Review
Neuropsychiatric outcomes of stroke Maree L Hackett, Sebastian Köhler, John T O’Brien, Gillian E Mead
The most common neuropsychiatric outcomes of stroke are depression, anxiety, fatigue, and apathy, which each occur in at least 30% of patients and have substantial overlap of prevalence and symptoms. Emotional lability, personality changes, psychosis, and mania are less common but equally distressing symptoms that are also challenging to manage. The cause of these syndromes is not known, and there is no clear relation to location of brain lesion. There are important gaps in knowledge about how to manage these disorders, even for depression, which is the most studied syndrome. Further research is needed to identify causes and interventions to prevent and treat these disorders.
Introduction Every year, about 16 million people worldwide have a firstever stroke. Of this population, about 5·7 million people die and another 5 million remain disabled.1 Neuropsychiatric disorders after stroke are common and can be distressing to patients and their families, but their effects are often underappreciated by health-care professions and patients’ treatment needs are often unmet.2 In this Review, we focus on the most common non-cognitive neuropsychiatric outcomes of stroke—ie, depression, anxiety, emotional lability, and apathy. We also discuss post-stroke fatigue (which is generally classified as a neuropsychiatric disorder), personality changes, psychosis, and mania. For each disorder, we discuss definition and identification, prevalence, associations, natural history and outcome, prevention, and treatment, and then make recommendations for future research. Researchers tend to consider each neuropsychiatric disorder separately, so we follow this approach, but we acknowledge that substantial overlap exists between the syndromes. Our management recommendations are based on data from randomised controlled trials or metaanalyses of these trials, but not from uncontrolled case series. In the absence of randomised data, we provide consensus recommendations.
Depression The fifth US Diagnostic and Statistical Manual of Mental Disorders (DSM-5)3 defines depression as depressed mood or anhedonia (loss of interest or pleasure) for 2 weeks or longer, plus the presence of at least four of the following symptoms when they are persistent and they interfere with daily life: substantial weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness or inappropriate guilt, diminished concentration, or indecisiveness. For diagnosis in busy and resource-poor clinical settings, it is often appropriate to use an interviewer-administered or self-completed depression case-finding or screening instrument that is validated for use in stroke4 (eg, the nine-item Patient Health Questionnaire,5 The Center of Epidemiological StudiesDepression Scale,6 Hospital Anxiety and Depression Scale [HADS], the Hamilton Depression Rating Scale, and the Beck Depression Inventory7). When clinicians diagnose depression, they should consider whether
somatic symptoms such as psychomotor retardation, fatigue, sleep, and appetite disturbances are related to mood and not to the physical symptoms of stroke. However, this step is difficult to implement in practice and psychomotor retardation and fatigue seem highly sensitive to depression after stroke.8 These symptoms are unpleasant and should be lessened when possible. Equally important is the need to ensure that disturbances in behaviour, facial expression, and verbal communication that result from the stroke do not mask symptoms of depression. The UK Royal College of Physicians’ guidelines9 recommend that all patients are screened for mood disorders within 6 weeks of a stroke. However, such screening is only worthwhile when followed by a fuller clinical diagnostic assessment and an agreed management plan.10 Observer-rated screening instruments (eg, Stroke Aphasic Depression Questionnaire11 or The Depression Intensity Scale Circles12) can be used to identify mood disturbance in people with aphasia or other communication problems; however, as with other screening methods, clinical judgment is then needed to decide whether the patient has depression and whether treatment is needed. Depression occurs more frequently in patients after stroke than in the general population. Data from two independent systematic reviews (43 cohorts including 20 293 people13 and 51 cohorts including 25 207 people14; 21 cohorts in both reviews) indicate that between 29%13 and 33%14 of patients have depression up to 1 year after a stroke. Estimates from