nonsignificant trend. The time course of specific depressive symptoms varied between patients with dementia and no dementia. At 36 months, slowness, psychic slowness, lack of energy and concentration difficulties were more frequent among depressed patients with dementia than among those who were not demented.

Barnes et al. (2006) USA

A prospective, longitudinal study (6 years) of 2220 community dwelling adults having no cognitive impairment and aged 65 or over at baseline. 799 participants had MRI evidence of vascular disease (large or small infarcts, or

high white matter grade 4). 106 presented with a history of vascular disease at baseline.

Depressive symptoms were associated with greater odds of developing mild cognitive impairment (MCI) (low depression OR = 1.38, mod – high depression OR = 2.20). While, participants with more depressive symptoms were more likely to have vascular disease (either by history or evidence on MRI), there was no interaction between the presence of vascular disease and depressive symptoms. However, patients with evidence of vascular disease either on MRI or by history were at greater risk for developing MCI than those with no vascular disease (OR = 1.63 & OR = 1.55 respectively).

Saxena et al. (2008) India & Singapore

The prevalence of PSD and cognitive impairment no dementia (CIND) was examined in 252 stroke patients admitted consecutively to 2 community hospitals on admission, planned discharge and at 6 months post stroke. Baseline risk factors for PSD and CIND at 6 months were identified.

On admission, depressive symptomatology was identified in 60% of patients while CIND was identified in 54%. By the time of discharge, there was a significant decrease in both the symptoms of depression and of cognitive impairment (p<0.05). However, corresponding improvement was not noted at 6 months. Baseline variables significantly associated with depression at 6 months were dependence in ADLs (OR = 5.28), cognitive impairment (OR=4.78) and recurrent stroke (OR-3.34).





http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0404.2007.00922.x/abstract?deniedAccessCustomisedMessage=&userIsAuthenticated=false


Baseline variables significantly associated with CIND at 6 months were age ≥76 yrs (OR=8.07), cognitive impairment at admission (OR=6.94), depression (OR=3.5) and dysphagia (OR=4.58).

Bour et al. (2010) Netherlands

116 individuals with stroke were followed for 2 years following the first ever stroke. Assessments were conducted at 1, 6, 12 and 24 months and included the 90-item symptom checklist (SCL-90) depression subscale and a composite score based on evaluations of executive function (Stroop Colour Word Test and Concept Shifting Test). In addition, patients were tested using both the MMSE and the CAMCOG evaluation.

46% of patients were identified with possible depression on the SCL-90 depression subscale; 24% had depression only, 22% demonstrated symptoms of depression and of executive dysfunction. An additional 11% of patients were identified with executive dysfunction (but no depression). Overall, individuals with executive dysfunction were older, had lower scores on cognitive testing, had more difficulties with activities of daily living and were more often depressed than those individuals with no executive dysfunction. In a multiple regression corrected for age, gender and diabetes, SCL-90 depression scores were identified as a significant predictor of executive dysfunction. Overall, patients with depression had lower scores on cognitive testing, more often had executive dysfunction and more difficulty with activities of daily living than non-depressed individuals. However, on regression analysis, executive function was not a significant predictor of depression. In depressed patients with no executive dysfunction, symptoms of depression improved significantly over time. However, in individuals with both depression and executive dysfunction, depression scores did not change significantly.

Discussion Overall, there appears to be a relationship between cognitive impairment and the presence of depression, although the reported results vary and the relationship appears complex. As is the case for many of the factors with which PSD has been associated, it is difficult to determine whether cognitive impairment results from depression, is a risk factor for depression, or both (Andersen et al. 1995; Bour et al. 2010; Saxena et al. 2008). Mostly recently, Bour et al. (2010) demonstrated that, over time, the presence of depression was a significant predictor for executive dysfunction, while the presence of executive dysfunction was also associated with depression. Based on a large sample of older adults (n=6,476) Chodosh et al. (2010) demonstrated that incident and prevalent depression along with stroke and functional deficits may be significant contributors to poorer cognitive functioning in a stepwise fashion; that is, depression or stroke may have a negative impact on cognitive function at the time of their onset. However, the presence of depression was not associated with continued deterioration in cognitive function over time. The authors note that depression, chronic disease and physical function probably have multidirectional relationships that confound our attempts to understand causation. However, Murata and colleagues (2000) demonstrated that, in 41 stroke patients with major depression diagnosed in an acute hospital setting, improvement in depression over 3 – 6 months was associated




with significantly greater increases in cognitive function when compared to depressed individuals with no mood improvements. The authors suggest that, since patients with major depression whose mood improved experienced greater cognitive improvement than any other group of study participants, depression leads to cognitive impairment and produces a “dementia of depression”. Further study is required to clarify the association between cognitive impairment and depression following stroke.

Conclusion Regarding Cognitive Impairment and Depression Post-Stroke Post-stroke depression appears to have a negative impact on cognition, particularly at the time of onset; however, the relationship between depression and cognitive impairment is likely reciprocal. Further research is required.

Post-stroke depression is associated with cognitive impairment.

18.5.4 Mortality and Depression Post-Stroke Recent attention has been paid to the association between depression and mortality. The presence of depressive symptomatology has been reported to be associated with an increase in stroke mortality. In a community-based sample followed for a period of 29 years, Everson et al. reported that the presence of 5 or more depressive symptoms was associated with a significant increase in risk for mortality from stroke in individuals who were healthy, and stroke free at the beginning of their surveillance (HR = 1.66, p<0.006) (Everson et al. 1998). This association maintained significance after adjustment for education, alcohol consumption, smoking, body mass index, hypertension and diabetes (HR=1.54; p<02). Every point increase in depressive symptomatology was associated with an 8% increase in risk for stroke mortality (p<0.003) (Everson et al. 1998). Similarly, Kamphuis et al. (2006) reported that, in a 10-year prospective study of 799 men who had no cardiovascular disease and were aged 70 – 90 at baseline, the risk of death from stroke increased as depressive symptomatology increased. Each 5-point increase on the Zung Self-rating Depression Scale was associated with a 35% increase in the risk for death from stroke HR = 1.35 95% CI 1.19 – 1.53 adjusted for country of origin, education, BMI, smoking, alcohol intake, cholesterol levels and level of physical activity). When compared to individuals with low symptomatology at baseline, individuals with high levels of depressive symptomatology were more than 3 times as likely to die from stroke (HR = 3.41 95% CI 1.69 – 6.90). Depression has also been linked to higher mortality among elderly patients with physical illness; however, how moods are linked to mortality remains unclear (House et al. 2001; Lewis et al. 2001; Morris et al. 1993). Individual studies focusing on the association between post-stroke depression and mortality appear in Table 18.9.

Table 18.9 Mortality and Depression Post-Stroke


PEDro Score

Methods

Outcomes


103 patients were assessed for major or dysthymic depression 2 weeks post stroke with use of structured mental examination and DSM-III diagnostic criteria. Life status determined for 91 patients 10 years later.

53% of the patients died. Those with either major or minor depression were 3.4 times more likely to die than non-depressed patients during the follow-up period. Patients who were depressed and socially isolated seemed to be most vulnerable.

House et al. 448 stroke in-patients were seen 1 month post-stroke Mood symptoms on a self-report rating scale





(2001) UK

and reassessed at 12 and 24 months. Mood symptoms were assessed via the Present State Examination and the General Health Questionnaire.

were associated with 12- and 24-month mortality after stroke, after adjustment for factors associated with stroke severity. Psychiatric disorders such as major depression, (according the International Classification of Disease, 10

th Revision), were not statistically

significantly associated with increased mortality at 12 or 24 months.

Lewis et al. (2001) UK

272 stroke patients were observed to determine whether attitude toward illness, as assessed by the Mental Adjustment to Stroke Scale, was associated with survival after stroke.

Fatalism and helplessness/hopelessness were both associated with decreased survival while fighting spirit, anxious preoccupation and denial/avoidance were not. Mood was not associated with survival.

Williams et al. (2004) USA

From the US Veteran’s Affairs administrative database, 51,119 patients hospitalized with ischemic stroke between 1990 & 1998 were identified. 55 patients with depression were identified and matched with 47 patients with other mental or substance abuse diagnoses and 95 patients with no recorded mental disorders or diagnoses. Using data extracted for the subset of patients, the relationship between the presence of PSD, other mental disorders, substance abuse and mortality was examined. Admission stroke severity was not significantly different between patients with and without PSD.

After controlling for cardiovascular risk factors and mortality risk associated with co-morbid conditions (assessed via the Charlson Index), the presence of PSD increased the risk of death by 13% (HR = 1.13, 95% CI 1.06 – 1.21). The presence of other mental disorders or substance abuse diagnosis also increased the risk of death (HR = 1.13, 95% CI 1.07 – 1.22).

Almeida & Xiao (2007) Australia

Administrative records of individuals with first –ever stroke and no previous mental health disorder were identified and followed for 10 years following the index stroke event. 287 individuals for whom mental health disorders were recorded in the first 2 years post stroke were paired with 287 age and gender matched control patients.

Cumulative incidence rates for mental health disorders were calculated using 1008 stroke patient records. 36.6% of patients received a mental health diagnosis – approximately ½ of these within the first 6 months. Rate of depression or dysthymia was 5.5% (0.91 per 1000 person years). Of the mental health disorders, only dementia and psychotic disorders significantly increased the risk for mortality (RR=1.78, p=0.011 & RR=2.03, p=0.005). On regression analysis, depression/dysthymia was not a significant predictor of mortality (HR = 1.26, p=0.436).

Reynolds et al. (2008) USA

Data from the first 3 waves of the AHEAD (Asset and Health Dynamics Among the Oldest Old) study were analysed to determine the relationship between depression, chronic disease and total life expectancy (TLE), disabled life expectancy (DLE) and active life expectancy (ALE = TLE - DLE) in men and women aged 70 and 85. Assessment of depressive symptomatology was via inclusion of the 8-item short form of the CES-D.

In both men and women and in both age groups, the presence of depressive symptomatology was associated with significant reduced total life expectancy. Similarly, the presence of stroke was associated with significant reduction in total life expectancy. However, in individuals with stroke, the presence of depressive symptomatology was not associated with significant further reductions in total life expectancy in either men or women aged 70 or 85. The presence of depressive symptoms in addition to stroke was associated with significant reductions in active life expectancy compared to individuals with stroke but no depressive symptoms (i.e. absence of difficulty in performance of any function







necessary for activities of daily living).

Naess et al. (2010) Norway

771 patients with stroke were screened for prior history of depression and use of SSRI medications. As inpatients all patients had CT or MRI and the NIHSS and modified Rankin Scale (mRS) was administered. Patients received a postal questionnaire (HADS-D) sent 6 months following stroke. Presence of PSD was defined as HADS-D score ≥11 points.

On logistic regression analysis, PSD was independently, and significantly, associated with prior depression, being unmarried, having a stroke in progression. There was a trend toward a significant association with higher age and a history of previous stroke. Among those individuals that returned completed questionnaires, mortality was significantly and independently associated with the presence of PSD (HR=4.4, p=0.002) and age (HR=1.08, p<0.001), but not with gender (p=0.28). For individuals who did not complete questionnaires (and therefore could not be assessed for PSD), mortality was significantly and independently associated with prior depression (HR=1.7, p=0.01), age (HR=1.06, p<0.001), mRS scores (HR=1.7. p<0.001) and MI (HR=2.2, p=0.001).

Peters et al. (2010) UK

Analysis of data from HYVET (Hypertension in the Very Elderly Trial) in which 2,656 participants completed the Geriatric Depression Scale (GDS) at baseline and annually thereafter. Approximately 8 – 9% of individuals in both the control and treatment arms of HYVET reported previous stroke at study entry, while 11-15% reported history of cardiovascular disease. For the purposes of this study, depression was defined as GDS score ≥6 points.

40.8% of individuals with previous cardiovascular disease were identified as depressed. Overall, GDS≥6 at baseline was associated with increased risk of all-cause mortality (HR=1.8, 95% CI 1.4-2.3), all stroke (HR=1.9, 95% CI 1.3-2.8), cardiovascular mortality (HR=2.2, 95% CI 1.6-3.1) and all cardiovascular events (HR=1.7, 95% CI 1.3-2.2). These relationships did not lose significance when examined by subgroups, including those individuals with previous history of cardiovascular disease.

Ellis et al. (2010) USA

Data was collected from 10, 025 participants in the National Health and Nutrition Examination Survey I (NHANES I) who were alive and interviewed in 1982 and had completed the depression assessment. Respondents were placed into one of 4 groups; 1) no stroke or depression (ref. Group), 2) no stroke with depression, 3) stroke, no depression and 4) stroke and depression present. Assessment of depression was based on completion of the CES-D (a self-report tool). Presence of depression was defined as CES-D score ≥16 points. Mean follow-up = 8 years. The main outcome was all-cause mortality.

Using individuals in group one as the reference, and adjusting for sociodemographic variables and clinical comorbidities, individuals with both stroke and depression had the greatest risk for mortality (HR = 1.88, 95% CI 1.27-2.79). Individuals with depression, but no stroke had the lowest risk relative to the reference group (HR=1.23 (95% CI 1.08-1.40). Individuals with stroke but no depression also had elevated risk (HR=1.74, 95% CI 1.06-2.85). Having both stroke and depression created the greatest risk, but the combination of each of these factors was not additive.

Pan et al. (2011) International

In an analysis from the Nun’s Study (n=78, 282), aged 54-79 in 2000 were followed through 2006. Associations between depression, diabetes and mortality were examined. Depression was defined as self-reported depression diagnosis, treatment with antidepressants or a Mental Health Index score ≤52. Study outcomes were all cause and cardiovascular disease specific mortality.

Age-adjusted relative risk for all-cause mortality in women with depression only was 1.76 (1.64-1.89) and 3.11 (2.7-3.58) in women reporting both diabetes and depression. Age adjusted relative risks for cardiovascular disease-related mortality were 1.81 for individuals with depression (1.54-2.13) and 5.38 for those with both conditions (4.19-6.91). Controlling for comorbidities (including stroke) resulted in an attenuation of effect; however, both depression







and diabetes are risk factors for stroke and other cardiovascular disease which may have resulted in an “over-adjustment”.

Discussion Overall, studies suggest that there is an association between psychological distress and mortality. Reynolds et al. (2008) demonstrated an association between the presence of symptoms of depression and shorter total life expectancy in both men and women aged 70 and 85. Although the reduction in life expectancy for individuals with depressive symptomatology and stroke (compared to stroke alone) did not reach significance, the presence of both variables was associated with a reduction in TLE of approximately 1.5 years in both men and women aged 70. Results of the study by Williams et al. (2004) demonstrated an increased risk for mortality for those patients with PSD and also indicated that other mental health conditions such as schizophrenia, major affective disorders (not depression), anxiety disorders, personality disorders and substance abuse/dependence have a similar association with long-term mortality risk. Results from House et al. (2001) and Lewis et al. (2001) suggest that the identified association may not be between depression and mortality per se, but is between a more general psychological distress and mortality instead. Further study is required to clarify this association in individuals who have experienced stroke.

Conclusions Regarding Mortality and Depression Post-Stroke The presence of mental health disorders post stroke, including depressive symptomatology, has been associated with an increased risk for mortality. Further study to clarify the association between psychological distress and mortality is required.

The presence of mental health disorders post-stroke is associated with increased risk for mortality.

18.6 Prevention of Post-Stroke Depression

Given the negative impact of post-stroke depression on stroke recovery, early initiation of antidepressant treatment in stroke patients to prevent the development of post-stroke depression has been investigated (Narushima et al. 2002; Palomaki et al. 1999). Individual studies examining the effectiveness of early initiation of antidepressant therapy in stroke patients are summarized in Table 18.10.

Table 18.10 The Prevention of Post-Stroke Depression


PEDro Score

Methods

Outcomes

Palomäki et al. (1999) Finland 8 (RCT)

100 stroke patients were involved in a double blind RCT of either 60 mg/d of mianserin or placebo for 1 year.

No significant difference between groups was found on the outcome measures Barthel Index, Hamilton Depression Scale and the Beck Depression Inventory.

Narushima et al. (2002) USA & Japan 8 (RCT)

48 nondepressed stroke patients were randomly allocated to receive treatment with nortriptyline or with fluoxetine or placebo for 3 months. Patients underwent psychiatric assessment using PSE modified to identify DSM-IV symptoms of depression and

During the treatment period, one minor depression was seen in nortriptyline group, three in the fluoxetine group and 5 in the placebo condition. Intention-to-treat analysis of active vs. placebo conditions revealed no





anxiety at initial and post treatment examination and again at 6, 9, 12 and 24 months.

significant difference between these 2 conditions. When treatment was discontinued, nortiptyline patients were more likely to develop depression and had significantly severe depression symptoms during the next 6 months compared to patients in the other 2 groups although there were no significant differences in prevalence of depression. At 9 months, active treatment groups had significantly greater frequency of depression than placebo at 9 months. There was no significant group difference at 12 and 24 months.

Rasmussen et al. (2003) Denmark 7 (RCT)

137 non-depressed stroke patients were randomized to receive either sertraline or placebo for the prevention of post-stroke depression.

Kaplan-Meier analysis demonstrated that sertraline has a significantly superior prophylactic efficacy compared to placebo. Overall, after 52 weeks of treatment, 8.2% of the sertraline-treated group developed depression compared to 22.8% of the placebo treated group assessed on the Hamilton Rating Scale for Depression.

Niedermaier et al. (2004) Germany 5 (RCT)

70 patients with acute ischemic stroke with no depression or use of antidepressants in the immediate pre-stroke period were randomly allocated to treatment with mirtazapine (n=35) or control (N=35). Patients in the treatment condition received 30 mg. once per day beginning one day after the qualifying stroke event, while control received no antidepressant medications. Patients were examined on day 7, 44, 90, 180 and 360.

40% of patients in the untreated control group developed post-stroke depression vs. 5.7% of treated patients (p<0.001). Of the 16 patients that developed PSD, 15 demonstrated remission of symptoms following treatment with mirtazapine.

Almeida et al. (2006) Australia 9 (RCT)

111 stroke patients were randomly assigned to receive either treatment with sertraline (50 mg once per day) or matching placebo. Treatment commenced within 2 weeks of a recent stroke event and continued for 24 weeks. Primary endpoint was development of significant symptoms of depression as assessed using the HADS-D scale or diagnosed by an attending physician. Patients were assessed at baseline, week 24 and week 52.

By 24 weeks, 21.6% of patients in the placebo condition and 16.7% of patients in the treatment condition were diagnosed with depression (OR = 0.8, p=0.59). Of the patients assessed at 52 weeks, 30% of placebo vs. 22.7% of treatment patients met the criteria for depression (ns). Treatment with sertraline did not result in improvements compared to the placebo group in terms of cognition, disability or mortality.

