Clinical manifestations

Presentation and course

Two depressive syndromes, major depression and minor (dysthymic) depression, have been reported in patients with stroke lesions. The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders defines poststroke major depression as "a mood disorder due to stroke with major depressive-like episode." Table 1 shows the Diagnostic and Statistical Manual of Mental Disorders criteria for major depression. The most frequent symptoms of major poststroke depression include sadness, anxiety, tension, loss of interest, sleep disturbances with early morning awakening, loss of appetite with weight loss, difficulty concentrating and thinking, and thoughts of death. The prevalence of the above symptoms in patients with poststroke depression is similar to the prevalence of depressive symptoms found in patients with primary (ie, no known brain injury) depression. Paradiso and colleagues demonstrated that only 2% to 3% of stroke patients have depressive symptoms without a depressed mood and suggested that these criteria do not over diagnose major depression among stroke patients (84). Depression interferes with rehabilitation (102; 86) by causing physical and cognitive function impairment (94). Older adults are more likely than younger ones to mask depression with somatic rather than psychiatric symptoms (59). Though the DSM-IV and Hamilton rating scale of depression treat apathy as 1 aspect of depression, the difference between apathy and depression may be somewhat unclear. Marin and associates found that the absolute levels of apathy and depression in patient groups varied considerably, although these 2 conditions do have some correlations (70). They suggested that apathy and depression are 2 distinct symptoms, and Levy and colleagues suggested that they may require different treatment approaches (64). Apathy is found in more than 20% of first-ever stroke patients and may impair functional recovery from stroke (98). Poststroke depression (mild to severe depression) in the elderly is associated with increased mortality and is detectable as early as 1 year (51) but lasts for at least 7 years poststroke (75). Other morbidities include dependency, risky behaviors including drug and alcohol abuse, increase in suicide rate, poor compliance with treatment and self care (54).

Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least 1 of the symptoms is either depressed mood or loss of interest or pleasure (See Table 1).

Table 1. Criteria for Major Depressive Episode *

	(1) Depressed mood most of the day, nearly every day, as indicated either by subjective report (eg, feels sad or empty) or observation.
	(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated either by subjective account or observation made by others).
	(3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day.
	(4) Insomnia or hypersomnia nearly every day.
	(5) Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).
	(6) Fatigue or loss of energy nearly every day.
	(7) Feelings of worthlessness or excessive or inappropriate guilt (these may be delusional) nearly every day (not merely self-reproach or guilt about being sick).
	(8) Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).
	(9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
* adapted from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (03).

A lesser form of depression, included in the Diagnostic and Statistical Manual of Mental Disorders, is minor depression. The "research criteria" for minor depression require depression or anhedonia with at least 1, but fewer than 4, additional symptoms of major depression or alternatively, a diagnosis of mood disorder due to stroke with depressive features.

Another diagnostic category offered by the Diagnostic and Statistical Manual of Mental Disorders is dysthymia (Table 2). One limitation of this diagnosis is that it requires that the syndromic cluster of depressive symptoms be present most of the time for more than 2 years. Because waiting for 2 years to diagnose a poststroke dysthymic disorder is not clinically useful, most studies have used the symptom criteria for dysthymic disorder excluding the 2-year criterion.

Table 2. Diagnostic Criteria for Dysthymic Disorder *

	(A) Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. (B) Presence, while depressed, of 2 (or more) of the following:
		(1) Poor appetite or overeating. (2) Insomnia or hypersomnia. (3) Low energy or fatigue. (4) Low self-esteem. (5) Poor concentration or difficulty making decisions. (6) Feelings of hopelessness.

* adapted from the Diagnostic and Statistical Manual of Mental Disorders (03).