individual studies of major depression that met DSM-3R or DSM-4 criteria varied across studies, from 2% of patients during admission in one cohort to 31% in another.15 In the latter cohort, researchers assessed major depression that met DSM-3R or DSM-4 criteria over 3 years. About 31% of patients had depression at 3 months after stroke, 16% at 1 year, 19% at 2 years, and 29% at 3 years after stroke (only 50 participants remained in the final cohort).16 Analyses of population-based stroke registers with long-term follow-up17–19 show that depression after stroke is a chronic relapsing disorder. Of people with depression at first assessment, between 13%18 and 52%19 still had depression after 1 year. About 15% of individuals without depression at initial assessment developed depression during the first year.17,19 Results from one systematic review of observational studies of depression after stroke (20 cohorts including 17 934 people)20 indicate
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
Lancet Neurol 2014 Published Online March 28, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70016-X The George Institute for Global Health, The University of Sydney, Sydney, NSW, Australia (M L Hackett PhD); University of Central Lancashire, Preston, UK (M L Hackett); Alzheimer Centre Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands (S Köhler PhD); Department of Psychiatry, University of Cambridge, Cambridge, UK (Prof J T O’Brien DM); Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK (Prof J T O’Brien); and Royal Infirmary, Edinburgh, UK (Prof G E Mead FRCP) Correspondence to: Prof Gillian E Mead, Royal Infirmary, Edinburgh EH16 4SA, UK [email protected]
1
Review
that only physical disability, stroke severity, and cognitive impairment consistently show a positive association with depression (note that most studies excluded people with depression before stroke).20 A second independent review using different methods included ten cohorts (16 045 patents; only one cohort was included in both reviews);13 the investigators reported that depression before stroke was associated with depression after stroke, and with disability, stroke severity, and cognitive impairment. Variables not associated with depression after stroke include older age, female sex, diabetes, stroke subtype, level of education, living alone, or a previous stroke.20 Only a small proportion of the variation in depression was accounted for, although the included studies generally had sample sizes that were too small for multivariate analyses. In 2008, Hackett and colleagues21 published a Cochrane review of pharmacological or psychological interventions to prevent depression after stroke and identified 14 trials involving 1515 people. The investigators reported a small but significant effect for use of psychological interventions (of various types; four trials), but no evidence of an effect for antidepressant drugs (ten trials). Four small trials of antidepressant drugs22–25 (384 people) that might Treatment Events Total
Control Events Total
Clinician interview or impression (number improved) Ohtomo27 1991 52 108 65 Subtotal (95% CI) 108 Total events 52 65 Heterogeneity: not applicable Test for overall effect: Z=2·61 (p=0·009) DSM-III Lipsey28 1984 Subtotal (95% CI) Total events
6
11 11
6 Heterogeneity: not applicable Test for overall effect: Z=0·06 (p=0·95)
HDRS Andersen29 1994 Fruehwald30 2003 Yang31 2002 Subtotal (95% CI) Total events
6 8 33
8
meet Cochrane criteria have been reported on since the 2008 article; three22,24,25 showed some evidence of benefit for antidepressant drugs, although their inclusion in the Cochrane review is unlikely to substantially change the overall estimates of effect. Hackett and colleagues26 published a second Cochrane review in 2008. This time they looked at pharmacological or psychological interventions to treat depression that occurred after stroke, and identified 16 trials recruiting 1655 people (figure 1). Antidepressant drugs (13 trials) were minimally effective (no evidence of differences in efficacy between antidepressant drugs), with an increase in gastrointestinal and CNS (eg, confusion, sedation, tremor) side-effects. These findings are consistent with results of a systematic review of trials in the general population that show antidepressant drugs to be minimally effective for mild to moderate depression,34 but of substantial benefit for severe depression. The investigators reported no evidence for effectiveness of psychological therapies alone (four trials) to treat depression after stroke.26 Since this review, we have identified one small trial of antidepressant treatment (of 150 people) that possibly