Robinson et al. (2008) USA 7 (RCT)

176 patients with no depression were randomly assigned to received 1 of 3 treatments within 3 months of stroke onset; i) escitalopram 10 mg/d (if <65 yrs, 5 mg/d for patients ≥ 65) ii) matching placebo or iii) problem-solving therapy (6 treatment sessions over 12 weeks + 6 reinforcement sessions over 9 months). Patients were evaluated using the structured clinical interview for the DSM-IV at 3, 6, 9 and 12 months.

Patients with a history of mood disorders were 5.2 times more likely to develop depression than those without (p<.001). Adjusted for previous history of mood disorders, patients assigned to the placebo condition were more likely to develop depression than individuals receiving either therapy with escitalopram (adj. HR= 4.5, 95% CI 2.4-8.2, p<0.001) or problem-solving therapy (adj. HR=2.2, 95% CI 1.4-3.5, p<0.001). On intention-to-treat analysis that included 27 patients who did not receive any treatment and assumed all untreated patients developed depression, escitalopram was still associated with a significantly reduced risk for depression







(23.1% vs. 34.5%, HR = 2.2 95% CI 1.2-39, p=0.007); however, problem-solving therapy was not (30.5% vs. 34.5%, HR=1.1, 95% CI 0.8-1.5, p=0.51).

Tsai et al. (2011) China 8 (RCT)

92 patients with first or recurrent ischemic stroke (within the preceding 4 weeks) and no depression were randomly assigned to receive either 50 mg milnacipran (titrated to 100 mg) per day, or matching placebo. Individuals with previous depression, those taking antidepressants or with possible, undiagnosed depression (HAM-D≥10) were excluded from the study. HAM-D (modified to remove item 14 – sexual behaviour), BI and NIHSS scales were administered at 3, 6, 9, and 12 month follow-up visits.

60.9% of patients completed the 12-month study. Incidence of depression was 2.22% in the treatment group and 15.22% in the control group. Side effects were reported by both groups – there was no significant between group difference reported for study withdrawal due to side effects. There was a statistically significant benefit associated with milnacipran over placebo (p=0.048).

Chollet et al. (2011) (FLAME study) France 9 (RCT)

118 patients were randomly assigned to receive either 20 mg/day fluoxetine or matching placebo within 5-10 days of stroke onset. Treatment continued for 3 months. All patients received usual rehabilitation care delivered by organised stroke teams. Primary study outcome was physical function assessed by the Fugl-Meyer scale. Secondary outcomes included depression (assessed using the MADRS scale). Assessments were conducted at baseline, day 30 and day 90.

Frequency of depression was significantly greater in the placebo group when compared to the treatment group (4 pts vs. 17, p=0.002). There was a significant between group difference reported in mean change in symptoms of depression over 90 days (p=0.032). Over the course of treatment, there was no change in depressive symptomatology in the treatment group (adjusted mean change = -0.1, 95% CI -2.1 to 1.9) while there was a significant increase in symptoms in the treatment group (adj. Mean change = 3.2, 95% CI 1.1-5.3). Change was adjusted for age, history of previous stroke and Fugl-Meyer score at baseline.

Discussion Overall, individual studies offer conflicting evidence with regard to prevention of PSD through pharmacological intervention. However, a positive trend toward protection against depression associated with prophylactic treatment appears to be present. Given that all of the studies summarized in Table 18.10 included only patients with no depression at baseline and used the appearance of depression as a primary study outcome, a pooled analysis of data was conducted to evaluate the effectiveness of pharmacological intervention in the prevention of depression following stroke (Figure 18.2). It should be noted that all but one study used an interview-based assessment to determine the presence of depression (Almeida et al. 2006). Pooled analysis of data demonstrated a significantly reduced risk for depression associated with pharmacological treatment (OR=0.38, 95%CI 0.24-0.61). Although there was no significant heterogeneity identified between studies, there are some notable differences such as variations in pharmacologic agents used, and length of treatment, that should be noted. Duration of treatment ranged from 3 months (Chollet et al. 2011; Narushima et al. 2002) to one year (Niedermaier et al. 2004; Palomaki et al. 1999; Rasmussen et al. 2003; Robinson et al. 2008; Tsai et al. 2011). Cases of depression presented in figure 18.2 were those recorded at the end of treatment in each study. Two of the studies that did not demonstrate a significant effect in favour of treatment reported a shorter duration of intervention; 3 months (Narushima et al. 2002) and 24 weeks (Almeida et al. 2006). Sudden cessation of preventative pharmacotherapy may be associated with an increased risk for post-stroke depression. In a follow-up to Robinson et al. (2008), Mikami et al. (2011) reported that 6 months





following discontinuation of treatment with escitalopram, study participants were at a significantly increased risk for developing depression when compared to those who had been assigned to either the problem-solving therapy or placebo study conditions (p=0.012).

Conclusion Regarding Prevention of Depression with Early Use of Antidepressants

There is strong (Level 1a) evidence that early initiation of antidepressant therapy, in non-depressed stroke patients is associated with reduced risk for the development of post-stroke depression. Further study is required to assess both duration of treatment and optimal timing for the initiation of therapy.

Early initiation of antidepressant therapy in non-depressed individuals is effective in preventing post-stroke depression

18.6.1 Care Provision and the Prevention of PSD The development of depression post stroke may also be influenced by the provision of regular contact, counselling and support within various models of care. The studies summarized in Table 18.11 have assessed the impact of care provision on the mental health and/or mood status of stroke patients.

Table 18.11 Impact of Care Provision Interventions on PSD


PEDro Score

Methods

Outcomes

Lincoln et al. (2003) UK 5 (RCT)

250 stroke patients and their informal caregivers were randomized to receive either Stroke Family Support Organiser (FSO) service which provided support, information to patients and carers and liaised with hospital or to standard care. Intervention was provided for up to 9 months and participants were assessed at 4 and 9 months.

There were no significant differences between groups on patients’ mood, independence in personal or instrumental activities of daily living, caregivers’ mood, strain or independence. The FSO group had better knowledge of stroke and was more satisfied with the service they received than the control group.

Burton and 176 inpatients with stroke were recruited from 2 district Patients in the intervention group were less

Study name Statistics for each study Odds ratio and 95% CI

Odds Lower Upper ratio limit limit p-Value

Palomaki et al. (1999) 0.957 0.259 3.533 0.947

Narushima et al. (2002) 0.314 0.071 1.392 0.127

Rasmussen et al. (2003) 0.325 0.118 0.897 0.030

Niedermaier et al. (2004) 0.091 0.019 0.441 0.003

Almeida et al. (2006) 0.727 0.265 1.998 0.537

Robinson et al. (2008) 0.321 0.106 0.967 0.044

Tsai et al. (2011) 0.143 0.016 1.252 0.079

Chollet et al. (2011) 0.173 0.054 0.555 0.003

0.341 0.219 0.529 0.000

0.01 0.1 1 10 100Favours Treatment Favours Placebo

Figure 18.2 Prevention of PSD

Meta Analysis





Gibbon (2005) UK 7 (RCT)

hospitals. Patients were randomly assigned to receive either extended stroke nurse follow-up post discharge (n=87) or usual care (n=89). Intervention included a single visit from a stroke nurse within 2 days following discharge to plan further follow-up. Subsequent follow-up/visits were determined according to need. Average number of contacts was 3. Contact was maintained for an average of 2 months. Control group participants received no further contact from the stroke nurse following discharge. Assessments included the Barthel Index, Nottingham Health Profile, Beck Depression Inventory, Frenchay Activities Index and the Caregiver Strain Index at 3 and 12 months post stroke.

likely to experience deterioration on the BI when compared to the control group (p=0.049) over 12 months. Intervention patients experienced greater improvement in perceived health than control patients (NHP, p=0.039). At 3 and 12 months, patients in the intervention group reported lower levels of emotional distress (p=0.01, p=0.037) and social isolation (p=0.045 and p=0.002) than the control group.

Joubert et al. (2006) Australia No Score

97 stroke patients, returned to their GPs for ongoing care management were assigned to receive either integrated care (n=46) or the control group (n=51). Integrated care patients received shared care: visits with the GPs at 2 weeks, 3 months, 6 months, 9 months and 1 year, ongoing consultations between GP and the patient’s neurologist, telephone calls prior to GP visits from the study coordinator in order to assess patient progress & screen for depression, transmission of information from telephone contact to the GP and follow-up telephone contact to discuss changes to medication and management, ongoing progress tracking to ensure that best-practice standards were being met and provisions to the GP of options for review, testing and treatment. Control patients were told that they would be contacted at 12 months to review test results and clinical data. Assessment at 12 months included London Handicap Scale, Carer Strain Index, PIE assessment, clinical status, Rankin scale, MMSE, BI, MOS-Social Support Survey and FAST.

80 of 97 patients remained for analysis at 12 months. More patients in shared care than the control group reached target BP, though this trend was not significant (p=0.11). Similarly, the mean cholesterol for patients in the shared group was lower than the control group (p=0.16). Exercise participation increased significantly among individuals in the shared care condition vs. control (p=0.048). At 12 months, 45% of individuals assigned to the control condition screened positively for depression vs. 20% of the shared care patients (p=0.06). A later report from Joubert et al. (2008) provided additional results from ongoing enrolment. Based on data from 186 patients (91 in integrated care, 95 in the standard care control group), the authors reported that individuals receiving integrated care demonstrated significantly fewer symptoms of depression (p=0.006) as assessed on the PHQ-9 (a 9-item self-report tool). At 12 months, 33% of patient in the treatment condition reported depressive symptoms compared with 55% of individuals receiving standard care.

Claiborne (2006) USA 5 (RCT)

28 patients with stroke were randomly allocated to intervention (n=16) or control conditions (n=12). The intervention condition was receipt of care coordination provided by a social worker. Care coordination consisted of a home visit (1 – 2 weeks following discharge from rehabilitation) followed by weekly telephone appointments 20 minutes – 1 hour in length over a 3-month period. Care coordination was characterized by ongoing monitoring of patient progress (biopsychosocial, service needs, self-care practices) and the use of a problem-solving approach to overcome barriers in these areas. Control received usual care.

There were no significant between group differences on the SF-36 physical components scale. However, significant differences were reported for the mental components scale (p<0.001), Geriatric Depression Scale (p<0.001) and adherence to prescribed regimens (p<0.05).

Watkins et al. (2007) UK 7 (RCT)

411 stroke patients were randomly allocated to either the treatment (n=207) or the control conditions (n=204). All patients received usual stroke care. Patients in the treatment condition also received 4 weekly, individual

A significant benefit on mood was associated with the treatment condition over usual care at 3 months (OR for normal mood = 1.60, p=0.03). Using a self-report (Yale) screening tool for








sessions of motivational interviewing. Sessions were conducted by the same therapist and lasted 30 – 60 minutes each. Motivational interviewing is a talk-based therapy intended to assist the patient in identifying personal goals for recovery and perceived barriers to achieving these goals. Patients are encouraged/ supported in the identification of solutions. Baseline assessments were conducted between 5 – 28 days following the stroke event. Initial appointments for motivational interviewing were set at the time of randomization. Outcomes were assessed via mailed questionnaire at 3 months. Primary outcome was mood as assessed on the GHQ-28.

depression, a protective effect of motivational interviewing was also identified (OR = 1.65, p=0.03). Motivational interviewing was not associated with reduced risk for dependency or morality.

Watkins et al. (2011) UK (follow-up study)

125 patients assigned to the control group and 164 assigned to the intervention participated in the 12 –month follow-up to Watkins et al. 2007). Analysis was conducted on an intention to treat basis.

At 12 months, the significant benefit associated with motivational interviewing appeared to be maintained (OR for normal mood = 1.66, 95% CI 1.08-2.55, p=0.02). The previously identified protective effect vs. depression (based on the Yale screening tool) was not present at 12 months (OR = 1.1, 95% CI 0.74-1.64, p=0.80).

Discussion Based on the studies summarized above, there is evidence that involvement in ongoing contact, counselling and support may decrease deterioration of mental health and/or mood state following stroke (Burton & Gibbon 2005; Claiborne 2006; Joubert et al. 2008; Joubert et al. 2006). Both studies by Joubert et al. (2008; 2006) and Claiborne (2006) included increased screening for the identification of depression. In the care coordination model of Claiborne (2006), social workers provided some counselling as necessary, or referred the patient for more extensive health services as deemed appropriate. Overall, ensuring that mental health issues were identified and addressed was associated with improved mental health, quality of life and a reduction of depressive symptoms. A single intervention evaluated the use of a specific intervention, motivational interviewing, and reported similarly positive results (Watkins et al. 2007). However, it was not clear whether the benefit associated with assignment to the motivational interviewing intervention could be attributed to the talk-therapy technique itself, or to the ongoing, increased, individualized attention and perceived support. Further study using an attentional control group may serve to clarify this issue.

Conclusions Regarding Care Provision and the Prevention of PSD There is strong (Level 1a) evidence that ongoing individualized contact and support provided via various care provision models is associated with less deterioration of mood and/or mental health state following stroke.

Ongoing, individualized contact and support may reduce the risk for deterioration of psychological health following stroke.




18.6.2 Dietary Supplementation

18.6.2.1 Omega-3 Fish Oil There has been considerable debate regarding the possible association between omega-3 polyunsaturated fatty acids and depressive disorders. Hibbeln (1998) proposed a simple, correlational model demonstrating an inverse association between fish consumption and prevalence of major depression based on the results of a multinational study. While some subsequent reports have provided support for this apparent association, other studies have shown no association at all between omega-3 PUFAs and depression (Appleton et al. 2010). However, numerous trials have been conducted to assess the potential for omega-3 fatty acids as a treatment for or prophylactic measure against depression. In a recent meta-analysis, Appleton et al. (2010) identified 35 randomized controlled trials evaluating the impact of omega-3 fatty acids on depressive symptomatology. Of these 35 trials, the authors were able to include 29 studies in a pooled analysis which demonstrated a significant treatment effect in favour of omega-3 PUFAs. The positive treatment effect appeared to be limited to trials enrolling individuals with a diagnosed depressive disorder (SMD = 0.41, 95% CI 0.26-0.55) vs. trials that included individuals with no depression (SMD=0.22, 95% CI -0.01-0.44). It should be noted that all pooled analyses demonstrated significant heterogeneity, perhaps due to publication bias (Appleton et al. 2010). Of the 35 trials identified in the Appleton et al. analysis, none were conducted in the population of individuals with stroke (Appleton et al. 2010). A single RCT has examined the impact of fish oil supplementation on mood following stroke (Table 18.26).

Table 18.12 Omega-3 Fish Oil Supplementation and Mood


PEDro Score

Methods

Outcomes

Poppit et al. (2009) Australia/New Zealand 9 (RCT)

102 stroke patients were randomly assigned to receive either 3 g/day encapsulated fish oil or a matching placebo oil (palm and soy oils). Assigned treatments were taken daily for a period of 12 weeks. Study outcomes included serum triglycerides, total cholesterol, lipoproteins, inflammatory and haemostatic markers, mood (GHQ-28) and HRQOL (SF-36). Assessments were performed at baseline and 12 weeks.

Compliance to treatment was approximately 90%. There were no significant effects reported for the primary study outcomes of serum triglycerides, lipids, inflammatory or haemostatic markers. There was a significant difference between groups reported for the total score of the GHQ-28 (p<0.04); however, this was attributable to a decrease in scores for the placebo condition. There was no effect of treatment on the depression subscale of the GHQ-28.

Discussion Poppitt et al. (2009) reported no significant impact on mood associated with a 12-week course of fish oil supplementation following stroke. It should be noted, that this study did not focus on individuals with depression, for whom this treatment has been identified as effective in other participant populations.




Conclusions regarding omega-3 fish oil supplementation and mood post stroke There is moderate (Level 1b) evidence that fish oil supplementation following stroke has no impact on mood.

Dietary supplementation with omega-3 fatty acids has no impact on mood post stroke.

18.6.2.2 B-Vitamins Depression and stroke share common cardiovascular risk factors. It has been suggested that elevated homocysteine may be one of these shared factors (Almeida et al. 2010). Previous studies have demonstrated that in older community-dwelling individuals, vitamin B12 deficiency may be associated with increased risk for depression (Kim et al. 2008; Tiemeier et al. 2002). As part of the Rotterdam study, Tiemeier et al. (2002) demonstrated that elderly individuals with lower levels of vitamin B12 (<258pmol/L) were significantly more likely to have a depressive disorder than individuals with normal levels of the vitamin (OR=1.63, 95% CI 1.03-2.58 adjusted for age, gender, general confounders, functional disability and the presence of cardiovascular risk factors). Similarly, in a sample of 40 individuals with first-ever lacunar stroke, Huijts et al. (2012) reported a significant association between vitamin B12 deficiency and both symptoms of depression and severe fatigue. Elevated levels of homocysteine and reduced levels of folate may also be associated with depression (Kim et al. 2008; Tiemeier et al. 2002); however, this association may be mediated by the presence of functional limitations (Tiemeier et al. 2002). A single study has examined the impact of B-vitamins on the risk for post stroke depression (Table 18.13)

Table 18.13 B-Vitamin Supplementation


PEDro Score

Methods

Outcomes

Almeida et al. (2010) VITATOPS-DEP Study Australia 10 (RCT)

This was an added substudy of the VITATOPS trial (a large multicenter RCT to evaluate the impact of B-vitamin therapy on risk for secondary stroke. Patients (n=563) with previous stroke /TIA were randomly allocated to treatment (n=284) with folic acid (2.0 mg/day), vitamin B6 (25 mg/day) & vitamin B12 (0.5 mg/day) or to treatment with matching placebo (n=279). The depression substudy included only individuals who did not fulfill criteria for a depressive disorder at baseline. Primary substudy outcome was development of major depressive disorder following randomization. Depression was assessed via the MINI interview based on DSM-IV criteria. Assessments were conducted every 6 months following baseline.

Mean length of follow-up was 6.9 years in the placebo group and 7.3 years in the treatment group (p=0.3). Compliance to treatment was approximately 80% in both groups. During the trial, more episodes of major depression occurred within the placebo group than in the group receiving vitamin therapy (23.3% vs. 18.4%; HR=0.48, 95% CI 0.27-0.86). At the final assessment, there were no between group differences in prevalence of depression; however, on logistic regression (adjusted for age, gender, antidepressant use, handicap, recurrence of stroke and presence of cognitive impairment), there was a non-significant trend toward reduced risk for major or minor depression associated with vitamin therapy (OR=0.58, 95%CI = 0.31-1.09) using intention-to-treat analysis. On per protocol analysis, the reduction in risk did reach significance (OR=0.48, 95% CI 0.25-0.91)




Discussion The results of a single RCT of high quality suggest that B-vitamin therapy may be protective for the development of depressive disorders following stroke. It should be noted, however, that this study was part of a larger effort to examine the impact of B-vitamin therapy on the recurrence of cardiovascular events. The optimal timing of for initiating vitamin therapy remains unknown as the average time from the index stroke event to study enrolment was 7 months. Given that the incidence of post stroke depression is highest in the first months following stroke, earlier initiation of preventive strategies might be more effective. In addition, the effectiveness of the vitamin therapy tested by Almeida et al. was not apparent until treatment had been administered for approximately 6 years (Almeida et al. 2010). Further study of duration, timing and dosage is required.

Conclusions Regarding B-Vitamin Therapy There is moderate (Level 1b) evidence that B-vitamin therapy, administered over a long period, may be associated with reduction in long-term risk for depression. Further study is required.

Long-term vitamin-B therapy may reduce risk for depression following stroke.

18.7 Pharmacologic Treatment of Post-Stroke Depression

Treatment of post-stroke depression may involve the use of medications, the rare use of electro-convulsive treatments and psychosocial therapies. Drug therapy for depression is based on the notion that depression is associated with an imbalance and under-activity of the cerebral noradrenergic and serotonergic systems. In a recent meta-analysis of 16 studies (including 6 studies from the Chinese literature) examining the use of antidepressants in individuals with post-stroke depression, Chen et al. (2006) reported a significant treatment response regardless of the definition of response used by individual study authors. In addition, treatment was associated with a significant reduction in depressive symptomatology on all scales used to assess outcome. Chen et al. (2006) also identified a relationship between duration and benefit of treatment. Pooled analysis of studies with treatment durations of 1 and 2 weeks revealed no significant treatment effects. However, from 3 weeks onward, demonstrated effects were, generally, of increasing significance. In an updated Cochrane review, Hackett et al. (2008) included 12 studies examining the use of pharmacological interventions for the treatment of PSD (Table 18.14). Like the Chen et al. (2006) review, Hackett et al. (2008) included trials examining a variety of agents initiated at a variety of times post stroke and for varying intervals. Using pooled analysis where possible, the authors concluded that use of pharmacotherapy was associated with a small, but significant, positive treatment effect. However, this should be considered in light of increasing reports of adverse effects associated with the use of antidepressant medications.

Table 18.14 Studies Included in Hackett et al. (2008)

Evaluation of Pharmacologic Interventions

Andersen et al. 1994 Fruehwald et al. 2003

Jiang et al. 2001a, 2001b Lai et al. 2006a

Lipsey et al. 1984 Murray et al. 2002

Ohtomo et al. 1991 Ponzio et al. 2001

Rampello et al. 2005 Reding et al. 1986 Wiart et al. 2000 Yan et al. 2002



18.7.1 Heterocyclic Antidepressants Cyclic antidepressants may block the reuptake of both serotonin and norepinephrine to different degrees within the cerebrum, thereby increasing the levels of these neurotransmitters in the brain. Finklestein et al. (1987) conducted a retrospective review study of 60 stroke patients with depression who were treated with one of several cyclic antidepressant drugs including doxepine, maprotiline, trazadone, desipramine, amitriptyline, imipramine or who received no treatments. It was found that only 17% of the untreated patients attained an improvement in depression scores compared to 40% of the drug responders. Furthermore, drug responders showed a greater improvement in depression change scores than non-drug responders or untreated patients. Although this was a comparative retrospective study it demonstrates the potential value of anti-depressants post stroke. There are several RCTs that have investigated the efficacy of heterocyclic drugs in the treatment of post-stroke depression (Tables 18.15 and 18.16).

Table 18.15 Heterocyclic Antidepressants in Post-Stroke Depression


PEDro Score

Methods

Outcomes

Lipsey et al. (1984) USA

39 stroke patients partook in a double blind, placebo controlled randomized trial evaluating

Patients who were treated with nortriptyline showed significantly greater improvement on the Hamilton

Nortriptyline treated group showed significantly greater improvement on the HDRS than the other 2 groups. Nortriptyline produced a significantly higher rate than fluoxetine or placebo in treating post-stroke depression, in improving anxiety symptoms and in improving recovery of activities of daily living as measured by the FIM.

Double blind, placebo controlled randomized crossover trial of 104 patients. 104 patients with stroke were randomly assigned to receive fluoxetine (10mg/day gradually increased to 40 mg/day), nortriptyline (dose of 25 mg/day gradually increased to 100 mg/day) or matching placebo over 12 weeks. Patients received 12 weeks of active treatment followed by a cross-over period of 12 weeks to placebo.

Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke (Robinson et al. 2000)

p=.002*

p=.05**

NS†

0

20

40

60

80

100

Su

cc

es

s R

ate

(%

)

Nortriptyline(1) Fluoxetine(2) Placebo(3)

Treatment

Treatment Success Rates

*Between (1) and (2); **Between (1) and (3);†Between (2) and (3)




8 (RCT) the efficacy of nortriptyline in treatment of post-stroke depression for six weeks with a single bedtime dose of 20mg during week 1, 50mg during week 2; late-starters received 70mg at week 1 & 100mg at week 2.

Depression Scale, Zung Self-Rating Depression Scale; the Present State Examination and on the Overall Depression Scores than those who received the placebo treatment.

Lauritzen et al. (1994) Denmark 7 (RCT)

This study involved a 6-week double blind RCT of imipramine plus mianserin and desipramine plus mianserin in 58 thromboembolic stroke patients with post-stroke depression. 25mg imipramine and 25mg desipramine given twice daily for the first week and thereafter dosage changed on basis of side effects to max dosage of 75mg twice daily. A fixed dose of 10mg mianserin was given the first wk and adjusted thereafter to a max of 30mg.

A significant mean improvement noted on the Melancholia Scale in favour of imipramine + mianserin.

Robinson et al. (2000) USA & Argentina 8 (RCT)

Double blind, placebo controlled randomized crossover trial of 104 patients. Patients randomly assigned to either fluoxetine (10mg/day gradually increased to 40 mg/day) or nortriptyline (dose of 25 mg/day gradually increased to 100 mg/day) or identical placebo given over 12 weeks. Patients received 12 weeks of active treatments and cross-over for 12 weeks of placebo treatment.

A significant time-by-treatment interaction was found on the repeated measure analysis of variance of the mean Hamilton Depression Scale score. Nortriptyline treated group showed significantly greater improvement on the HDRS than the other 2 groups. Nortriptyline produced a significantly higher rate than fluoxetine or placebo in treating post-stroke depression, in improving anxiety symptoms and in improving recovery of activities of daily living as measured by the FIM.

Discussion All 3 studies investigating the efficacy of heterocyclic antidepressants in post-stroke depression were of “good” quality. When compared to placebo, heterocyclic antidepressant medications demonstrated a significant treatment effect (Lipsey et al. 1984; Robinson et al. 2000). Robinson et al. (2000) compared a heterocyclic antidepressant with a serotonin reuptake inhibitor and found nortriptyline (a heterocyclic drug) to be more effective than the serotonin reuptake inhibitor fluoxetine. Robinson et al. (2000) observed nortriptyline improved the Hamilton Depression Scale scores significantly more than fluoxetine and/or placebo. In addition, the response rate of nortriptyline was significantly greater than both fluoxetine and placebo (Robinson et al. 2000). While the Lipsey et al. (1984) study results were promising, they noted confusion, drowsiness and agitation were significant side effects that may pose risks to elderly patients. Likewise, while the heterocyclic combination of imipramine and mianserin significantly improved melancholia scale scores, Lauritzen et al. (1994) noted that a significant number of patients dropped out of their study because of side effects. In all the studies mentioned, patients with myocardial infarctions were excluded. Furthermore, those with cardiac arrhythmias, heart block, urinary outlet obstructions and narrow-angle glaucoma are advised against the use of heterocyclic antidepressants and, indeed, the use of amine medications (including imipramine, amitripyline, nortriptyline or desipramine) has been linked to adverse cardiovascular, anticholinergic and antihistamine effects (Kumar 1999). Most recently, Steffens et al. demonstrated a significant association between use of tricyclic antidepressants and worsening of white matter lesions (OR = 1.77, 95% CI 1.07 to 2.94) (Steffens et al. 2008). Although the use of SSRI therapy was also associated with an increased risk for progression of white matter lesions, the effect was not significant.





The relatively high incidence of side effects associated with heterocyclic antidepressants, especially in elderly patients, must be taken into account when deciding on their use. Despite the risk profile associated with this class of medications, tricyclic antidepressants have been reported to be used commonly for the treatment of depression in the elderly. In a large collaborative study of aging (Brown et al. 1995), tricyclic antidepressants accounted for over 90% of the antidepressant medications used by study participants.

Conclusions Regarding Heterocyclic Antidepressants in Post-Stroke Depression There is strong (Level 1a) evidence that heterocyclic antidepressants improve depression post stroke. Side effects in elderly patients mean that these medications should be used with caution in that population.

Heterocyclic antidepressants improve post-stroke depression.

18.7.2 Selective Serotonin Reuptake Inhibitors (SSRIs) Selective serotonin-reuptake inhibitors selectively block serotonin-reuptake rather than blocking both serotonin and norepinephrine reuptake. They are commonly used to treat depression and have been studied in the treatment of post-stroke depression. Studies examining the use of SSRIs in the treatment of PSD are summarized in Table 18.17.

Table 18.17 Selective Serotonin Reuptake Inhibitors in Post-Stroke Depression


PEDro Score

Methods

Outcomes

Andersen et al. (1994) Denmark 8 (RCT)

66 stroke patients with depression 2 to 52 weeks after stroke participated in a double blind RCT of citalopram. Patients received either 20 mg/d of citalopram before bedtime if younger than 66 years old, 10 mg/d in older patients, or received a placebo.

Significant improvement was noted on the Hamilton Rating Scale for Depression (HRSD) and the Melancholia Scale with citalopram when compared to placebo

Robinson et al. (2000) USA & Argentina 8 (RCT)

Double-blind, placebo controlled randomized crossover trial of 104 patients. Patients randomly assigned to either fluoxetine (10mg/d gradually increased to 40 mg/day) or nortriptyline (does of 25 mg/day gradually increased to 100 mg/day) or identical placebo given over 12 weeks. Patients received 12 weeks of active treatments and crossed-over to 12 weeks of placebo treatment.

There was no significant difference between fluoxetine and placebo. Response rate of treatment was not significantly different between flouxetine and placebo. Fluoxetine induced significant weight loss in elderly patients.

Wiart et al. (2000) France

31 patients with post-stroke depression involved in a double blind RCT of 20mg/d of fluoxetine or a placebo

A significant improvement was noted on the Montgomery Ashberg Depression Rating Scale in

Table 18.16 Summary of Heterocyclic Antidepressants in Post-Stroke Depression Authors/Year PEDro

Score N Drug Result

Robinson et al. 2000 8 104 Nortriptyline +

Lauritzen et al. 1994 8 58 Imipramine + Mianserin

+

Lipsey et al. 1984 8 39 Nortriptyline +






8 (RCT) treatment. favour of the fluoxetine treatment group.

Fruehwald et al. (2003) Austria 9 (RCT)

54 patients suffering from moderate to severe post-stroke depression were randomized within 2 weeks of stroke to either treatment with fluoxetine or to placebo control.

Significant improvement was seen in both groups within 4 weeks; however no advantage of fluoxetine was noted at this time. Beck Depression Inventory scores of patients treated with fluoxetine decreased until the follow-up at 12 weeks whereas the scores increased in the placebo group. At long-term follow up, 18 months after inclusion, patients treated who had been treated with fluoxetine were significantly less depressed than placebo treated patients.

Murray et al. (2005) Sweden 9 (RCT)

123 stroke patients with either a major or minor depressive episode (defined according to the DSM-IV) were assigned to either the treatment or placebo conditions. 62 patients received sertraline (50 – 100 mg/day) and 61 received a matching placebo. Primary study outcome was change in MADRS score from baseline to weeks 6 and 26.

Both groups demonstrated significant improvements over the study period. There were no significant between group differences on the primary study outcomes whether the patient was diagnosed with major or minor depression. There was a significant difference between groups favouring treatment identified on the Emotional Distress Scale (p<0.05). Improvement in global quality of life was greater for those patients treated with sertraline at week 26 than for those patients in the control group (p<0.05).

Choi-Kwon et al. (2006) Korea 7 (RCT)

152 stroke patients with one of post stroke depression (average = 14 months post stroke), emotional incontinence or anger proneness were randomly assigned to receive either fluoxetine 20 mg/day (n=76) or matching placebo (n=79). Treatment continued for a period of 3 months. Primary outcomes were mean score on Beck Depression Inventory (BDI) for PSD, and percentage change in VAS score for emotional incontinence and anger proneness.

A total of 32 patients in the treatment group and 19 patients in the control group were diagnosed with PSD. The severity of PSD was judged to be mild (mean BDI = 19). Treatment with fluoxetine was not associated with a significant improvement in depression when compared to the placebo condition.

Discussion Of the 6 RCTs reviewed on the efficacy of selective serotonin reuptake inhibitors in post-stroke depression, all were of “good” quality. Three of these RCTs demonstrated positive results favouring the treatment of serotonin reuptake inhibitors while two studies demonstrated no evidence for its therapeutic effects (Table 18.18). A single RCT demonstrated benefits to quality of life associated with treatment but no improvement in assessments of depression.

Table 18.18 Summary of Serotonin Reuptake Inhibitors in Post-Stroke Depression

Author, Year PEDro

N Drug Main Outcome(s) Result

Anderson et al. (1994) 8

66 Citalopram +

Robinson et al. (2000) 8

104 Fluoxetine -

Wiart et al. (2000) 8

31 Fluoxetine +

Fruehwald et al. (2003) 9

54 Fluoxetine +






Although the drug’s effect in the Fruehwald et al. (2003) study was not evident at the first assessment, it should be noted that patients were included at 2 weeks post-stroke and the many therapeutic efforts that take place during the acute phase of stroke rehabilitation may facilitate spontaneous recovery from depression. However, the advantages of treatment with fluoxetine were observed at 12 and 18 weeks after treatment initiation. Response to treatment was reported to be quicker than for the heterocyclic drugs, taking effect 3 weeks into the treatment. Furthermore, side effects were found to be mild and transient and significantly less severe than those associated with the heterocyclic drugs. However, Robinson et al. (2000) noted that there was no significant difference between fluoxetine and placebo. Robinson et al. (2000) observed fluoxetine-induced significant weight loss in the elderly patients studied. In order to assess the overall effect of the administration of SSRIs on post stroke depression when compared with a placebo, we carried out a pooled analysis (Figure 18.3) based on the frequency of response to treatment. With the exception of the study by Choi-Kwon et al. (2006), all studies provided a definition of response to treatment (Table 18.19) and corresponding data reflecting number of “responders”. Some recent studies have examined the potential risks associated with the use of antidepressants in older individuals (Coupland et al. 2011; Wu et al. 2011). Both demonstrated increased risk for such adverse outcomes as stroke/TIA and mortality associated with use of antidepressant medication.

Murray et al. (2005) 9

123 Sertraline - + (QoL)

Choi-Kwon et al. (2006) 8

51 Fluoxetine -

Table 18.20 Studies included in the review by Tuunainen et al. (2009)

Benedetti et al. 2003 Bloching et al. 2000 Colombo et al. 2000

Fritzsche et al. 2001 a,b Giedke et al. 1989

Holsboer-Trachsler et al. 1994 Kripke et al. 1983, 1985, 1987, 1992

Loving et al. 2002 Mackert et al. 1991

Moffit et al. 1993 (dissertation) Neumeister et al. 1996 a,b

Prasko et al. 2002 Schuchardt et al. 1993

van den Burg et al. 1990 Yamada et al. 1995

Figure 18.3 Response to SSRI Treatment of Post-Stroke Depression



Coupland et al. (2011) identified a large cohort (n=65, 746) of individuals with depression between the ages of 65 and 100. In general, use of antidepressant medications were associated with significantly increased risk for a variety of adverse outcomes including all-cause mortality, attempted suicide/self-harm, falls, fractures and upper GI bleeding when compared to when antidepressants were not being used. The pattern of association with adverse outcomes varied with the class of drug examined. Overall, use of SSRIs was associated with the greatest risk for falls (HR=1.66, 95%CI 1.58-1.73) and hyponatraemia (HR=1.52, 95% CI 1.33-1.75) when compared to no use. Absolute risk for all-cause mortality was 10.61% for individuals taking SSRIs vs. 7.04% for individuals taking no antidepressants. It should be noted that although approximately 10% of identified records were for individuals with previous stroke, there were no analyses reported that examined this subgroup specifically. Rather, analyses were adjusted for the presence of previous stroke as a confounding factor. In a retrospective study conducted in the United States, Ried et al. (2011) demonstrated that treatment with an SSRI antidepressant prior to stroke only was associated with an increased risk for mortality following stroke (HR=3.12, 95% CI 1.6 to 6.09). However, SSRI treatment for depression both before and after the stroke was found to be protective for mortality when compared to no post-stroke treatment (HR=0.31, 95% CI 0.11-0.86).

Conclusions Regarding SSRIs in Post-Stroke Depression Based on the results of meta-analysis, there is strong (Level 1a) evidence that selective serotonin reuptake inhibitors are effective in the treatment of post-stroke depression. Further placebo studies should be conducted using a blinded administrator and an optimal treatment duration in order to address methodological differences across current studies.

SSRI antidepressants are effective in the treatment of post-stroke depression. Further study is required.

18.7.2.1 Adjunctive Light Therapy

Administration of bright light has been demonstrated to be effective, not only for the treatment of seasonal affective disorder, but also for non-seasonal depression. In a recently updated Cochrane review, Tuunainen et al. (2004) identified 20 studies (49 reports) examining the use of bright light vs. inactive placebo as a treatment for non-seasonal depression (Table 18.20). Overall, the treatment response was greater in bright light conditions than in control treatment groups, particularly in studies considered high quality. The majority of studies examined the use of light therapy in combination with drug treatment (14 of 20 studies). Evaluation of these studies alone revealed a significant effect in favour of bright light vs. control (SMD=-0.25, 95% CI -0.47 to -0.02). It should be noted that reporting quality was considered to be generally poor; studies were short, underpowered

Table 18.19 Criteria used to define response to treatment

Author, Year Definition of Response to Treatment

Andersen et al. (1994) 50% decrease in baseline Hamilton Rating Scale for Depression (HRSD) score

Robinson et al. (2000) 50% decrease in baseline HRSD score

Wiart et al. (2000) 50% decrease in baseline MADRS score

Fruehwald et al. (2003) HRSD score <13 at long-term follow-up

Murray et al. (2005) 50% decrease in baseline MADRS score



and did not report outcomes with sufficient detail (Tuunainen et al. 2004). The authors conclude that bright light therapy, administered during the first week of treatment, offers promising antidepressant efficacy. Studies examining the use of adjunctive light therapy in the treatment of PSD are summarized in Table 18.21.