Weight (%)
Random effects odds ratio M–H (95%)
Random effects odds ratio M–H (95%CI)
98 98
18·5 18·5
0·47 (0·27–0·83) 0·47 (0·27–0·83)
15 15
10·8 10·8
1·05 (0·22–5·00) 1·05 (0·22–5·00)
20 24 57 101
10·7 13·1 14·0 37·7
0·09 (0·02–0·42) 1·33 (0·38–4·63) 0·08 (0·03–0·25) 0·21 (0·03–1·40)
61 114 175
15·2 17·7 33·0
1·59 (0·60–4·21) 0·50 (0·25–0·97) 0·84 (0·27–2·62)
389
100·0
0·47 (0·22–0·98)
8
18 26 64 108
17 6 53
47 76 Heterogeneity: τ2=2·29; χ2=12·44, df=2 (p=0·002); I2=84% Test for overall effect: Z=1·61 (p=0·11)
MADRS Murray32 2002 Ponzio33 2001 Subtotal (95% CI) Total events
12 82
62 111 173
8 97
94 105 Heterogeneity: τ2=0·50; χ2=3·74, df=1 (p=0·05); I2=73% Test for overall effect: Z=0·30 (p=0·76) 400
Total (95% CI) Total events
199
254
Heterogeneity: τ =0·68; χ =23·60, df=6 (p=0·0006); I =75% Test for overall effect: Z=2·02 (p=0·04) Test for subgroup differences: τ2=2·42, df=3 (p=0·49); I2=0% 2
2
2
0·01
0·1 Favours treatment
1
10
100
Favours control
Figure 1: Forest plot of treatments for depression after stroke Used by permission of Cochrane Library.26 M–H=Mantel–Haenszel. DSM=Diagnostic and Statistical Manual of Mental Disorders. HDRS=Hamilton Depression Rating Scale. MADRS=Montgomery–Åsberg Depression Rating Scale. 27–33
2
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
Review
meets Cochrane criteria, which noted a small benefit of antidepressant treatment.35 The Royal College of Physicians9 guidelines recommend that support and advice should be provided as first-line management for patients with mild or moderate symptoms of depression and that psychosocial interventions should be considered. These guidelines also recommend increased social interaction, exercise, and goal setting (although our searches did not show sufficient evidence to support or refute the effectiveness of these actions).9 The American36 and European37 guidelines recommend pharmaceutical treatment (selective serotonin-reuptake inhibitors or heterocyclic antidepressant drugs) for patients with depression.36,37 The guidelines recommend that treatment should be monitored for effectiveness, and antidepressant treatment (if used) continued for at least 6 months after initial recovery. The choice of antidepressants for individual patients can be guided by side-effect profile— eg, antidepressants with sedative properties might be appropriate for patients with disturbed sleep.
Anxiety For patients to meet diagnostic criteria for a generalised anxiety disorder, anxiety symptoms that are out of proportion to the actual threat or danger the situation poses must be present for 6 months, plus at least three of the following: feeling wound-up, tense, or restless; fatigue; difficulty concentrating; irritability; substantial muscle tension; and difficulty sleeping. To our knowledge, the Hamilton Depression Rating Scale8 is the only anxiety-specific case-finding instrument validated for use in stroke research and clinical settings with published data for sensitivity and specificity.38,39 If the Hamilton Depression Rating Scale is used to screen for anxiety, then, as with other screening instruments, clinical judgment is needed to decide whether the patient has anxiety and whether treatment is needed. Results of a systematic review (39 cohorts including 4706 people)40 indicated that 24% of stroke patients had anxiety symptoms as assessed by a rating scale, and 18% had an anxiety disorder in the first 5 years after stroke. Three cohort studies (856 people) reported anxiety in participants; the proportion of patients with persistent anxiety ranged from 38% to 76%. Investigators have narratively (but not systematically) reviewed studies of factors correlated with anxiety in more than five cohorts.40 Depression was positively correlated with anxiety in six of six cohorts, and quality of life was negatively correlated with anxiety in four of five cohorts. No association was shown with age, sex, or location of brain lesion. The factors that are associated with anxiety in stroke patients without depression are not known. There are no studies for anxiety prevention after stroke. Contributors to a Cochrane review of interventions to treat anxiety after stroke identified two trials involving 175 people.41 Both trials included people with comorbid anxiety and
depression but neither was placebo controlled. Antidepressant drugs alone or with psychotherapy might reduce anxiety symptoms, but there is not enough evidence from the Cochrane review to inform clinical practice.
Emotional lability DSM-53 describes emotional lability in patients as unstable emotional experiences and frequent mood changes, with emotions that are easily aroused, intense, or out of proportion to events and circumstances. It is also referred to as emotionalism, pathological laughing or crying, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect. There is no standard method of assessment. Emotional lability usually presents as an increase in crying or, less commonly, laughing, and can coexist with depression or depressive symptoms, but can also occur without depression. Symptoms are generally mild and transient, but when severe, can cause great distress, embarrassment, and avoidance of social contact. The reported prevalence of emotional lability varies across studies,42–48 from 8% of people who have had a stroke at 4 months in one cohort42 to 32% of people 3–12 months after stroke in another.44 Symptoms are thought to reduce in the 6 months after stroke.45 The factors associated with reduction in symptoms are not known. No systematic reviews have been done for the associations of emotional lability after stroke. Most research has focused on biological explanations, with an association between emotional lability and frontal lesions reported in four cohorts43,48–50 and an association with dorsal lesions in the other.51 In their Cochrane review of pharmacological interventions to treat emotional lability after stroke (seven trials, 739 people, recruited at 6 days to 13 years after stroke), Hackett and colleagues52 reported that antidepressant treatment reduced the frequency and severity of emotional lability, but that confidence intervals were wide (odds ratio of diminished tearfulness with treatment was 9·35, 95% CI 4·26–20·54; figure 2). Use of antidepressant treatments for persistent emotional lability that is frequent and severe enough to warrant the known risks of these drugs is appropriate; but the optimum class, duration, or dose is not known.3
Fatigue after stroke There is no standardised definition for fatigue after stroke.57 The published work distinguishes between physiological (or normal) fatigue (a state of general tiredness that develops acutely after overexertion and improves after rest), and pathological fatigue (constant weariness unrelated to previous exertion levels and not usually ameliorated by rest).58 In neurological disorders, pathological fatigue is more prominent than is physiological fatigue.59 Fatigue after stroke can be identified with use of a self-report fatigue scale52 or a structured interview to establish fulfilment of a case
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
3
Review
Treatment Events Total 50% reduction in emotionalism Brown53 1998 7 9 Subtotal (95% CI) 9 Total events 7 Heterogeneity: not applicable Test for overall effect: Z=2·56 (p=0·01)
Control Events Total
0
Weight (%)
10 10
0
Improved score on lability scale (House 1989 measure) Burns54 1999 13 14 9 14 Subtotal (95% CI) 14 14 Total events 13 9 Heterogeneity: not applicable Test for overall effect: Z=1·68 (p=0·09) Clinician-interview-based impression of change—improved score Burns54 1999 13 14 9 14 Subtotal (95% CI) 14 14 Total events 13 9 Heterogeneity: not applicable Test for overall effect: Z=1·68 (p=0·09) Diminished tearfulness Burns54 1999 Choi-Kwon55 2006 Murray56 2005 Subtotal (95% CI) Total events
14 37 13
14 44 24 82
9 14 4
14 48 20 82
Random effects odds ratio M–H (95%)
Random effects odds ratio M–H (95%CI)
100·0% 100·0%
63·00 (2·63–1511·41) 63·00(2·63–1511·41)
100·0% 100·0%
7·22 (0·72–72·70) 7·22 (0·72–72·70)
100·0% 100·0%
7·22 (0·72–72·70) 7·22 (0·72–72·70)
6·8% 59·6% 33·6% 100·0%
16·79 (0·83–340·08) 12·84 (4·63–35·59) 4·73 (1·22–18·39) 9·35 (4·26–20·54)
64 27 Heterogeneity: τ2=0·00; χ2=1·49, df=2 (p=0·48); I2=0% Test for overall effect: Z=5·57 (p
Neuropsychiatric outcomes of stroke Maree L Hackett, Sebastian Köhler, John T O’Brien, Gillian E Mead
The most common neuropsychiatric outcomes of stroke are depression, anxiety, fatigue, and apathy, which each occur in at least 30% of patients and have substantial overlap of prevalence and symptoms. Emotional lability, personality changes, psychosis, and mania are less common but equally distressing symptoms that are also challenging to manage. The cause of these syndromes is not known, and there is no clear relation to location of brain lesion. There are important gaps in knowledge about how to manage these disorders, even for depression, which is the most studied syndrome. Further research is needed to identify causes and interventions to prevent and treat these disorders.