Table 18.21 Adjunctive Light Therapy for Post-Stroke Depression


PEDro Score

Methods

Outcomes

Sondergaard et al. (2006) Denmark 5 (RCT)

63 patients with acute stroke who were diagnosed with major depression (DSM-IV) were included in the study. All patients were treated with 20 mg. citalopram daily for 4 weeks. At baseline, participants were randomly assigned to high or moderate light conditions. Intensity was manipulated via distance from the light source. High intensity conditions were 10,000 lux (30 cm) while moderate light was 4,000 lux (60 cm). Light therapy was conducted every morning for 30 minutes over 14 days. Assessments included the Hamilton Rating Scale for Depression (17 and 6 items versions) as well as the Bech-Rafaelsen Melancholia Scale (MES).

All patients experienced similar reductions in reported symptoms of depression over the first 2 weeks of treatment. At two weeks, there were no significant between group differences reported. At 4 weeks, however, there was a statistically significant reduction in depressive symptomatology on the HRSD-6 in favour of the high intensity light treatment vs. moderate intensity (p<0.05). There were no significant side effects reported and no patients left the study due to side effects.

Conclusions Regarding Adjunctive Light Therapy Based on the results of a recent meta-analysis, there is strong (Level 1a) evidence that the use of bright light therapy in conjunction with SSRI antidepressants is an effective treatment for non-seasonal depression, in general. There is moderate (Level 1b) evidence that adjunctive bright light therapy may be more effective than moderate intensity light therapy in the treatment of post-stroke depression. Further research is required to examine timing, duration and optimal intensity.

Bright light therapy may be an effective adjunct to treatment with SSRI antidepressants.

18.7.3 Selective Noradrenaline Reuptake Inhibitors (NARI) Selective noradrenaline reuptake inhibitors are a class of antidepressants that function to inhibit noradrenaline reuptake. Patients suffering from depression characterized by lethargy, slowness to initiate action and displaying “anergia, hypokinesis and hypomimia” are said to be suffering from a retarded depression (Rampello et al., 2005). Antidepressant treatment with SSRIs may be more appropriate to treatment of anxious depression, characterized by anxiety, insomnia, hostility, restlessness and trepidation. NRIs are proposed as an alternative to SSRIs for individuals experiencing retarded depression (Rampello et al., 2005). A single RCT has examined the effectiveness of the NARI, reboxetine, in the treatment of this specific form of post-stroke depression (Table 18.22).




Table 18.22 Reboxetine and Treatment of Post-Stroke Depression


PEDro Score

Methods

Outcomes

Rampello et al. (2005) Italy 8 (RCT)

31 patients who had experienced stroke within the preceding 12 months & were diagnosed with major or minor depression according to the DSM-IV criteria and who presented with the characteristics of retarded depression were randomly allocated to treatment or control conditions. Treatment consisted of 4 mg. of reboxetine twice daily (n=16) while the control condition received a matching placebo. Treatment continued for 16 weeks. Outcomes were assessed via the Hamilton Rating Scale for Depression

Patients in the treatment condition experienced significant improvement from baseline to 4, 8 & 16 weeks on both the Hamilton Rating Scale for Depression and the Beck Depression Inventory (p<0.01). There was no significant change reported for patients who were assigned to receive placebo. At each assessment time, comparisons to the placebo group revealed significant improvement on the part of patients enrolled in the reboxetine treatment group (p<0.01). The most commonly reported side effects associated with reboxetine treatment were dryness of fauces, constipation and hyperperspiration.

Discussion Treatment with reboxetine, a NARI, was associated with improvement in “retarded” depression over a 16-week course of treatment. During that time, no serious side effects were reported and no patients in the treatment condition withdrew from the study (Rampello et al., 2005). However, further study is required to assess the safety effectiveness of long-term treatment with reboxetine.

Conclusions Regarding the use of Selective Noradrenaline Reuptake Inhibitors in Post-Stroke Depression There is moderate (Level 1b) evidence that reboxetine, a noradrenaline reuptake inhibitor, is effective in reducing retarded post-stroke depression.

Reboxetine is an effective treatment for “retarded” post-stroke depression characterized by lethargy and slowness to initiate action.

18.7.4 Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) Venlafaxine and duloxetine is an antidepressant characterized by the inhibition of the reuptake of serotonin, norepinephrine and, to a lesser extent, dopamine (Staab & Evans 2000). The use of venlafaxine in the treatment of geriatric depression has been examined in several randomized controlled trials and open label studies. Results of these trials have supported the safety and efficacy of venlafaxine within this population (Staab & Evans 2000). Studies examining the use of this drug within the population of individuals with stroke are summarized in Table 18.23.

Table 18.23 Serotonin and Noradrenaline Reuptake Inhibitors in Treatment of Post-Stroke Depression


PEDro Score

Methods

Outcomes

Dahmen et al. 12 patients with recent stroke (within 2 weeks) and Treatment was well tolerated and treatment



http://stroke.ahajournals.org/content/30/3/691.long


(1999) Germany No Score

depression (DSM-IV diagnosis) were treated for 5 weeks with venlafaxine (75 mg/day for first 2 days, 150 mg/day for rest of the treatment period). Depressive symptomatology was assessed at baseline, after 2 weeks and at end of treatment using the HRSD and the MADRS.

was not discontinued in any cases. There were no cardiovascular or hepatic disturbances recorded with the exception of one case of elevated liver enzymes in one patient with chronic hepatitis. At 2 weeks, there was a positive treatment response recorded in 10/12 patients (reduction of ≥ 50% on HRDS). Scores on the MADRS showed a similar response.

Kucukalic et al. (2007) Bosnia & Herzegovina No Score

30 patients with PSD (within 3 months of the stroke event) were treated with venlafaxine over a period of 3 months. Assessments with the HRSD were performed at baseline, 1 month and at end of treatment.

There were significant reductions in depressive symptomatology at 1 and 3 months (p<0.001). At 1 month, there was notable improvement in 80% of patients and after 3 months of treatment, there was a clinical response (reduction of ≥ 50%) in 53.3% of patients and remission of depression in 26.6%. Two patients reported side effects (increase in blood pressure), but these were mild and transient.

Zhang et al. (2013) China 7 (RCT)

118 participants were randomly allocated to a control group or a duloxetine group. The treatment group received a daily dose of 30mg which was increased to up to 90mg/day (according to clinical need) for 12 weeks. Outcomes including National Institute of Stroke Scale (NIHSS), Hamilton Depression Scale (HAMD), SF-36 were assessed at 2, 4, 12 and 24 weeks post treatment.

Duloxetine was shown to be significantly reduce the incidence of minor and depression among individuals in the treatment group compared to the control group (p<0.05). The study reported improvement in the health domains on the SF-36 among individuals in the treatment group (<0.05).

Discussion Although venlafaxine has been demonstrated to be safe and effective when used in the treatment of geriatric depression, there is little evidence to support the use of this drug in individuals with PSD. In one RCT, duloxetine was shown to be an effective prophylactic in reducing the incidence of minor and major depression among individuals with ischemic stroke. Although the studies summarized in Table 18.21 reported positive results, both were small studies of single-group design. Controlled trials are required.

Conclusions Regarding Serotonin Norepinephrine Reuptake Inhibitors There is an absence of evidence regarding the effectiveness of venlafaxine and duloxetine, SNRI, as a treatment for post-stroke depression. Randomized controlled trials are required.

There is insufficient evidence regarding the use of venlafaxine and duloxetine for PSD. Randomized controlled trials are required.

18.7.5 Gamma Aminobutyric Acid Compounds (GABA) Nefiracetam is a novel cyclic gamma aminobutyric acid compound (GABA) with documented effects on neurotransmission, regional blood flow and glucose utilization. Use of nefiracetam for the treatment of post-stroke depression has been studied in a single randomized controlled trial (Table 18.24).





Table 18.24 Nefiracetam and the Treatment of Post-Stroke Depression


PEDro Score

Methods

Outcomes

Robinson et al. (2008) USA/Canada 8 (RCT)

159 patients with post-stroke depression were randomly assigned to receive 1 of 34 treatments: i) 600 mg nefiracetam (n=55), ii) 900 mg nefiracetam (n=48) or iii) matching placebo. Patients were evaluated (HRSD) at baseline, 4, 9 and 12 weeks (end of treatment)

There was no significant time X treatment effect of 600 mg or 900 mg nefiracetam when compared with placebo. There were no significant effects identified on an item-by-item analysis of the HRSD. A post hoc analysis identified a significant effect of treatment among the most severely depressed quintile of patients treated with 900 mg nefiracetam compared with placebo (p=0.05).

Conclusions Regarding Gamma Aminobutyric Acid Compounds There is moderate (Level 1b) evidence that the GABA compound, nefiracetam, is not more effective than placebo in the treatment of post-stroke depression.

Nefiracetam is not an effective treatment for post-stroke depression.

18.7.6 Psychostimulants in the Treatment of Symptoms of Depression Methylphenidate, presently approved for treating attention-deficit disorders, has been used in the treatment of depression in the elderly as an alternative to tricyclics or other antidepressants. The states of the depressed elderly are often described as suffering a “lack of interest and emotional involvement in one’s surroundings” and this has been attributed to patients described as “rehabilitation failures secondary to poor cooperation and motivation,” (Johnson et al. 1992). Psychostimulants such as methylphenidate usually are effective in treating this state of apathy. Several studies suggest that use of psychostimulants in the treatment of post-stroke depression may be an effective treatment. Methylphenidate has its effects in the cortical and subcortical areas of the brain and thus is thought to heighten mood by affecting several neurotransmitter systems, in particular the noradrenergic system. In addition, it blocks the reuptake of serotonin and norepinephrine and has dopaminergic activity. Therefore, it is thought that methylphenidate may affect post-stroke depression by correcting the depletion of biogenic amines caused by stroke and to relieve apathy (Johnson et al. 1992). Individual studies are summarized in Table 18.25.

Table 18.25 Psychostimulants for Post-Stroke Depression


PEDro Score

Methods

Outcomes

Lingman et al. (1988) USA No Score

Retrospective review of 25 stroke patients with a diagnosis of major depression by the DSM-III criteria occurring after stroke with no other precipitant than the stroke who had been given an adequate trial of methylphenidate. Only patients who showed complete remission of depression symptoms were rated as

52% of patients recovered completely from their depression. These responders did not differ significantly from the 12 non-responders on demographic characteristics, location of stroke and other variables. Mood usually improved within 48 hours with only 3 patients experiencing





responders. Patients who showed partial response, no response, or worsening of depressive symptoms were considered non-responders.

side effects.

Masand et al. (1991) USA No Score

Hospital charts of 17 patients with post-stroke depression who were treated with either dextroamphetamine or methylphenidate during a 5-year period were examined. Patients rated as markedly improved showed complete or nearly complete remission of all depressive symptoms. Those rated as moderately improved showed decided improvement in several symptoms without complete remission and those rated minimally improved showed a minor increase in mood or energy without improvement in other symptoms.

82% of patients showed improvement after psycho-stimulant treatment. 47% of all patients showed marked or moderate improvement in depressive symptoms. There were no significant differences between the two psycho-stimulants across the diagnostic categories for depression. 55% of those on dextroamphetamine as opposed to 33% of all patients receiving methylphenidate showed marked or moderate improvement. Patients improved quickly within the first 2 days of treatments. Side effects were noted in only 3 patients.

Johnson et al. (1992) USA No Score

10 stroke patients were placed on methylphenidate for treatment of post-stroke depression. 8 patients had an adjustment disorder with depressed mood, 1 with major depression, 1 had a combination of major depression and anxiety disorder and 8 had concomitant attention depression. All patients were observed to have cognitive deficits on initial evaluation.

Dose range of methylphenidate was 5mg (q.am.) to 15 mg (b.id.) and length of therapy ranged from 5 days to 1 month. 70% of all patients showed clinical improvement after therapy with methylphenidate. 3 patients did not respond to treatment.

Lazarus et al. (1992) USA No Score

10 patients meeting DSM-III-R criteria for major depression were followed up during a 3-week efficacy and side-effect trial of methylphenidate. Methylphenidate was begun at a dose of 2.5 mg or 5 mg p.o. q. a.m. and q. noon that was slowly increased to as much as 40 mg/day. Mean dosage used at about the 10

th day was 17.0 mg/day. A decrease ≥50% from

baseline on the Hamilton Rating Scale for Depression was considered significantly positive response to treatment and a decrease of 25% or greater in the HAM-D was considered a partial response to treatment.

80% of the patients showed either a full or partial response as measured by the Hamilton Rating Scale for Depression scores. 6 significant side effects were reported. No patient had to be discharged from the study.

Lazarus et al. (1994) USA No Score

58 hospital charts of elderly stroke patients with major depression (DSM-III-R criteria) that were treated with either methylphenidate (n=28) or nortripyline (n=30) were reviewed retrospectively.

53% of the methylphenidate treated patients experienced complete remission compared to 43% of the nortripyline treated patients. The speed of response was better in the methylphenidate group. There was no difference between the groups in adverse effects.

Grade et al. (1998) USA 7 (RCT)

A double blind RCT of 21 stroke patients comparing the efficacy of methylphenidate during stroke rehabilitation. Patients were randomized to receive either 5mg in the morning & 30mg before bedtime of methylphenidate or a placebo treatment.

Patients receiving methylphenidate scored lower on HAM-D (p=0.028) and the Zung scale (p=0.055). Significant improvement was also reported in patients receiving methylphenidate on the motor FIM (p=0.32). While scores on the FMA were higher in the treatment group, they did not reach significance (p=0.075).

Discussion Six studies examining the efficacy of psychostimulants for post-stroke depression were identified. One study was a retrospective single group intervention study, two were retrospective cohort studies, two









were single group intervention studies and one was a randomized controlled trial. Methylphenidate has been observed to have an early onset of action within 2 to 10 days of treatment onset whereas tricyclic antidepressants onset usually does not begin until 2 to 4 weeks after treatment has begun. The fast action of methylphenidate is of particular interest given patients are treated for a limited amount of time in a rehabilitation setting. It must be used with caution in individuals with cardiovascular disorders.

Conclusion Regarding Psychostimulants for Post-Stroke Depression There is moderate (Level 1b) evidence that methylphenidate is more effective than placebo in improving both symptoms of depression and functional recovery. Methylphenidate (a psychostimulant) has an earlier onset of action than traditional antidepressants.

Methylphenidate (a psychostimulant) appears to be effective in treating symptoms of depression and has an earlier onset of action than traditional antidepressants.

18.7.7 Melatonin Agonist in the Treatment of Depression Post Stroke Valdoxan is a melatonin receptor agonist and an antagonist of 5-HT2c serotonin receptors. This synergistic effect results in increased dopamine and noradrenaline release; however no effect on monoamines has been observed. In a meta-analysis, Valdoxam at a dose 25-50mg was found to decrease depression symptomatology by 2 weeks in individuals with major depression (Montgomery et al. 2006).

Table 18.26 Melatonin Agonist in Treatment for PSD


PEDro Score

Methods

Outcomes

Bogolepova et al. (2011) Russia No Score (Pre-Post)

40 individuals post stroke, aged 55-85 years were prescribed 25mg/day of valdoxan for 3 months. Outcomes including Hamilton Depression Scale (HDS) and the Hospital Anxiety and Depression Scale (HADS) were measured at baseline, 14, 30, 60 and 90 days of treatment.

Significant improvement in depressive symptoms were seen on the HDS and HADS by 2 weeks and continued to show improvement throughout followup (p<0.05). The HADS also found significant improvement in anxiety symptoms post treatment (p<0.05).

Discussion In one small pre-post study, found valdoxan is effective in the treatment of post stroke depression. The study found improvement in HDS and HADS depressive and anxiety symptoms post treatment and at follow up.

Conclusion Regarding Melatonin Agonist There is insufficient evidence that melatonin agonist are effective in management of PSD.

Melatonin agonist may be effective in management of PSD; however, more studies need to be conducted.




18.7.7 Care Management for Post-Stroke Depression A single randomized controlled trial has assessed the impact of a care management intervention on the effectiveness of treatment (including pharmacologic intervention) for PSD (Table 18.26).

Table 18.27 Care Management and Treatment for PSD


PEDro Score

Methods

Outcomes

Williams et al. (2007) USA 8 (RCT)

188 patients with depression 1-2 months post stroke were randomly allocated to receive either the Activate-Initiate-Monitor (AIM) intervention or control conditions. The AIM intervention consisted of 3 steps: 1) activate stroke survivors to understand and accept the diagnosis of depression and its treatment 2) initiate antidepressant medication 3) monitor treatment effectiveness (including dose adjustment and medication change as necessary). The control condition consisted of usual care plus an identical number of baseline and telephone sessions as were received by the treatment condition in order to control for an attention effect. The primary study outcome was proportion of patients who had achieved significant response (HRSD <8 or 50% decline in score) following 12 weeks of treatment.

Compared to control participants, patients receiving the AIM intervention were more likely to demonstrate the defined response on the HRSD (51% vs 30%, p=0.005). This significant difference in favour of intervention was confirmed on multivariate regression, controlling for the influence of important covariates (age, race, sex, presence of caregiver) (p=0.037). Significant between group differences emerged at 6 weeks and were maintained at 12.

Discussion The care management intervention implemented by Williams et al. (2007) was associated with significant improvement in depressive symptomatology over the course of 12 weeks. This significant improvement was particularly notable in that 56% of individuals in the control or usual care condition also received treatment with antidepressants and an equal number of contacts as the intervention group.

Conclusion Regarding Care Management There is moderate (Level 1b) evidence that an active care management program including patient education and ongoing monitoring may enhance effectiveness of pharmacologic treatment for post stroke depression.

Active care management in conjunction with antidepressant therapy may improve response to treatment.

18.7.8 Alternative Medicine Given general concerns regarding potential side effects from the use of antidepressants, individuals with depression may choose to self-medicate, often with herbal products (Davidson & Zhang 2008). Unfortunately, there is little evidence from controlled trials evaluating the use of these preparations for the treatment of depression.