Introduction Every year, about 16 million people worldwide have a firstever stroke. Of this population, about 5·7 million people die and another 5 million remain disabled.1 Neuropsychiatric disorders after stroke are common and can be distressing to patients and their families, but their effects are often underappreciated by health-care professions and patients’ treatment needs are often unmet.2 In this Review, we focus on the most common non-cognitive neuropsychiatric outcomes of stroke—ie, depression, anxiety, emotional lability, and apathy. We also discuss post-stroke fatigue (which is generally classified as a neuropsychiatric disorder), personality changes, psychosis, and mania. For each disorder, we discuss definition and identification, prevalence, associations, natural history and outcome, prevention, and treatment, and then make recommendations for future research. Researchers tend to consider each neuropsychiatric disorder separately, so we follow this approach, but we acknowledge that substantial overlap exists between the syndromes. Our management recommendations are based on data from randomised controlled trials or metaanalyses of these trials, but not from uncontrolled case series. In the absence of randomised data, we provide consensus recommendations.
Depression The fifth US Diagnostic and Statistical Manual of Mental Disorders (DSM-5)3 defines depression as depressed mood or anhedonia (loss of interest or pleasure) for 2 weeks or longer, plus the presence of at least four of the following symptoms when they are persistent and they interfere with daily life: substantial weight loss or gain, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, worthlessness or inappropriate guilt, diminished concentration, or indecisiveness. For diagnosis in busy and resource-poor clinical settings, it is often appropriate to use an interviewer-administered or self-completed depression case-finding or screening instrument that is validated for use in stroke4 (eg, the nine-item Patient Health Questionnaire,5 The Center of Epidemiological StudiesDepression Scale,6 Hospital Anxiety and Depression Scale [HADS], the Hamilton Depression Rating Scale, and the Beck Depression Inventory7). When clinicians diagnose depression, they should consider whether
somatic symptoms such as psychomotor retardation, fatigue, sleep, and appetite disturbances are related to mood and not to the physical symptoms of stroke. However, this step is difficult to implement in practice and psychomotor retardation and fatigue seem highly sensitive to depression after stroke.8 These symptoms are unpleasant and should be lessened when possible. Equally important is the need to ensure that disturbances in behaviour, facial expression, and verbal communication that result from the stroke do not mask symptoms of depression. The UK Royal College of Physicians’ guidelines9 recommend that all patients are screened for mood disorders within 6 weeks of a stroke. However, such screening is only worthwhile when followed by a fuller clinical diagnostic assessment and an agreed management plan.10 Observer-rated screening instruments (eg, Stroke Aphasic Depression Questionnaire11 or The Depression Intensity Scale Circles12) can be used to identify mood disturbance in people with aphasia or other communication problems; however, as with other screening methods, clinical judgment is then needed to decide whether the patient has depression and whether treatment is needed. Depression occurs more frequently in patients after stroke than in the general population. Data from two independent systematic reviews (43 cohorts including 20 293 people13 and 51 cohorts including 25 207 people14; 21 cohorts in both reviews) indicate that between 29%13 and 33%14 of patients have depression up to 1 year after a stroke. Estimates from individual studies of major depression that met DSM-3R or DSM-4 criteria varied across studies, from 2% of patients during admission in one cohort to 31% in another.15 In the latter cohort, researchers assessed major depression that met DSM-3R or DSM-4 criteria over 3 years. About 31% of patients had depression at 3 months after stroke, 16% at 1 year, 19% at 2 years, and 29% at 3 years after stroke (only 50 participants remained in the final cohort).16 Analyses of population-based stroke registers with long-term follow-up17–19 show that depression after stroke is a chronic relapsing disorder. Of people with depression at first assessment, between 13%18 and 52%19 still had depression after 1 year. About 15% of individuals without depression at initial assessment developed depression during the first year.17,19 Results from one systematic review of observational studies of depression after stroke (20 cohorts including 17 934 people)20 indicate