The Chinese herbal preparation, Free and Easy Wanderer Plus (FEWP) is one such alternative medicine. FEWP is a combination of 11 herbal drugs and is used for the treatment of mood disorders. A recent randomized controlled trial of individuals with unipolar and bipolar depression demonstrated that treatment with a standardized preparation of FEWP was associated with greater improvement in greater reduction of depressive symptoms and higher clinical response rates (≥50% reduction in HRSD scores) when compared to the placebo condition (Zhang et al. 2007). The use of this alternative, herbal medicine has also been examined in a group of individuals with post-stroke depression (Table 18.27).

Table 18.28 Herbal Medicine and the Treatment of PSD


PEDro Score

Methods

Outcomes

Li et al. (2008) China 8 (RCT)

150 individuals with recent stroke (within 6 weeks) and depression were randomly assigned to receive either1) FEWP (18 mg twice daily), 2) fluoxetine monotherapy (titrated from 20 – 40 mg /day) or 3) matching placebo. HRSD and BI scores were obtained at weeks 2, 4 and 8 (end of trial). Positive clinical response was defined as a reduction in HRSD scores ≥50%.

No serious side effects were reported. Patients complaining of nausea (n=2,6 & 3 in the FEWP, fluoxetine and placebo groups respectively) were treated with massage. At 2 weeks, there was a significant decrease in HRSD scores in the FEWP group vs. placebo (p<0.01), but not in the fluoxetine group. At 4 weeks and 8 weeks, there was a significant decrease in HRSD scores vs. placebo in both of the treatment groups (p<0.01). Scores were not significantly different between the FEWP and fluoxetine groups. There were significantly more responders in the FEWP group than the fluoxetine group at 2 weeks (15% vs. 3.3%, p<0.05). At 4 & 8 weeks, there was no significant difference between treatments for % of participants who demonstrated a clinical response. Over time, BI scores increased in all 3 groups. At the end of the trial patients in both treatment groups demonstrated significantly greater improvements than those in the placebo group (p<0.01) and patients receiving FEWP improved more than those receiving fluoxetine (p<0.01). At 2 and 4 weeks there were no significant between-group differences reported.

Discussion In the sole study identified to date, treatment with FEWP appeared to be as effective as fluoxetine when used in the treatment of post-stroke depression within the first 6 weeks of a stroke event. In addition, FEWP appeared to have an effect on both the experience of depressive symptomatology and the recovery of physical function sooner than fluoxetine (Zhang et al. 2007). However, it should be noted that relatively little is known about the specific effects of each of the components in FEWP and how each of them might interact with other medications commonly prescribed to stroke patients (Davidson & Zhang 2008). Further research is required.

Conclusions Regarding Alternative Medicine




There is moderate (Level 1b) evidence that treatment with the herbal preparation, Free and Easy Wanderer Plus (FEWP), may be as effective as fluoxetine in the treatment of post-stroke depression.

The herbal medicine Free and Easy Wanderer Plus may be effective in the treatment of PSD. Further research is required.

18.8 Impact of Pharmacologic Treatment of PSD on Rehabilitation Outcomes

18.8.1 Functional Recovery Associated with Pharmacologic Treatment of Post-Stroke Depression As established earlier, depression has a negative impact on function and cognitive recovery and thus the appearance of post-stroke depression is believed to adversely affect the rate of recovery and rehabilitation of stroke survivors. A secondary analysis of data collected as part of the Activate-Initiate-Monitor (AIM) Study demonstrated that individuals reported improvement of in depressive symptomatology were more likely to be independent at 12 weeks post-stroke than those who did not improve over the same period of time (p=0.012) (Schmid et al. 2011). Saxena et al. (2007) examined both depressive symptoms and functional variables in a group of 141 stroke patients. Linear regression analysis demonstrated that greater change in BI scores from rehabilitation admission to 6 months was associated with better mood status at baseline and greater improvement in depressive symptoms (p=0.02 and p<0.001, respectively). Other significant predictors of functional recovery included baseline neurological status, neurological improvement, baseline functional status and age. The authors concluded that improvement in depressive symptomatology may accelerate functional recovery, but the level of function achieved is determined by neurological and cognitive factors. A non-RCT study by Gainotti et al. (2001) demonstrated that treatment with fluoxetine was associated with an improvement in functional recovery in addition to recovery from depression; a finding which is supported by Gonzalez-Torrecillas et al. (1995), Dam et al. (1996), Miyai and Reding (1998), and Narushima et al. (2003) (see Table 18.27). Although several studies also documented the effectiveness of treatment with nortriptyline in terms of physical function, Miyai and Reding (1998) noted that trazodone and fluoxetine improved self-care function and depression after stroke while nortripyline improved depression but not self-care. Serotonergic antidepressants should be further investigated for possible efficacy in promoting functional recovery in stroke patients undergoing rehabilitation (Dam et al. 1996; Gainotti et al. 2001; Miyai & Reding 1998). In addition, the effect of timing of treatment on the recovery of ADL requires further investigation. While the majority of studies examine the effectiveness of treatment initiated more than one month post stroke, the studies of Narushima et al. (2003) and Gonzalez-Torrecillas et al. (1995) focus on treatment beginning in the first month following the stroke event. Gonzalez-Torrecillas et al. (1995), in an open label study, demonstrated that early treatment, initiated within 4 weeks of the index event, was associated with significant improvements in physical, cognitive and neurological function by the end of the 6-week treatment period. Similarly, Narushima et al. (2003) report a significantly greater improvement in physical function over the active treatment period (12 weeks) for patients with early treatment initiation (within 4 weeks of stroke) than for patients whose treatment started later. In addition, during a “naturalistic” period of observation, patients with late



onset of treatment experienced gradual deterioration in function between 12 and 24 months post stroke while patients in the early treatment group continued to improve slowly over the same period of time. These significant between group differences were not attributable to time since stroke. Logistic regression controlling for treatment type, initial diagnosis, presence/absence of motor impairment, past psychiatric history and continued use of medication past the end of the treatment phase demonstrated a significant effect of early versus late treatment on FIM scores at 12 – 24 months (Narushima et al. 2003).

Conclusion Regarding Functional Recovery and Treatment of Depression Post Stroke There is strong (Level 1a) evidence that pharmacologic treatment of depression is associated with improved functional recovery post-stroke.

Pharmacologic treatment of post-stroke depression is associated with improved functional recovery.

18.8.2 Mortality and Pharmacologic Treatment of Post-stroke Depression In 1993, Morris et al. (1993) reported that stroke patients suffering from post-stroke depression were 3.4 times more likely to have died by 9-year follow-up than stroke patients without depression. Given the link between post-stroke depression and mortality (see section 18.5.4) the effect of treatment on mortality has been evaluated. One randomized controlled trial evaluating the effect of antidepressant treatment on post-stroke mortality was identified.

Table 18.29 Summary of Stroke Recovery after Treatment of PSD with Antidepressant Medications (Clinical Trials)

Author, Year PEDro Score

Drug Recovery Outcome

Mikami et al. (2011) fluoxetine or nortriptyline

mRS + (1 yr. follow-up of Robinson et al. 2000)

Narushima et al. (2003)

nortriptyline or fluoxetine

Physical function

+ early treatment vs. later treatment

Chemerinksi et al. (2001)

nortriptyline ADL + When depression remitted

Robinson et al. (2000) fluoxetine or nortriptyline

ADL -

Wiart et al. (2000) fluoxetine ADL -

Miyai & Reding (1998) desipramine, fluoxetine or

trazodone

Functional + (trazodone & fluoxetine)

Dam et al. (1996) maprotiline or fluoxetine

ADL and neurological

+ fluoxetine

Raffaele et al. (1996) trazodone-HCI ADL - Pts. with +ve dexamethasone suppression

Gonzalez-Torrecillas et al. (1995)

nortriptyline or fluoxetine

Functional + (nortriptyline & fluoxetine)

Reding et al. (1986) trazodone (Desyrel)

Functional + Pts. with +ve dexamethasone suppression

Lipsey et al. (1984) nortriptyline Functional -



Table 18.30 Mortality and Treatment of Post-Stroke Depression


PEDro Score

Methods

Outcomes

Jorge et al. (2003) USA 7 (RCT)

104 patients were enrolled within 6 months of a stroke event. Depressed and non-depressed patients were randomized to receive a 12-week course of treatment with fluoxetine (n=40), nortiptyline (n=31) or placebo (n=33). Patients were assessed at enrolment, 3 6, 9 and 12 weeks. Mortality data was obtained for all patients at a maximum of 9 years after enrolment.

48.1% of patients had died by 9-year follow-up. Survivors were significantly younger (p=0.0005). There was no significant association between depression at baseline and long-term mortality. Survival analysis on an intention to treat basis demonstrated that the probability of survival was greater in patients who had been assigned to receive antidepressant treatment (p=0.03). Probability of survival was greater in patients who had completed antidepressant treatment (p=0.004). Improved survival was associated with treatment whether or not the patient had been depressed at the time of study enrolment (p=0.02 in depressed and non-depressed patients). The association between treatment and survival remained significant after taking age, stroke type, comorbid diabetes and depression relapse into account.

Discussion Early treatment with antidepressants, even for a relatively short period, may have a prolonged, protective effect on mortality rates following stroke (Jorge et al. 2003). Furthermore, the association between antidepressant treatment and improved survival was demonstrated not only in patients who were depressed at the time of study enrolment, but also in those who were not. The authors speculate that the use of antidepressant medications following stroke may alter pathophysiological mechanisms associated with mortality or with the development of later depression. In a retrospective study conducted in the United States, Ried et al. (2011) demonstrated that treatment with an SSRI antidepressant prior to stroke only was associated with an increased risk for mortality following stroke (HR=3.12, 95% CI 1.6 to 6.09). However, SSRI treatment for depression both before and after the stroke was found to be protective for mortality when compared to no treatment during the first year post-stroke (HR=0.31, 95% CI 0.11-0.86) as was SSRI treatment only after stroke (HR=0.57, 95%CI 0.25-1.32), though the post-stroke treatment effect did not reach statistical significance. After 7 years post stroke, SSRI use was again associated with increased mortality risk. Diagnosis of depression following stroke was, of course, associated with a significant increase in risk for mortality (HR=1.87, 95% CI 1.24-2.82).

Conclusions Regarding Mortality and Treatment of Post-Stroke Depression There is moderate evidence (Level 1b) that early treatment with antidepressants post stroke is associated with improved long-term survival. Further research is required.

Treatment with antidepressants following stroke may improve long-term survival.




18.9 Non-Pharmacologic Treatment of Post-Stroke Depression

18.9.1 Electroconvulsive Therapy Electroconvulsive therapy (ECT) is an older treatment for major depression that has traditionally been considered effective (Janicak et al. 2002).

Table 18.31 Electroconvulsive Therapy for Post-Stroke Depression


PEDro Score

Methods

Outcomes

Murray et al. (1986) USA No Score

Medical records of 14 patients who received ECT for post-stroke depression were reviewed.

12 patients demonstrated marked improvement in depression after ECT. A transitory cardiac arrhythmia developed in 1 patient but none of the patients had an exacerbation of stroke or a worsening of neurologic status.

Currier et al. (1992) USA No Score

Medical record of 20 medically ill geriatric patients who received ECT for post-stroke depression was retrospectively reviewed.

19 of 20 patients demonstrated a marked or moderate response to ECT. Only 1 patient did not improve with ECT. 7 of the 20 patients experienced a relapse approximately 4 months following ECT. 5 patients (25%) experienced significant ECT-related complications. An additional 3 patients experienced minor ECT-related complications. No patients experienced worsening of neurological deficits and ECT therapy was not associated with development of new neurological deficits.

Discussion Two retrospective studies suggest that ECT is a relatively safe and effective treatment for post-stroke depression, although Currier et al. reported that patients were at risk for relapse following ECT despite good initial responses and maintenance therapy with antidepressant medications (Currier et al. 1992). There have been no prospective controlled clinical trials evaluating the use of ECT in post-stroke patients.

Conclusions Regarding ECT for Post-Stroke Depression Based on two small, retrospective studies, there is an absence of evidence regarding the effectiveness of electroconvulsive therapy as a treatment for post-stroke depression.

There is insufficient evidence to evaluate the use of electroconvulsive therapy as a treatment for post-stroke depression.

18.9.2 Repetitive Transcranial Magnetic Stimulation Recent randomized controlled trials have demonstrated antidepressant effects associated with repetitive transcranial magnetic stimulation (rTMS) in populations of patients suffering from major depression (Grunhaus et al. 2003; Janicak et al. 2002; Loo et al. 2003). Treatment effects comparable to






those associated with ECT have been reported (Grunhaus et al. 2003; Janicak et al. 2002), although more modest results have been demonstrated among patients with resistant depression (Loo et al. 2003). Mild adverse effects were associated with rTMS. Randomized controlled trials examining the possible efficacy of rTMS in the treatment of PSD are summarized in Table 18.28.

Table 18.32 Repetitive Transcranial Magnetic Stimulation


PEDro Score

Methods

Outcomes

Jorge et al. (2004) USA 7 (RCT)

20 patients with stroke and DSM-IV diagnosis of depression were randomised to receive either active left prefrontal rTMS or sham stimulation to duplicate the appearance/sensation of treatment. Patients had failed to respond to 2+ trials of antidepressants. Treatments consisted of 10 sessions of active or sham stimulation over a 2-week period. Final assessment was performed 1 week following the last treatment.

Active rTMS treatment was associated with a significant reduction in depressive symptomatology on the HAM-D (p<0.0006). Cognitive and neuropsychological assessments were conducted to monitor for possible adverse effects. MMSE scores in the active treatment group increased by a mean 1.5 points, though this was not significantly different from the sham treatment group. There were no significant neuropsychological difference between the sham and active treatment groups demonstrated. All adverse events registered during the course of treatment were mild and included mild headache (6 patients), local discomfort at the stimulation site due to cap tightness (5 patients) and exacerbation of insomnia (1 patient).

Kim et al. (2010) Korea 8 (RCT)

18 individuals with stroke were randomly assigned to one of three treatment groups; low-frequency (1 Hz), high-frequency (10Hz) or sham (control) rTMS stimulation to the left dorsolateral prefrontal cortex (DLPFC). Patients received 10 treatment session; 5 times per week over a 2-week period). During the study period, all participants also received conventional cognitive rehabilitation 2 or 3 times per week. Assessment was conducted at baseline and immediately following end of treatment (2 weeks). Evaluations included the Computerized Neuropsychological Test (digit span, visual span, verbal learning, visual learning, visual continuous performance, auditory continuous performance & word-colour tests), the Tower of London Test (planning ability), the modified Barthel Index and Beck Depression Inventory.

Treatment at either frequency was not associated with any significant difference on any cognitive assessment including Tower of London reaction time when compared to the control group. However, treatment was associated with lower scores on the Beck Depression Inventory.

Discussion Both RCTs identified above reported improvement in depressive symptomatology; however, participants in the Kim et al. (2010) trial had not been diagnosed with depression at study entry. As in previous studies, in non-stroke populations, rTMS appears to be well tolerated by patients and was associated with mild adverse effects only. Both studies are very small and while Jorge et al. include patients with





PSD, they represent a select group in whom depression had proven resistant to pharmacotherapy (Jorge et al. 2004). A larger trial evaluating the efficacy of rTMS with citalopram maintenance therapy is currently underway (Jorge et al. 2004).

Conclusions Regarding Repetitive Transcranial Magnetic Stimulation There is strong (Level 1a) evidence that use of rTMS is associated with improvement in depressive symptomatology.

Use of repetitive transcranial magnetic stimulation is associated with reduced symptoms of depression.

18.9.3 Cognitive Behavioural Therapy Cognitive behavioural therapy is an active, directive, structured intervention for numerous psychological disorders. The approach is based on the notion that emotion and behaviour are determined by experience. Accordingly, cognitive behavioural therapy concentrates on altering and restructuring the individual’s interaction with their environment and their interpretation of their experiences. Therapy tools include behavioural tests, graded task assignments and scheduling of activities (Lincoln et al. 1997). Individual studies examining the use of cognitive behavioural therapy in the treatment of post-stroke depression are summarized in Table 18.29.

Table 18.33 Cognitive Behavioural Therapy for Post-Stroke Depression


PEDro Score

Methods

Outcomes

Lincoln et al. (1997) UK No Score

19 stroke patients who had scored more than 13 on the Beck Depression Inventory or more than 10 on the Hospital Anxiety and Depression Scale partook in an AB single case design where they received cognitive behaviour therapy administered by a community psychiatric nurse or by an assistant psychologist during the treatment period.

4 patients showed benefits of the treatment, 6 showed some benefits and 9 showed no benefits during the treatment period. For the group as a whole, there was a significant decrease in depression during the treatment period on the Beck Depression Inventory.


123 stroke patients admitted to hospital with >10 score on Beck Depression Inventory (BDI) or >18 on Wakefield Depression Inventory (WDI) were randomly assigned to receive cognitive behaviour psychotherapy (10 1hr. sessions over 3 months) (n=39) or standard care (n=41) or “attention placebo” (n=41; patients offered 10 visits over 3 months, but no formal therapy). Assessments at 3 and 6 months included BDI, WDI, EADL, London Handicap Scale and satisfaction with care.

No significant differences were reported on any measure.

Chang et al. (2011) China (RCT)

66 individuals with hemiplegic stroke were randomly assigned to receive either conventional care (prescribed medications + rehabilitation training) or conventional care in addition to counselling. Counselling consisted of knowledge and behavioural therapy (based on rational emotive behavioural therapy, a form of cognitive behavioural therapy). Counselling/behaviour therapy was provided weekly in sessions 1-2 hours in length for

Individuals assigned to the intervention group demonstrated significant improvements in state-anger, hostility, anger-out, anger control, anxiety, depression, QOL and functional ability over time (p<0.001 for all). When effect sizes for change were compared between groups, the authors reported that the treatment group demonstrated significantly greater improvement






1 month and included, belief change, forgiveness and anger management training. Education was also provided re: lifestyle risks and lifestyle changes to reduce risk for subsequent stroke. Assessments conducted before and after the intervention included the Chinese Versions of the Hamilton Depression Scale, the Hamilton Anxiety Scale, the Stroke specific Quality of Life scale, the Barthel Index and the State-Trait Anger Expression Inventory (STAXI).

than the control group in terms of state anger, anger control, depression, quality of life and functional ability. On analysis of variance, there were significant group X time interactions identified for state anger (F=24.57, p<0.001), anger-out (F=24.87, p<0.001), anger control (F=21.24, p<0.001), depressive symptoms (F=27.64, p<0.001), quality of life (F=41.96, p<0.001) and functional ability (F=24.2, p<0.001).