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
Lancet Neurol 2014 Published Online March 28, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70016-X The George Institute for Global Health, The University of Sydney, Sydney, NSW, Australia (M L Hackett PhD); University of Central Lancashire, Preston, UK (M L Hackett); Alzheimer Centre Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands (S Köhler PhD); Department of Psychiatry, University of Cambridge, Cambridge, UK (Prof J T O’Brien DM); Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK (Prof J T O’Brien); and Royal Infirmary, Edinburgh, UK (Prof G E Mead FRCP) Correspondence to: Prof Gillian E Mead, Royal Infirmary, Edinburgh EH16 4SA, UK [email protected]
1
Review
that only physical disability, stroke severity, and cognitive impairment consistently show a positive association with depression (note that most studies excluded people with depression before stroke).20 A second independent review using different methods included ten cohorts (16 045 patents; only one cohort was included in both reviews);13 the investigators reported that depression before stroke was associated with depression after stroke, and with disability, stroke severity, and cognitive impairment. Variables not associated with depression after stroke include older age, female sex, diabetes, stroke subtype, level of education, living alone, or a previous stroke.20 Only a small proportion of the variation in depression was accounted for, although the included studies generally had sample sizes that were too small for multivariate analyses. In 2008, Hackett and colleagues21 published a Cochrane review of pharmacological or psychological interventions to prevent depression after stroke and identified 14 trials involving 1515 people. The investigators reported a small but significant effect for use of psychological interventions (of various types; four trials), but no evidence of an effect for antidepressant drugs (ten trials). Four small trials of antidepressant drugs22–25 (384 people) that might Treatment Events Total
Control Events Total
Clinician interview or impression (number improved) Ohtomo27 1991 52 108 65 Subtotal (95% CI) 108 Total events 52 65 Heterogeneity: not applicable Test for overall effect: Z=2·61 (p=0·009) DSM-III Lipsey28 1984 Subtotal (95% CI) Total events
6
11 11
6 Heterogeneity: not applicable Test for overall effect: Z=0·06 (p=0·95)
HDRS Andersen29 1994 Fruehwald30 2003 Yang31 2002 Subtotal (95% CI) Total events
6 8 33
8
meet Cochrane criteria have been reported on since the 2008 article; three22,24,25 showed some evidence of benefit for antidepressant drugs, although their inclusion in the Cochrane review is unlikely to substantially change the overall estimates of effect. Hackett and colleagues26 published a second Cochrane review in 2008. This time they looked at pharmacological or psychological interventions to treat depression that occurred after stroke, and identified 16 trials recruiting 1655 people (figure 1). Antidepressant drugs (13 trials) were minimally effective (no evidence of differences in efficacy between antidepressant drugs), with an increase in gastrointestinal and CNS (eg, confusion, sedation, tremor) side-effects. These findings are consistent with results of a systematic review of trials in the general population that show antidepressant drugs to be minimally effective for mild to moderate depression,34 but of substantial benefit for severe depression. The investigators reported no evidence for effectiveness of psychological therapies alone (four trials) to treat depression after stroke.26 Since this review, we have identified one small trial of antidepressant treatment (of 150 people) that possibly
Weight (%)
Random effects odds ratio M–H (95%)
Random effects odds ratio M–H (95%CI)
98 98
18·5 18·5
0·47 (0·27–0·83) 0·47 (0·27–0·83)
15 15
10·8 10·8
1·05 (0·22–5·00) 1·05 (0·22–5·00)
20 24 57 101
10·7 13·1 14·0 37·7
0·09 (0·02–0·42) 1·33 (0·38–4·63) 0·08 (0·03–0·25) 0·21 (0·03–1·40)
61 114 175
15·2 17·7 33·0
1·59 (0·60–4·21) 0·50 (0·25–0·97) 0·84 (0·27–2·62)
389
100·0
0·47 (0·22–0·98)
8
18 26 64 108
17 6 53
47 76 Heterogeneity: τ2=2·29; χ2=12·44, df=2 (p=0·002); I2=84% Test for overall effect: Z=1·61 (p=0·11)
MADRS Murray32 2002 Ponzio33 2001 Subtotal (95% CI) Total events
12 82
62 111 173
8 97
94 105 Heterogeneity: τ2=0·50; χ2=3·74, df=1 (p=0·05); I2=73% Test for overall effect: Z=0·30 (p=0·76) 400
Total (95% CI) Total events
199
254
Heterogeneity: τ =0·68; χ =23·60, df=6 (p=0·0006); I =75% Test for overall effect: Z=2·02 (p=0·04) Test for subgroup differences: τ2=2·42, df=3 (p=0·49); I2=0% 2
2
2
0·01
0·1 Favours treatment
1
10
100
Favours control
Figure 1: Forest plot of treatments for depression after stroke Used by permission of Cochrane Library.26 M–H=Mantel–Haenszel. DSM=Diagnostic and Statistical Manual of Mental Disorders. HDRS=Hamilton Depression Rating Scale. MADRS=Montgomery–Åsberg Depression Rating Scale. 27–33
2
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
Review
meets Cochrane criteria, which noted a small benefit of antidepressant treatment.35 The Royal College of Physicians9 guidelines recommend that support and advice should be provided as first-line management for patients with mild or moderate symptoms of depression and that psychosocial interventions should be considered. These guidelines also recommend increased social interaction, exercise, and goal setting (although our searches did not show sufficient evidence to support or refute the effectiveness of these actions).9 The American36 and European37 guidelines recommend pharmaceutical treatment (selective serotonin-reuptake inhibitors or heterocyclic antidepressant drugs) for patients with depression.36,37 The guidelines recommend that treatment should be monitored for effectiveness, and antidepressant treatment (if used) continued for at least 6 months after initial recovery. The choice of antidepressants for individual patients can be guided by side-effect profile— eg, antidepressants with sedative properties might be appropriate for patients with disturbed sleep.
Anxiety For patients to meet diagnostic criteria for a generalised anxiety disorder, anxiety symptoms that are out of proportion to the actual threat or danger the situation poses must be present for 6 months, plus at least three of the following: feeling wound-up, tense, or restless; fatigue; difficulty concentrating; irritability; substantial muscle tension; and difficulty sleeping. To our knowledge, the Hamilton Depression Rating Scale8 is the only anxiety-specific case-finding instrument validated for use in stroke research and clinical settings with published data for sensitivity and specificity.38,39 If the Hamilton Depression Rating Scale is used to screen for anxiety, then, as with other screening instruments, clinical judgment is needed to decide whether the patient has anxiety and whether treatment is needed. Results of a systematic review (39 cohorts including 4706 people)40 indicated that 24% of stroke patients had anxiety symptoms as assessed by a rating scale, and 18% had an anxiety disorder in the first 5 years after stroke. Three cohort studies (856 people) reported anxiety in participants; the proportion of patients with persistent anxiety ranged from 38% to 76%. Investigators have narratively (but not systematically) reviewed studies of factors correlated with anxiety in more than five cohorts.40 Depression was positively correlated with anxiety in six of six cohorts, and quality of life was negatively correlated with anxiety in four of five cohorts. No association was shown with age, sex, or location of brain lesion. The factors that are associated with anxiety in stroke patients without depression are not known. There are no studies for anxiety prevention after stroke. Contributors to a Cochrane review of interventions to treat anxiety after stroke identified two trials involving 175 people.41 Both trials included people with comorbid anxiety and
depression but neither was placebo controlled. Antidepressant drugs alone or with psychotherapy might reduce anxiety symptoms, but there is not enough evidence from the Cochrane review to inform clinical practice.