Johansson et al. (2012) Sweden 6 (RCT)

29 individuals aged 30-65yrs with mental fatigue for at least 1 year were included. Participants were randomized to a mindfulness based stress reduction (MBSR) training group or a control waitlist group. Individuals in the intervention group received eight weekly 2.5 hour sessions with guided instructions and CDs for home practice. Outcomes were assessed at baseline and post intervention including Mental fatigue (MFS) and comprehensive psychopathological rating scale (CPRS).

Significant improvement in the MFS outcomes were seen at 8 weeks between the MBSR group compared to the control waitlist group (p=0.008). Furthermore, significant decrease in depression and anxiety symptoms were seen based on time in individuals receiving treatment (p<0.002).

Thomas et al. (2013) UK 7 (RCT)

105 aphasic stroke patients with low mood based on the Stroke Aphasic Depression Questionnaire (SADQ) were randomly allocated to behavioural therapy or usual care group. Patients in the treatment group received 20 sessions of treatment over 3 months with focus on mood elevating activities such as activity scheduling and education. Outcomes including SADQ, Visual Analogue Self Esteem Scale and Nottingham Leisure Questionnaire were assessed at 3 and 6 months.

After controlling for baseline factors and communication impairments, a significant improvement in the SADQ and Visual analogue self-esteem scale was seen (p<0.05). These results remained significant for up to 6 months post intervention. No significant improvement in the Nottingham Leisure Questionnaire was seen.

Conclusions Regarding Cognitive Behavioural Therapy and Post-Stroke Depression There is conflicting evidence that cognitive behavioural therapy is effective as a treatment for post-stroke depression.

Cognitive behavioural therapy may not effective in the treatment of post-stroke depression. Further research is required.

18.9.3.1 Combined Therapy Although psychotherapeutic interventions have been successfully used in the treatment of other forms of depression, there has been little evidence to support their use in the treatment of PSD (Hackett et al. 2008). Supplementation of antidepressant use with therapy intended to change behaviours associated with depression could result in a more effective intervention (Mitchell et al. 2008). A single study examining the use of antidepressant therapy in addition to a psychosocial behavioural intervention was identified (Table 18.30).

Table 18.34 Combined Therapy


PEDro Score

Methods

Outcomes

Mitchell et al. 101 individuals with stroke (within the past 4 At baseline 60% of patients in each group






(2009) USA 7 (RCT)

months) and diagnosed with clinical depression were randomly assigned to receive either a brief psychosocial, problem-solving intervention + possible antidepressant medication or usual care + possible antidepressant medication. The psychosocial intervention consisted of 9 sessions over 8 weeks of problem-solving therapy and increased pleasant social and physical activity provided by a study interventionist. Usual care were treated by their primary care physician. Patients in both groups could be prescribed antidepressant medication as deemed appropriate. In the treatment condition, sertraline was the recommended first choice of possible medications. Medication use was tracked using a medication diary. Measures of depressive symptoms (HRSD), stroke impact (Stroke Impact Scale) and perceived recovery (Stroke Impact Scale and Barthel Index) were assessed at 9 weeks, 21 weeks, 12 months and 24 months.

were receiving antidepressant therapy. This rose to 77% in both groups at 8 weeks. Type of drug and dose were not standardized. There were significantly greater reductions in HRSD scores in the treatment than in the usual care group at 9 weeks (p<0.001) and at 12 months (p<0.023), though not at 6 weeks or 24 months. The percentage of patients in remission from depression (HRSD ≤9) was larger in the treatment vs. the usual care group at 9 and 21 weeks and at 12 months (p<0.001, p=0.008 and p=0.031, respectively), although the difference in favour of the treatment group diminished over time. Remission from depression was associated with better physical function (strength p<0.001, mobility p<0.001, and ADL p=0.004) and improved social participation (communication p=0.005, work and recreation p<0.001) at 12 months. Barthel Index scores demonstrated a trend toward improved recovery associated with depression remission (p=0.09).

Conclusions Regarding Combined Therapy There is moderate (Level 1b) evidence that the provision of a brief psychosocial intervention in addition to antidepressant therapy may be more effective than antidepressant therapy alone in terms of depressive symptomatology, functional ability and social participation.

Psychosocial behavioural therapy may be used as an effective adjunct to treatment with antidepressants.

18.9.4 Music Therapy The use of music therapy in the treatment of physical, cognitive, communicative, social and emotional rehabilitation has recently gained attention. Music therapy builds a relationship between the therapist and patients (or client) through the use of music, instruments and voice. Marwick (1996) reported that the use of music therapy in stroke rehabilitation might improve behaviour, communication and psychological state based on limited observations. Individual studies examining the effectiveness of music therapy are presented in Table 18.31.

Table 18.35 Music Therapy for Post-Stroke Depression


PEDro Score

Methods

Outcomes

Purdie et al. (1997) Scotland

In this quasi-randomised trial, 40 patients received either 12 sessions of music therapy (once weekly) or standard care (no music therapy). Assessments

Only 15 participants completed all assessments. Both the control group and treatment group demonstrated a decline in depression over the


http://journals.lww.com/intjrehabilres/Citation/1997/09000/Music_therapy__facilitating_behavioural_and.9.aspx


No Score administered at baseline, week 6 and week 12 and included depression (HADS), communication (FAST), and behaviour rating scales.

study period. However, the treatment group demonstrated a greater decline than the control group (-1.65 ±1.59 vs. -1.57 ±1.59).

Nayak et al. (2000) USA No Score

18 patients with traumatic brain injury or stroke were assigned to receive music therapy, 2 to 3 times a week for the duration of their stay in the hospital and received a maximum of 10 treatment sessions in addition to their standard therapy or to receive standard therapies that are part of inpatient rehabilitation regimen only. Patients rated their own mood on the Faces Scale (McDonnell & Newell 1996). Family and therapists rated patients’ mood on a 7-point visual analogue scale with not depressed at all on one end and very depressed on the other end. Higher scores indicated more depression.

Significant difference between groups on social interaction scale was noted in favour of the music therapy group. Staff rated participants’ social interaction in music as more actively involved in therapy and were more motivated to participate. Although not statistically significant, self-report, family and therapists’ rating of patients’ mood improved.

Sarkamo et al. (2008) Finland 6 (RCT)

60 patients with middle cerebral artery stroke were randomly allocated to music listening, language listening or control groups as soon as possible following discharge from acute care. Patients in the music and language listening groups both received portable CD players and CD’s of either music or narrated audio books as appropriate & were instructed to listen to the material by themselves for a minimum of 1 hr/day for a period of 2 months. Patients assigned to the control group received no listening material. 54 patients completed the trial (music = 18, language = 19, control = 17). Follow-up neuropsychological assessments were performed at 3 and 6 months post stroke along with the Profile of Mood States (POM) and an assessment of health-related quality of life.

At baseline, there were no significant differences between groups on cognitive or mood assessments. However, at three months, there were significant between group differences on the depression subscale of the POM, such that depression scores were significantly lower in the music listening group (p=0.024). At 6-month assessment, the music listening group still demonstrated a significant trend toward lower depression scores (p=0.071).

Kim et al. (2011) Korea No Score

18 patients (with MMSE scores >20) within 6 months of stroke onset received either regular rehabilitation treatment (PT, OT, SLP + psychotherapy) or regular rehabilitation treatment plus music therapy. Music therapy sessions were 40 minutes in length per session. A total of 8 sessions were provided (twice/week over 4 weeks). Each session consisted of a hello song, personal sharing, and planned musical activities including use of instruments, singing, and improvisation. Assessment included administration of the Beck Depression Inventory and Beck Anxiety Inventory before and after the intervention period for both groups.

Over the course of the intervention depression scores improved significantly in the intervention group (p=0.048), but not in the control group. The authors do not report between group comparisons. There were no significant changes reported for scores on the anxiety inventory in either group. 77.8% of patients and 66.7% of caregivers reported that they perceived music therapy to be associated with a positive psychological change.

Discussion Music therapy appears to provide a stimulating environment that may promote rehabilitation gains. In a small, randomized controlled trial, Sarkamo et al. (2008) demonstrated less self-reported depressive symptomatology associated with music listening and, in general, results associated with the provision of music therapy have seemed favourable. However, RCTs are needed to assess the possible role of music therapy in the treatment of post-stroke depression.


http://psycnet.apa.org/journals/rep/45/3/274/




Conclusion Regarding Music Therapy for Post-Stroke Depression There is moderate (Level 1b) evidence that music listening is associated with fewer reported symptoms of depression following stroke. There is limited (Level 2) evidence that music therapy may have a positive impact on mood following stroke.

Music therapy and listening to music may have a positive influence on mood post stroke.

18.9.5 Speech Therapy in Post-Stroke Depression The counselling role of speech therapists is thought to help patients, in particular aphasic patients, adapt to their communication disturbances and better express their needs that in return may alleviate emotional problems (Lincoln et al. 1985). Two studies examining the impact of speech therapy on emotional outcomes are summarized in Table 18.32.

Table 18.36 Speech Therapy and Psychological Disorders


PEDro Score

Methods

Outcomes


At 10 weeks, 168 patients were randomized to receive either two 1-hour sessions a week of speech therapy for 24 weeks or to receive no speech therapy. All other rehabilitation carried out as usual.

No significant differences were found between treatment and control patients on Multiple Adjective Checklist (MAACL) scores on anxiety, depression and hostility.

Hoen et al. (1997) Canada No Score

Evaluation of the York-Durham Aphasia Centre’s community-based programme. Patient and family members’ psychological well-being was evaluated using the Ryff’s Psychological Well-being Scale to 35 patients and 12 family members.

Patients were observed to show positive significant change on five of six measures of well-being: self-acceptance, purpose of life, personal growth, autonomy and environmental mastery.

Discussion The result from Lincoln et al. (1985) did not indicate any psychological benefits from receiving speech therapy in aphasic patients or their spouses. However, the role of speech therapy and its place in overcoming speech disturbances that result from stroke in order for patients to communicate their emotional needs should be further investigated.

Conclusion Regarding Speech Therapy in Post-Stroke Depression There was moderate (Level 1b) evidence that speech therapy does not improve depression scores or improve overall psychological wellbeing.

Speech therapy does not appear to improve depression post-stroke.




http://www.tandfonline.com/doi/abs/10.1080/02687039708249415#.Uda9gfnPniQ


18.9.6 Physical Activity In a systematic review of 13 studies examining the impact of physical exercise on depression in individuals aged 60 or over, Sjosten and Kivela (2006) reported that physical exercise appeared to be an effective means by which to decrease depression. However, this effect was noted only in individuals experiencing either major or minor depression or elevated, but sub-clinical symptoms of depression. Improvements may be seen after only a few weeks of exercising, but diminish quickly upon cessation of activity (Sjosten & Kivela 2006). Studies examining the impact of exercise programs on symptoms of depression are summarized in Table 18.33.

Table 18.37 Impact of Exercise on Depression


PEDro Score

Methods

Outcomes

Lai et al. (2006) secondary analysis of Duncan et al. 2003 USA 8 (RCT)

100 patients with stroke were randomized to receive structured, progressive, physiologically based exercise program to or usual care in a single blinded RCT. Intervention was a structured, progressive physiologically based, therapist-supervised, in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility, strength balance, endurance and upper-extremity function.

At baseline 18% vs. 22% of participants in the intervention vs. usual care groups had GDS scores ≥6 (presence of significant depressive symptoms). GDS scores and rates of significant symptomatology were significantly lower in the intervention group vs. usual care immediately following the intervention (0.01<p<0.05). At 9 months, GDS scores were still significantly lower in the intervention group (p<0.05). Individuals in the exercise group also demonstrated higher QOL scores (SIS) and higher SF-36 emotional subscale scores. Use of antidepressant medication was comparable in both groups. Overall gains in impairments and functional limitations were greater in the exercise group vs. usual care and did not appear to be limited by the presence of depressive symptomatology.

Mead et al. (2007) UK 8 (RCT)

66 ambulatory patients stroke patients who had completed inpatient rehabilitation were randomized to receive a 12-week outpatient program of strength and resistance exercise (n=32) or relaxation (n=34). Treatments were provided for 1.5 hrs, 3 times per week. Outcomes were assessed at 3 and 7 months and included: FIM, Nottingham Extended Activities of Daily Living; Rivermead Mobility Index; functional reach; sit-to-stand; elderly mobility score; timed up-and-go; Medical Outcomes Study 36-Item Short Form Questionnaire, version 2 (SF-36); Hospital Anxiety and Depression Score; aspects of physical fitness (comfortable walking speed, walking economy, and explosive leg extensor power).

At 3 months, the role-physical component of the SF-36, timed up and go and walking economy were significantly better among patients in the exercise group compared with the relaxation group. By 7 months, the only difference that remained between groups was the role physical component of the SF-36. At 3 and 7 months, assessment of depression identified no significant within-group change over time (ES=0.008, 0.001, respectively) and no significant between group differences (p=0.56, 0.82, respectively).

Smith and Thompson (2008) USA No Score

Participants with previous ischemic stroke (at least 3 months prior to baseline) were enrolled in a matched pair controlled trial to examine the effectiveness of a 12-session treadmill training intervention on depression. 20 individuals were assigned to the

Within groups analysis demonstrated a significant reduction of symptoms of depression reported on the BDI in the intervention group over time (p<0.05) – both by the end of intervention and at the end of follow-up. There







intervention condition and 20 to the control group. Those in the intervention condition received 12 sessions of treadmill training over a 4-week period (20 min/session). The control group received weekly phone calls and were encouraged to record life events in a personal log. Assessments were conducted at baseline, at 4 weeks (end of intervention) and at 6 week follow-up. Assessments included the Beck Depression Inventory and Stroke Impact Scale.

was no significant difference in BCI score over time reported within the control group. In addition, there was a significant group X time interaction reported (F=2.61, p<0.01).

Macko et al. (2008) Italy No Score

20 patients with chronic hemiparesis following stroke were enrolled in a 2-month group exercise program. Twice weekly, 1-hour long sessions focused on mobility, balance and stretching exercises. A home regimen of walking, stair climbing and stretching was also provided. Evaluations were conducted at baseline, one month later (prior to session to establish stability) and then at the end of the intervention. Assessments included Motricity Index, Short Physical Performance Battery (SPPB), 6-minute walk, Berg Balance, Barthel Index, Stroke Impact Scale and Geriatric Depression Scale.

79% of individuals had scores >6 on the Geriatric Depression Scale at baseline. There was significant improvement in depression (p=0.01) over time, although the mood score of the Stroke Impact Scale did not show similar improvement (p=0.33). The proportion of individuals with GDS>6 did not change significantly over time (15/19 vs. 12/19, p=0.2). Scores on the motricity index (upper and lower limb), 6-minute walk test, Berg balance scale, SPPB and Barthel Index all demonstrated significant improvements over time.

Lennon et al. (2008) Ireland 7 (RCT)

48 individuals with stroke, living within the community, were assigned randomly to received either regular physiotherapy and occupational therapy services in addition to a cardiac rehabilitation program (intervention) or just the regular therapy services alone (control). If assigned to the Cardiac Rehabilitation Program participants attended cycle ergometry (aerobic training) exercise sessions (30 minutes in length) for either the upper or lower limbs twice per week for 10 weeks. In addition, they were provided with 2 life skills classes. Control group participants received no additional intervention beyond regularly available therapy services. Assessments were conducted at baseline and at the end of intervention (week 10). Assessments included (in addition to a wide variety of physical performance measures), the Frenchay Activities Index and Hospital Anxiety and Depression Scale.

Pre and post assessment of depressive symptomatology (HADS) demonstrated that the HADS depression scores improved significantly over time within the intervention group (p<0.001), but not in the control group. However, when the difference in change scores was examined there was no significant difference in between group change reported (p=0.22).

Stuart et al. (2009) Italy No Score

40 individuals with stroke participated in the Adaptive Physical Activity (APA-stroke) program (a “community-based exercise program”). 38 individuals, from neighbouring communities, served as a control group and did not participate in the program. The APA program provides walking, strength and balance exercise specifically designed for individuals who have experienced stroke in a group/class setting. The exercises increase in duration and intensity over the course of the 3-month program of activity. Classes were available to individuals within the community for a small fee and were supervised by trained therapists. Assessments were conducted at baseline and 6 months and included the following: MMSE, Hamilton rating

In a within-groups analysis (an including only those individuals with symptoms of depression at baseline), there was a significant improvement in symptoms of depression demonstrated in the intervention group (p<0.01) over time, but not in the control group (p=0.88). The APA intervention was associated with significantly greater improvement in depression when compared to the control condition (p<0.003).






Scale for Depression, Motricity Index, 6MWT, Berg Balance Scale, Barthel Index and the Stroke Impact Scale.

Sims et al. (2009) Australia 7 (RCT)

45 patients > 6 months post stroke and diagnosed with PSD were randomly assigned to either progressive resistance training (PRT) twice per week for 10 weeks or to a waiting list (control) condition. Sessions were provided in small groups within a community setting. Primary study outcome was depressive symptomatology as assessed on the CES-D. Primary and secondary outcomes were assessed at 10 weeks (end of treatment) and 6 months by mailed self-report questionnaires.

At baseline, individuals in the control group had more severe depression as assessed on the CES-D (p=0.003). At 10 weeks and at 6 months, individuals assigned to PRT had fewer symptoms of depression (p=0.08 and p=0.004, respectively); however, these between group differences were non-significant when controlling for baseline depression. Approximately 50% of patients in each group experienced a clinically significant (>5 pts on CES-D) reduction in depressive symptoms, and at 6 months, this reduction was maintained in 30% of individuals in the treatment group vs. 15% in the control group. This difference was not statistically significant.

Brittle et al. (2009) UK 5 (RCT)

56 residents in 5 long-term care homes received either group exercise or usual care. Randomization was by facility. Exercise training focused on flexibility, sitting balance, poster, coordination, strengthening and cardiovascular fitness. Sessions were 40 – 60 minutes in length and were provides twice weekly for 5 weeks. The usual care group received no exercise training or regular physiotherapy. Assessments were conducted at baseline, 3 months (after the intervention) and 6 months (follow-up). Measures included the Rivermead Mobility Index, HADS and the SADQ.

Approximately one-quarter of all participants had a history of at least one stroke (21% and 25% of individuals in the control and exercise groups, respectively). There were no significant improvements reported, for any of the outcomes assessed, in favour of the exercise intervention. Individuals with severe cognitive impairments had difficulty participating in the program and some were disruptive.

Harrington et al. (2010) UK 7 (RCT)

243 individuals with stroke were randomly assigned to receive either standard care or a peer-volunteer-facilitated exercise and education intervention. Intervention sessions were conducted twice/week for 8 weeks. Each session consisted of one hour exercise (with qualified instructors) followed by a short break and1 hour of interactive education. Sessions were intended to be fun and non-didactic, encouraging group participation – these also included some goal-setting sessions, social sessions and unstructured group discussion times. Home exercise manuals and directories of local resources were also provided to participants. Family members and carers were encouraged to attend and help in the exercise sessions. One session was dedicated to family members. Control participants received standard care + an information sheet about local groups. Three primary study outcomes measures were the SIPSO (Subjective Index of Physical and Social Outcome), FAI (Frenchay Activities Index) and RMI (Rivermead Mobility Index) assessed at baseline, 9 weeks and 6 months. Depression (HADS) was assessed as a secondary outcome.

Although there was a significantly greater improvement in the psychological domain of the WHOQol-Bref at 6 month in the intervention vs. control group (p=0.01), there were no significant between group differences at 9 weeks, 6 months or one year for any of the secondary outcomes assessed, including depression.

Van de Port et al. A multi-centred study in which individuals with stroke Individuals in the circuit training received a







(2012) Netherlands 8 (RCT)

discharged home from inpatient rehabilitation (& able to walk 10 m unassisted) were randomly assigned to participate in either a group-based, task-oriented circuit training program (n=126) or usual care (n=124). The circuit training program was 90-minutes in length (warm-up, circuit training, evaluation, short break and group game) and offered 2X/week for 24 weeks. Usual care consisted of one-to-one physiotherapy treatments over the same period of time. Primary study outcome was mobility as assessed on the mobility domain of the SIS. Secondary outcomes included the remainder of the SIS, RMI, falls efficacy (FES), Nottingham EADL, HADS and fatigue severity (FSS). All secondary assessments were performed at baseline, 12 and 24 weeks.

mean of 72 minutes (± 39) per session compared with 34 minutes (± 10) in the control group (p<0.05). There was no significant group X time interaction for the mood and emotions domain of the stroke impact scale from baseline to 12 week assessment (p=0.41) or from 12 to 24 week assessment points (p=0.41). Similarly, there was no significant group X time interaction identified for change in HADS scores from baseline to 12 weeks (p=0.86) or from 12 to 24 week assessments (p=0.37).

Discussion Based on the results of studies examining physical activity and depression in older individuals without stroke, the idea that exercise would have a positive impact on PSD seems reasonable. However, the results from the studies identified here seem less clear cut. The types and intensity of exercise vary between study and the results appear inconsistent. Within groups analyses seem generally positive, but for many studies, between groups comparisons are non-significant. It should also be noted that none of these interventions were evaluated as treatment for diagnosable depression; rather the effects of exercise interventions were evaluated in terms of the effect on symptoms of depression only. In addition, depression was evaluated as a secondary outcome only. A summary of the types of intervention and the study outcome in terms of the impact on depression outcomes is provided in table 18.34.

Table 18.38. Summary of Exercise Interventions

Author, Year PEDro Score

N Intervention Effect* Depression Outcome Assessed

Lai et al. (2006) 8

100 12-week structured, progressive, in-home exercise program (flexibility, strength, balance, endurance)

vs. usual care

+ GDS score

Mead et al. (2007) 8

66 12- week outpatient strength and resistance training vs. relaxation

NS HADS score

Smith and Thompson (2008)

No score

40 4-week treadmill training vs. weekly phone calls + BDI score

Macko et al. (2008) No Score

**

20 2-month group exercise program (twice/week) focusing on mobility, balance and stretching

supplemented by a home regimen (walking, stair climbing and stretching)

+ GDS score (within group only)

Lennon et al. (2008) 7

48 Cardiac rehabilitation program (aerobic training twice/week for 10 weeks) + life skills classes vs.

usual care.

NS HADS (+ for within group only)

Stuart et al. (2009) No Score

78 Adaptive physical activity program (community-based exercise program – classes focused on

walking strength and balance) vs. non-participation

+ HRSD



Sims et al. (2009) 7

45 Progressive resistance training (small group sessions) twice/week for 10 weeks vs. a waiting list

condition.

NS CES-D

Brittle et al. (2009) 5

56 Group exercise training (flexibility, sitting balance, coordination, strength and cardiovascular fitness) vs. regular physiotherapy provided to long-term

care home residents.

NS HADS or SAD-Q

Harrington et al. (2010) 7

243 Group exercise (peer-volunteer-facilitated) & interactive education sessions (2X/week for 8

weeks) vs. control

NS HADS

Van de Port et al. (2012) 8

250 Task-oriented, group-based circuit training vs. usual care

2X/week for 12 weeks

NS HADS

*+represents a significant positive outcome in favour of the intervention; NS = no significant effect.**Single group study only

Conclusions Regarding Exercise Although within groups comparisons might suggest that, over time, exercise could have a positive influence on mood, based on between groups comparisons there is strong (Level 1a) evidence that progressive, structured exercise programs do not provide significant benefit in terms of reduction in depressive symptomatology. There is limited (Level 2) evidence, based on one non-randomised pilot study, that treadmill training is not associated with reduction of symptoms of depression. There is moderate (Level 1b) evidence that cardiac rehabilitation (aerobic training) is not associated with a reduction in symptoms of depression. There is moderate (Level 1b) evidence that resistance training is not an effective means to reduce depressive symptomatology.

Exercise training, whether progressive group programs, treadmill training or aerobic training, does not appear to be associated with a reduction in symptoms of depression post stroke. Further

research is required.

18.9.7 Ecosystem Focused Therapy. The developers of ecosystem focused therapy have approached the treatment of post stroke depression from the point of view of stroke as a catastrophic event separates the individual from his or her usual skills and competencies (Alexopoulos et al. 2012). The family of the individual with stroke also experiences significant upheaval associated with the stroke event and so Ecosystem Focused Therapy (EFT) was designed to target both the individuals with stroke and his/her family members (Alexopoulos et al. 2012). A recent RCT examining the effectiveness of EFT in the treatment of PSD is summarized in Table 18.35.

Table 18.39 Ecosystem Focused Therapy


Methods

Outcomes



PEDro Score

Alexopoulos et al. (2012) USA 6 (RCT)

24 individuals diagnosed with post stroke depression (via SCI for DSM-IV-TR) were randomly assigned to receive either ecosystem focused therapy (EFT) or education on stroke or depression. EFT was provided in 12 weekly sessions of approximately 45 minutes in length. Inpatients had the first session prior to discharge; the remaining sessions were conducted in the participants’ homes. EFT uses an integrated, educational, problem-solving approach to work through 5 therapy components – 1) provide an action-oriented perspective to recovery; 2) form a treatment “adherence enhancement structure” 3) provide a “problem solving structure” 4) help the family “re-engineer” to accommodate changed abilities and 5) coordinate with therapists and resources to develop a rehabilitation plan. Depression was assessed using the Hamilton Rating Scale for Depression over the course of the 12-week intervention.

Group X time analysis revealed an interaction suggesting that there was a greater decline in symptoms of depression associated with EFT vs. education (p=0.054). The mean HRSD score at 12 weeks was 8.2 (sd=6.63) for individuals in the intervention group and 13.2 (sd=5.37) for individuals assigned to the education control group. In addition, remission of depression was recorded for 8/12 participants receiving EFT (66.7%) vs. 2/12 (16/7%) participants in the education group (OR = 10, 95% CI 1.44, 69.26).

Conclusions Regarding Ecosystem Focused Therapy

There is moderate (level 1b) evidence that ecosystem focused therapy is more effective than education regarding stroke and depression in reducing depressive symptoms in individuals with PSD.

Ecosystem focused therapy may be an effective treatment for post-stroke depression. Further study is required.

18.10 Guidelines for Treatment of Post-Stroke Depression

There are several sets of current rehabilitation guidelines that make recommendations for the assessment and treatment of mood disorders following stroke. In general, all acknowledge the importance of identification and diagnosis of depression. All recommend the use of standardized assessment and most indicate that a clinical interview conducted by an appropriate mental healthcare professional is required for diagnosis. Treatment, in the form of antidepressant medication (usually an SSRI), is recommended, though the details and possible duration of treatment are not clearly stated. The possible role of psychotherapy is acknowledged although there is little evidence of its effectiveness within this population. The most recent clinical guidelines are the “Stroke Rehabilitation Clinical Practice Guidelines” from the Veterans Affairs-Department of Defense (VaDoD) recently endorsed by the American Heart Association/American Stroke Association (AHA/ASA) (Duncan et al. 2005). These guidelines appear in Table 18.36.

Table 18.40 AHA/ASA Endorsed Guidelines for the Management of Adult Stroke Rehabilitation Care

Recommendations for Mood Disturbance: Depression and Emotionalism

Assessment

The Working Group makes no recommendation for the use of any specific diagnostic tool over another

Recommend using a structured inventory to assess specific psychiatric symptoms and monitor symptom change over time

Recommend assessing poststroke patients for other psychiatric illnesses, including anxiety, bipolar illness and pathological affect.

Treatment




Strongly recommend that patients with a diagnosed depressive disorder be given a trial of antidepressant medication, if no contraindication exists.

The Working group makes no recommendation for the use of one class of antidepressants over another; however, side effect profiles suggest that SSRIs may be favoured in this patient population.

Recommend SSRIs as the antidepressant of choice in patients with severe, persistent, or troublesome tearfulness.

There is insufficient evidence to recommend for or against the use of individual psychotherapy alone in the treatment of PSD.

Recommend patients be given information, advice, and the opportunity to talk about the impact of the illness on th eir lives.

Routine use of prophylactic antidepressants is not recommended in post- stroke rehabilitation.

Recommend that mood disorders causing persistent distress or worsening disability be managed by, or with the advice of, an experienced clinical psychologist or psychiatrist.

While the preferred mode of treatment is specified, there are no guidelines provided regarding how treatment plans should be developed, how or for how long treatment should be provided and what happens at the end of the course of treatment. The National Clinical Guidelines for Stroke (Party 2004) suggest that antidepressant treatment for PSD should begin only after a period of “watchful waiting” to determine if the depressive episode will become persistent. Following this, treatment may be initiated for persistent episodes by an “appropriately trained and supervised practitioner.” Treatment should be kept under review and should continue for at least 6 months, if a good response is achieved. Persistent disorders causing distress or worsening disability “should be managed by or with advice from an experienced clinical psychologist or psychiatrist.” In 2005, the British Society of Rehabilitation Medicine and the British Geriatrics Society in association with the Royal College of Physicians published concise guidelines for the use of antidepressant medication following “acquired brain injury” (Turner-Stokes & MacWalter 2005). The recommendations were intended for clinicians working with individuals who had sustained brain injury from any cause, including stroke and include recommendations for screening and assessment, issues to consider prior to the commencement of treatment, as well as suggestions for treatment planning, evaluation and withdrawal. A summary of the guidelines is provided in Table 18.37.

Table 18.41 Summarized Guidelines for Use of Antidepressant Medication Following Brain Injury (British Society of Rehabilitation Medicine & the British Geriatric Society).

Assessment

Recommend informal screening at each assessment point (e.g. ask patient about mood or ask family about behaviours that might suggest depression)

If depression is suspected, proceed to more formal, detailed assessment (using validated measures, interview and/or observation

Treatment

Clinicians should observe patients carefully regarding impact of depression on function, social participation and QOL

Clinicians should attempt to determine if other, simple, interventions might be appropriate to “boost the patient’s mood”

Possible risks and contraindications for treatment should be considered carefully along with issues of informed consent and patient/family education

Antidepressants should be prescribed according to an agreed-upon plan of treatment that includes: baseline assessment using a validated measure, assessment of appropriate baseline biochemical markers, selection of an appropriate agent, clinical review of response to optimize dose (at 2-3 weeks) and repeat assessment at 6 – 8 weeks. Given a positive response to treatment, planned use would extend to 6 months with a procedure for withdrawal at the end of treatment.



An alternate plan should be in place should treatment with an antidepressant be ineffective.

During Treatment

Patients should see doctor regularly during treatment (every 2 months) – any clinical deterioration should be investigated – particularly known side effects such as hyponatraemia, seizures, GI bleeding, anti-cholinergic symptoms, sexual dysfunction, sedation, hallucinations, increased confusion, headache

Antidepressant medication should not be given with repeat prescription and no more than 2 months supply should be written

Referral for Formal Psychiatric Interview

If depression is severe or resistant to treatment

Past history of psychiatric disorder and/or use of antidepressant

Patient shows evidence of suicidal ideation or intent

Seems that the patient needs to be treated under Mental Health Act 1983 or equivalent (UK)

Withdrawal from Treatment

At end of treatment (generally 4 – 6 months), there should be a planned period of withdrawal taking place gradually over a period of 1 – 2 months

Prior to withdrawal, patient mood should be re-evaluated (using same measure as at baseline)

Patient/family should be warned re: possibility of rebound symptoms. For longer lasting relapse of depression, long-term treatment may be considered. Formal psychiatric advice should be sought.

Though the 2005 guidelines for use of antidepressants post brain injury do not include specific recommendations for a particular antidepressant agent, the authors suggest that SSRIs, while as effective as heterocyclic antidepressants, have fewer reported side effects.

Conclusions Regarding Treatment Guidelines Current guidelines recommend both screening and appropriate assessment of depression in patients with stroke. Treatment with an appropriate antidepressant is recommended for a period of approximately 6 months (given evidence of treatment effectiveness). Treatment (and subsequent withdrawal) should be monitored closely by an appropriately trained healthcare professional.

Guidelines for the treatment of post stroke depression recommend screening, assessment and treatment with an appropriate antidepressant for a period of approximately 6 months.

18.11 Post-Stroke Emotionalism

Pathological crying or laughing following stroke has been given many different labels within the literature including emotional incontinence, emotional lability, pathological display of affect, pseudobulbar affect or emotionalism (Andersen et al. 1995; J. 1993). While there appears to be no consensus regarding the most appropriate label or diagnostic criteria for this condition, many reports refer to the definition provided by House et al. as part of the Oxfordshire Community Stroke Project (House et al. 1989). The authors presented the defining characteristics of emotionalism as “an increase in tearfulness with episodes of crying that were sudden or unheralded and not all under normal social control”. While this definition focuses on pathological crying, similar criteria were applied to pathological laughing (House et al. 1989). Patients who are severely affected may have as many as 100 episodes per day, each lasting from 1 – 10 minutes. Patients who are the least affected may present with excessive and/or inappropriate facial grimacing. In either case, individuals experiencing post-stroke emotionalism may withdraw from participation in normal social roles due to distress and fear of social embarrassment (Andersen 1995).



18.11.1 Prevalence and Natural History of Post-stroke Emotionalism The reported frequency of emotionalism following stroke ranges from 11% (House et al. 1989) to 34% (Kim & Choi-Kwon 2000). However, this figure depends on both the criteria used to define emotionalism and the time elapsed since stroke onset. Kim et al. (2000) used criteria that differed from House et al. (1989) in that the patient and relatives had to agree that excessive and inappropriate laughing or crying had occurred on more than two occasions. Inappropriateness is not included in the House et al. criteria (House et al. 1989). House et al. (1989) suggested that, emotionalism represents a loss of ability to control emotional response at a low level of stimulation rather than simple inappropriateness of response. The majority of participants in the House et al. (1989) and the Calvert et al. (1998) studies were able to identify provoking stimuli for their episodes of uncontrollable crying; in the House et al. (1989) study most were provoked by stimuli related to sadness and sentimentality. In a comparison of the two criteria, it was reported that use of the Kim (2000) criteria resulted in a much higher frequency of reported emotionalism (17.9% in the first 3 months following stroke) than the use of the criteria proposed by House et al. (1989) (6.3%). Clearly, there is a need to develop a single set of criteria with which to diagnose post-stroke emotionalism. Within the first few months of stroke onset, reported estimates of the frequency of emotionalism ranges from 12% (Langhorne et al. 2000) to 29.2% (Eccles et al. 1999). House et al. (1989) reported that most patients identified the onset of emotionalism as within the first 4 to 6 weeks following stroke. While the frequency and severity of crying episodes have been reported to improve over the course of the first year post stroke and some cases resolve spontaneously (Andersen 1997; House et al. 1989), the frequency of emotionalism at 12 months has been reported as 11% (Andersen et al. 1995; House et al. 1989). A significant association has been reported between post-stroke emotionalism and post-stroke depression (Calvert et al. 1998; House et al. 1989; Kim & Choi-Kwon 2000; MacHale et al. 1998) (Andersen et al. 1995), though most individuals with emotionalism do not have significant or diagnosable depression (Calvert et al. 1998; Kim & Choi-Kwon 2000). Patients experiencing post-stroke emotionalism may have more symptoms of psychological disorders or syndromes, in general, than those without emotionalism. Both Eccles et al. (1999) and Calvert et al. (1998) reported that the presence of emotionalism was associated with significantly greater emotional distress and a greater likelihood for the presence of other diagnosable psychiatric disorders. In both studies, it was suggested that post-stroke emotionalism could share common characteristics with post-traumatic stress disorder.

In the first 6 months following stroke, post-stroke emotionalism affects approximately one-quarter of stroke survivors.

18.11.2 Risk Factors for Post-Stroke Emotionalism Risk factors for the development of post-stroke emotionalism have not been well defined. Post-stroke emotionalism has been associated with younger age (Calvert et al. 1998), the presence of cognitive impairment (Andersen et al. 1995; House et al. 1989), female sex (Kim & Choi-Kwon 2000), ischemic stroke vs. haemorrhagic stroke (Kim & Choi-Kwon 2000), motor impairment (Andersen et al. 1995; Kim & Choi-Kwon 2000), functional ability (Andersen et al. 1995), history of depression (Tang et al. 2004) and cortical infarcts (Tang et al. 2004). Tang et al. (2004) also noted an association between emotionalism and younger age, previous TIA or stroke and stroke severity on univariate analysis. However, when entered into a multivariate regression model, only history of depression and the presence of cortical



infarcts remained as significant independent predictors. Andersen et al. (1995) found no association between emotionalism and sex, age, history of depression or lesion location. As is the case for post-stroke depression, studies have attempted to determine a relationship between lesion location and the development of emotionalism with similarly varied results. House et al. (1989) reported that emotionalism was associated with larger lesions and lesions located in the left frontal and temporal regions. This has been confirmed in studies by Andersen et al. (1995) and MacHale et al. (1998); however, MacHale et al. (1998) also reported a significant association between emotionalism and lesions in the right cerebral hemisphere (p<0.01). Andersen et al. (1995) reported that severe emotionalism was associated with the presence of large, bilateral pontine lesions while moderate emotionalism was associated with lesions of the basal ganglia or periventricular structures. Mild emotionalism was associated with the presence of large, unilateral subcortical lesions (Andersen 1995). A more recent study by Kim et al. (2000) demonstrated that while lesion location was an important factor in the development of both post-stroke depression and post-stroke emotionalism, it was more strongly associated with depression (p<0.05). The authors report that while lesions associated with emotionalism were distributed in a similar pattern to those associated with post-stroke depression, emotionalism was associated more closely with lesions occurring in the lenticulocapsular area. There was also a non-significant trend noted toward an association between pontine base, medial medulla and cerebellar lesions and post-stroke emotionalism (Kim & Choi-Kwon 2000). The study by Kim et al. (2000) also confirmed a significant association between the presence of emotionalism and anterior cortical lesions. It has been postulated that, given the pattern of association with lesion location, post-stroke emotionalism may be attributable to changes in neurochemical pathways or, more specifically, damage inflicted on the serotonergic system (Andersen 1997; Kim & Choi-Kwon 2000) (Andersen 1995).