Emotional lability DSM-53 describes emotional lability in patients as unstable emotional experiences and frequent mood changes, with emotions that are easily aroused, intense, or out of proportion to events and circumstances. It is also referred to as emotionalism, pathological laughing or crying, emotional incontinence, involuntary emotional expression disorder, and pseudobulbar affect. There is no standard method of assessment. Emotional lability usually presents as an increase in crying or, less commonly, laughing, and can coexist with depression or depressive symptoms, but can also occur without depression. Symptoms are generally mild and transient, but when severe, can cause great distress, embarrassment, and avoidance of social contact. The reported prevalence of emotional lability varies across studies,42–48 from 8% of people who have had a stroke at 4 months in one cohort42 to 32% of people 3–12 months after stroke in another.44 Symptoms are thought to reduce in the 6 months after stroke.45 The factors associated with reduction in symptoms are not known. No systematic reviews have been done for the associations of emotional lability after stroke. Most research has focused on biological explanations, with an association between emotional lability and frontal lesions reported in four cohorts43,48–50 and an association with dorsal lesions in the other.51 In their Cochrane review of pharmacological interventions to treat emotional lability after stroke (seven trials, 739 people, recruited at 6 days to 13 years after stroke), Hackett and colleagues52 reported that antidepressant treatment reduced the frequency and severity of emotional lability, but that confidence intervals were wide (odds ratio of diminished tearfulness with treatment was 9·35, 95% CI 4·26–20·54; figure 2). Use of antidepressant treatments for persistent emotional lability that is frequent and severe enough to warrant the known risks of these drugs is appropriate; but the optimum class, duration, or dose is not known.3
Fatigue after stroke There is no standardised definition for fatigue after stroke.57 The published work distinguishes between physiological (or normal) fatigue (a state of general tiredness that develops acutely after overexertion and improves after rest), and pathological fatigue (constant weariness unrelated to previous exertion levels and not usually ameliorated by rest).58 In neurological disorders, pathological fatigue is more prominent than is physiological fatigue.59 Fatigue after stroke can be identified with use of a self-report fatigue scale52 or a structured interview to establish fulfilment of a case
www.thelancet.com/neurology Published online March 28, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70016-X
3
Review
Treatment Events Total 50% reduction in emotionalism Brown53 1998 7 9 Subtotal (95% CI) 9 Total events 7 Heterogeneity: not applicable Test for overall effect: Z=2·56 (p=0·01)
Control Events Total
0
Weight (%)
10 10
0
Improved score on lability scale (House 1989 measure) Burns54 1999 13 14 9 14 Subtotal (95% CI) 14 14 Total events 13 9 Heterogeneity: not applicable Test for overall effect: Z=1·68 (p=0·09) Clinician-interview-based impression of change—improved score Burns54 1999 13 14 9 14 Subtotal (95% CI) 14 14 Total events 13 9 Heterogeneity: not applicable Test for overall effect: Z=1·68 (p=0·09) Diminished tearfulness Burns54 1999 Choi-Kwon55 2006 Murray56 2005 Subtotal (95% CI) Total events
14 37 13
14 44 24 82
9 14 4
14 48 20 82
Random effects odds ratio M–H (95%)
Random effects odds ratio M–H (95%CI)
100·0% 100·0%
63·00 (2·63–1511·41) 63·00(2·63–1511·41)
100·0% 100·0%
7·22 (0·72–72·70) 7·22 (0·72–72·70)
100·0% 100·0%
7·22 (0·72–72·70) 7·22 (0·72–72·70)
6·8% 59·6% 33·6% 100·0%
16·79 (0·83–340·08) 12·84 (4·63–35·59) 4·73 (1·22–18·39) 9·35 (4·26–20·54)
64 27 Heterogeneity: τ2=0·00; χ2=1·49, df=2 (p=0·48); I2=0% Test for overall effect: Z=5·57 (p