18.11.3 Treatment of Post-Stroke Emotionalism There are relatively few published studies regarding effective treatment of post-stroke emotionalism. No reports of non-pharmacologic treatment could be located. Instead, treatment, in general, consists of administration of an antidepressant medication – most often a selective serotonin reuptake inhibitor (SSRI). A recent Cochrane meta-analysis included 5 trials of antidepressant medication in the treatment of post-stroke emotionalism (Table 18.38) (House et al. 2004). Three trials assessed the effectiveness of SSRIs, while the remainder examined the effectiveness of tricyclic anti-depressants (TCAs). Although the authors did not pool results, due to the heterogeneity of assessment methods used in the included studies, House et al. (2004) did conclude that the use of antidepressants appears to be associated with reductions in the frequency and severity of episodes of pathological crying. This effect was not specific to either class of medication used. The present review identified 5 trials investigating the effectiveness of pharmacologic treatment of post-stroke emotionalism. Details of these studies are provided in Table 18.39.

Table 18.43 Pharmacologic Treatment of Post-Stroke Emotionalism

Table 18.42. Studies included in Meta-analysis by House et al. (2004)

Author Antidepressant studied

Ohkawa et al. 1989 [Japanese]

Amitriptyline (TCA)

Andersen et al. 1993 Citalopram (SSRI)

Robinson et al. 1993 Nortriptyline (TCA)

Brown et al. 1998 Fluoxetine (SSRI)

Burns et al. 1999 Sertraline (SSRI)




PEDro Score

Methods

Outcomes

Andersen et al. (1993) Denmark 6 (RCT)

In a cross-over design, 16 patients with pathological crying following stroke were randomly assigned to receive either 21 days of citalopram 20 mg/day (for patients under age 65 or 10 mg/day for older patients) or matching placebo. Following first 21-day treatment period, participants entered a 7-day washout followed by a second baseline and then crossed over to the second 21-day treatment period. Primary outcome was reduction in recorded crying frequency. Response to treatment was defined as a reduction of 50% or more in the frequency of crying episodes. Crying frequency was assessed via interview, patient diary and rating on a 5-point scale.

Frequency of crying could be assessed in 13/16 patients. Treatment with citalopram was associated with significant reduction in crying episodes when compared with placebo (p<0.005). Frequency of crying was reduced by 50% or more in all patients treated with citalopram, but in only 2 patients assigned to the placebo condition (p<0.005). When compared to baseline, treatment with citalopram resulted in a significant reduction in the mean number of episodes per day (p<0.05). Although no patients were diagnosed with depression during baseline, treatment with citalopram was also associated with reduction in scores on the Hamilton Rating Scale for Depression (p<0.005). All patients experienced a relapse of crying episodes when treatment was stopped. No significant side effects were detected, however, transient orthostatic dizziness, insomnia and increased spasticity were all reported in a global assessment.

Robinson et al. (1993) USA 7 (RCT)

28 individuals with stroke and who self-referred for treatment of pathological laughing or crying were randomly allocated to receive either treatment with nortriptyline (20 mg/day for 1 wk, 50 mg/day for 2 weeks, 70 mg for 1 wk and 100 mg/day for the last 2 weeks) or matching placebo. (Total treatment time = 6 weeks.) Evaluations took place at 2-week intervals via the Pathological Laughter and Crying Scale, the MMSE, the HRSD and the John Hopkins Functioning Inventory.

26 individuals completed the study (N=13 in each group). 8/13 patients receiving nortriptyline and 11/13 patients receiving a matching placebo were diagnosed with major depression prior to the commencement of treatment. Both groups experienced improvement in depression over the period of treatment; however, significantly greater improvement was associated with treatment with nortriptyline. On the Pathological Laughter and Crying Scale, patients treated with nortriptyline demonstrated greater improvement than those receiving placebo (p=0.008). While both groups experienced improvement over time, patients in the nortriptyline group improved more quickly than those in the placebo condition (p<0.001). When a subgroup of patients from each condition were matched for depression, patients treated with nortriptyline demonstrated greater improvement than those who were not (p=0.002). Comparison of depressed vs. non-depressed patients demonstrated a significant treatment effect (vs. placebo) that was not affected by depression.





Brown et al. (1998) UK 8 (RCT)

20 patients with at least a 4-week history of emotionalism following stroke were randomly assigned to receive either 20mg fluoxetine per day for 10 days (n=10) or matching placebo (n=10). One subject withdrew from the treatment condition. Emotionalism was assessed using the Lawson & MacLeod Rating Scale as well as by patient interview. Patients recorded the frequency of outbursts and rated change in outbursts on a 5-point scale. Significant change was defined as a 50% or more reduction in frequency of outbursts.

By the third day, ratings of emotionalism on the Lawson & MacLeod scale had improved substantially among patients treated with fluoxetine when compared to placebo (p=0.017). At day 10, these results remained constant. Similarly, on self-ratings of change in emotionalism, by day 3, patients in the treatment group reported improvements of at least 2 points more often than patients in the placebo group (p=0.0049). This difference also remained constant by day 10 (p=0.0049). At day 3, more patients in the treatment group (8/9) than the placebo group (3/10) reported a 50% reduction or more in outbursts (p=0.015). By day 10, this difference between groups remained significant (p=0.0007), with 7/9 patients receiving fluoxetine and 2/10 patients receiving matching placebo reporting significant reductions in outbursts. Patients in the treatment group did not report more side effects than those in the control condition.

Burns et al. (1999) UK 7 (RCT)

28 patients with emotionalism at least one-month post stroke were randomly assigned to treatment with 50 mg sertraline/day (n=14) or matching placebo (n=14). Patients participated in a single-blind run-in phase (2 weeks), followed by a double-blind treatment phase (8 weeks) and a follow-up placebo phase (2 weeks). Primary, outcomes included frequency of outbursts, ratings of emotionalism (based on the criteria of House et al. 1989), Clinician’s Interview-based impression of change(CIBIC).

Following the first 2-week run-in phase, 50% of patients in the placebo condition demonstrated improvement in tearfulness compared with 97% of patients receiving sertraline. By 8 weeks, patients receiving treatment with sertraline demonstrated greater improvements on the CIBIC as well as improvements in emotional lability and frequency of episodes of tearfulness when compared to patients in the placebo condition (p=0.41). Following the final 2-week washout period, all between group differences became non-significant.


152 stroke patients with one of post stroke depression (average = 14 months post stroke), emotional incontinence or anger proneness were randomly assigned to receive either fluoxetine 20 mg/day (n=76) or matching placebo (n=79). Treatment continued for a period of 3 months. Primary outcomes were mean score on Beck Depression Inventory (BDI) for PSD, and percentage change in VAS score for emotional incontinence and anger proneness.

Overall, 110 patients demonstrated emotional incontinence at baseline. 51 patients in the treatment group and 55 in the control group exhibited emotional incontinence for crying. 13 in the placebo group and 18 in the treatment group exhibited emotional incontinence for laughter. By three months, treatment with fluoxetine was associated with significant reduction in emotional incontinence (crying) when compared to the control group (p<0.01). At 1, 3 and 6 months, the percentage change in VAS score for emotional incontinence (crying) was significantly greater among patients who received treatment than for those receiving placebo (p<0.01). There was no significant difference demonstrated between treatment and control conditions for mean scores or percentage change scores for emotional incontinence (laughing). Subjective reports of improvement were greater for patients with emotional incontinence of both types when receiving treatment vs. placebo (p<0.05 at all






assessments).


A secondary analysis of data collected from Choi-Kwon et al. 2006. Assessments performed at 3 and 6 months as well as at 12 months (6 months after study was opened for open-label continuation). Evaluations at 12 months included health-related quality of life assessed using the SF-36 as well as emotional dysfunctions.

107 patients provided data at 12 month follow-up. Treatment was associated in significantly higher SF36 mental health scores at 3 (p<0.01), 6 (p<0.05) and 12 months (p<0.01) compared to the placebo condition. In addition, at 12 months, individuals in the fluoxetine group had significantly higher scores on the general health (p<0.01) and social function (p<0.05) subscales vs. placebo. For individuals with emotional disturbances following stroke, treatment with the antidepressant, fluoxetine may improve the mental health aspects of health-related quality of life.

The results of 5 RCTs of “good” quality demonstrate a significant and positive effect on post-stroke emotionalism associated with treatment with an anti-depressant, whether an SSRI or TCA (Table 18.40). In general, treatment appeared to be well-tolerated and was associated with a reduction in the frequency and severity of crying episodes while cessation of treatment was associated with a recurrence of outbursts. Certainly, the suggestion that treatment of post-stroke emotionalism with SSRIs is effective seems reasonable, particularly if emotionalism develops as a result of damage to serotonergic pathways (Andersen 1995; Andersen 1997; Kim & Choi-Kwon 2000). However, as noted by House et al. (2004), study results should be interpreted with caution. Most studies, with the exception of Choi-Kwon et al. (2006) were quite small and used varying definitions for post-stroke emotionalism. There was considerable variation in the methods used to assess emotionalism; most studies relied upon a combination of interview-based and self-report data to determine frequency and severity of episodes or outbursts. A single study (Robinson et al. 2000) evaluated the measurement properties of a scale specific to the evaluation of pathological crying and laughing, but it was not used in subsequent studies. Although there is a known relationship between depression and emotionalism, few studies attempted to control or adjust for the possible effects of depression on study outcomes. While Brown et al. (1998) and Burns et al. (1999) excluded patients with major depression, they included patients with minor depressive disorders. Similarly, Andersen et al. (1993) noted that no patients were diagnosed with major depression at baseline. Choi-Kwon et al. (2006) placed patients with post stroke depression, emotional incontinence and post-stroke anger proneness in groups for analysis; however, the groups do not appear to be mutually exclusive. Robinson et al. (1993) noted that a substantial proportion of study participants were experiencing major post stroke depression. The authors of this study did attempt to provide an analysis of the impact of depression on the improvement in emotionalism based on a subgroup analysis of 8 pairs of participants matched for depression scores. Within this small subgroup, treatment of emotionalism with nortriptyline was reported to be effective independent of depression (Robinson et al. 1993). Duration of treatment and time since stroke also varied between studies. Given that the outbursts associated with post-stroke emotionalism tend to become less frequent and less severe over the first 12 months post stroke, further study is required to determine the optimal timing and duration of treatment.




Conclusions Regarding the Treatment of Post-Stroke Emotionalism Based on the results of 5 RCTs of “good” quality, there is strong (Level 1a) evidence that antidepressant medications, and SSRIs in particular, are an effective treatment for post-stroke emotionalism.

Antidepressants, and SSRI antidepressants in particular, are effective in the treatment of post-stroke emotionalism. Further study is required to determine optimum timing and duration for

treatment.

Table 18.44 – Summary of Results and Adverse Effects for Pharmacologic Treatment of Post-Stroke Emotionalism

Authors, Year PEDro Score

N Drug Result Adverse Effects

Anderson et al. (1993) 6

16 Citalopram + None significantly associated with treatment (trend toward orthostatic dizziness, insomnia,

increased spasticity).

Robinson et al. (1993) 7

28 Nortriptyline + A single patient dropped out due to “sedation”. No other adverse effects requiring study

withdrawal.

Brown et al. (1998) 8

20 Fluoxetine + No difference in adverse effects between treatment and placebo

Burns et al. (1999) 7

28 Sertraline + No major side effects reported.

Choi-Kwon et al. (2006) 8

110 Fluoxetine + No difference in adverse effects treatment vs placebo, though more patients in treatment than

placebo dropped out due to adverse effects



18.12 Summary

1. At least one-third of stroke patients will experience depression. While the patterns of incidence and recovery change over time, for many individuals PSD may be persistent.

2. Commonly identified risk factors include female sex, previous history of depression, functional limitations and cognitive impairment.

3. Prior treatment of depression and the need for assistance with activities of daily living may be the factors most predictive of risk.

4. There remains a wide diversity of findings in studies looking at the relationships between stroke location and depression. Not all studies have confirmed this relationship and more recent meta-analyses have failed to establish a definitive relationship between the site of the brain lesion and depression.

5. Depression may have a significant and negative impact on functional ability following stroke.

6. Early identification and treatment of post-stroke depression may serve to enhance functional recovery.

7. Depression is significantly associated with social integration and isolation post-stroke.

8. Post-stroke depression appears to have a negative impact on cognition, particularly at the time of onset; however, the relationship between depression and cognitive impairment is likely reciprocal. Further research is required.

9. The presence of mental health disorders post stroke, including depressive symptomatology, has been associated with an increased risk for mortality. Further study to clarify the association between psychological distress and mortality is required.

10. There is strong (Level 1a) evidence that early initiation of antidepressant therapy, in non-depressed stroke patients is associated with reduced risk for the development of post-stroke depression. Further study is required to assess both duration of treatment and optimal timing for the initiation of therapy.

11. There is strong (Level 1a) evidence that ongoing individualized contact and support provided via various care provision models is associated with less deterioration of mood and/or mental health state following stroke.

12. There is moderate (Level 1b) evidence that fish oil supplementation following stroke has no impact on mood.



13. There is moderate (Level 1b) evidence that B-vitamin therapy, administered over a long period, may be associated with reduction in long-term risk for depression. Further study is required.

14. There is strong (Level 1a) evidence that heterocyclic antidepressants improve depression post stroke. Side effects in elderly patients mean that these medications should be used with caution in that population.

15. Based on the results of meta-analysis, there is strong (Level 1a) evidence that selective serotonin reuptake inhibitors are effective in the treatment of post-stroke depression. Further placebo studies should be conducted using a blinded administrator and an optimal treatment duration in order to address methodological differences across current studies.

16. Based on the results of a recent meta-analysis, there is strong (Level 1a) evidence that the use of bright light therapy in conjunction with SSRI antidepressants is an effective treatment for non-seasonal depression, in general.

17. There is moderate (Level 1b) evidence that adjunctive bright light therapy may be more effective than moderate intensity light therapy in the treatment of post-stroke depression. Further research is required to examine timing, duration and optimal intensity.

18. There is moderate (Level 1b) evidence that reboxetine, a noradrenaline reuptake inhibitor, is effective in reducing retarded post-stroke depression.

19. There is an absence of evidence regarding the effectiveness of venlafaxine and duloxetine, SNRI, as a treatment for post-stroke depression. Randomized controlled trials are required.

20. There is moderate (Level 1b) evidence that the GABA compound, nefiracetam, is not more effective than placebo in the treatment of post-stroke depression.

21. There is moderate (Level 1b) evidence that methylphenidate is more effective than placebo in improving both symptoms of depression and functional recovery. Methylphenidate (a psychostimulant) has an earlier onset of action than traditional antidepressants.

22. There is insufficient evidence that melatonin agonist are effective in management of PSD.

23. There is moderate (Level 1b) evidence that an active care management program including patient education and ongoing monitoring may enhance effectiveness of pharmacologic treatment for post stroke depression.



24. There is moderate (Level 1b) evidence that treatment with the herbal preparation Free and Easy Wanderer Plus (FEWP) may be as effective as fluoxetine in the treatment of post-stroke depression.

25. There is strong (Level 1a) evidence that pharmacologic treatment of depression is associated with improved functional recovery post-stroke.

26. There is moderate evidence (Level 1b) that early treatment with antidepressants post stroke is associated with improved long-term survival. Further research is required.

27. Based on two small, retrospective studies, there is an absence of evidence regarding the effectiveness of electroconvulsive therapy as a treatment for post-stroke depression.

28. There is strong (Level 1a) evidence that use of rTMS is associated with improvement in depressive symptomatology.

29. There is conflicting evidence that cognitive behavioural therapy is effective as a treatment for post-stroke depression.

30. There is moderate (Level 1b) evidence that the provision of a brief psychosocial intervention in addition to antidepressant therapy may be more effective than antidepressant therapy alone in terms of depressive symptomatology, functional ability and social participation.

31. There is moderate (Level 1b) evidence that music listening is associated with fewer reported symptoms of depression following stroke.

32. There is limited (Level 2) evidence that music therapy may have a positive impact on mood following stroke.

33. There was moderate (Level 1b) evidence that speech therapy does not improve depression scores or improve overall psychological well being.

34. Although within groups comparisons might suggest that, over time, exercise could have a positive influence on mood, based on between groups comparisons there is strong (Level 1a) evidence that progressive, structured exercise programs do not provide significant benefit in terms of reduction in depressive symptomatology.

35. There is limited (Level 2) evidence, based on one non-randomised pilot study, that treadmill training is not associated with reduction of symptoms of depression.

36. There is moderate (Level 1b) evidence that cardiac rehabilitation (aerobic training) is not associated with a reduction in symptoms of depression.

37. There is moderate (Level 1b) evidence that resistance training is not an effective means to reduce depressive symptomatology.



38. There is moderate (level 1b) therapy that ecosystem focused therapy is more effective than education regarding stroke and depression in reducing depressive symptoms in individuals with PSD.

39. Current guidelines recommend both screening and appropriate assessment of depression in patients with stroke. Treatment with an appropriate antidepressant is recommended for a period of approximately 6 months (given evidence of treatment effectiveness). Treatment (and subsequent withdrawal) should be monitored closely by an appropriately trained healthcare professional.

40. Based on the results of 5 RCTs of “good” quality, there is strong (Level 1a) evidence that antidepressant medications, and SSRIs in particular, are an effective treatment for post-stroke emotionalism.



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Post Stroke Depression · 2015-03-03 · 18. Post Stroke Depression pg. 3 of 104 Reboxetine is an...

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