Gainotti and colleagues examined the phenomenology of poststroke depression using the Poststroke Depression rating scale, which assesses depressed mood, feelings of guilt, thoughts of death or suicide, autonomic symptoms, apathy and loss of interest, anxiety, catastrophic reactions, hyperemotionalism, anhedonia, and diurnal mood variation. They found 2 profiles of depression after stroke: (1) an "endogenous" type, with higher scores on suicide and anhedonia; and (2) a "reactive" type, with higher scores on catastrophic reaction, hyperemotionalism, and diurnal mood variation (37). Both catastrophic reaction and hyperemotionalism (also known as "pathological affective display") were reported by other authors to be significantly associated with depression in stroke patients (92). However, many depressed stroke patients may lack those symptoms, which raises the question about the validity of the "endogenous" and "reactive" constructs.

Beblo and Driessen compared 20 patients with poststroke depression and 41 patients with depression without a known neuropathology (“primary depression”). They observed that patients with poststroke depression exhibited no melancholia and fewer cyclic and ideational disturbances, but more physical signs than primary depression (10). Tateno and colleagues examined patients with early-onset poststroke minor and major depression (diagnosed 3 to 6 months poststroke) and late-onset poststroke minor and major depression (diagnosed 12 to 24 months poststroke). They reported that early-onset poststroke major depression was associated with higher frequency of vegetative symptoms and larger lesion volume than late-onset major depression, whereas early-onset minor depression was associated with poorer social functioning and a higher frequency of melancholic, vegetative, and psychological symptoms of depression than late-onset minor depression (114).

Berg and coworkers found in their comparative study that Beck Depression Inventory, Hamilton Rating Scale for Depression, and Clinical Global Impression assessment by professionals, in addition to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised Diagnosis, are useful in assessing depression, but none of these instruments clearly stood apart from the others (13). They feel that proxy ratings should be used with caution, and the use of the Visual Analogue Mood Scale among patients with aphasia and other cognitive impairments cannot be recommended.

Proxies tended to score the patients as more severely affected than the patients scored themselves (121; 48).

Chronic illness and acute health events are more frequent among older adults, and the comorbidity of somatic illness and psychiatric distress complicates the diagnosis and treatment of depression. Depression causes enormous additional stress on caregivers (04).

Prognosis and complications

Although major poststroke depression was reported to last about 1 year, minor (dysthymic) poststroke depression was found to have a more variable duration, lasting from 3 months to more than 2 years.

Robinson and colleagues examined the long-term evolution of major and minor poststroke depression (93). One year after the stroke, 60% of the patients with major depression at the initial evaluation were still depressed, although none of them had major depression at the 2-year evaluation. Also, 60% of the patients with dysthymia were still depressed at the 2-year evaluation. However, Morris and colleagues and House and colleagues reported that most patients with minor depression were not depressed 3 to 6 months after the acute event (77; 49). Differences in case ascertainment (acute stroke patients vs. community-dwelling patients) or differences in premorbid personality characteristics may explain these discrepancies. Kauhanen and colleagues examined the longitudinal evolution of depression in 106 poststroke patients and found an increasing frequency of major depression during the first year poststroke (55). They reported 53% of patients had depression after 3 months post stroke (44% minor and 9% major depression) and 42% after 12 months poststroke (26% minor and 16% major depression). Seventy percent of the dysphasic patients were depressed during the study, of whom 58% had minor depression and 12% had major depression at 3 months, whereas 25% and 35% had minor and major depression, respectively, at 1 year.

Lesion location may also influence the duration of poststroke depression. Starkstein and colleagues demonstrated that patients with subcortical (primarily basal ganglia) or cerebellar and brainstem lesions recovered significantly faster from poststroke depression than patients with cortical lesions (110). Chemerinski and colleagues reported that remission of poststroke depression over the first months after stroke was associated with a significant recovery in activities of daily living (22). In 1 study, Kimura and colleagues reported that patients with remission of poststroke depression after treatment with nortriptyline had a greater recovery in cognitive function over the course of the treatment period than patients whose depression did not remit (58).

Clinical vignette

A 52-year-old married man suffered a heart attack while playing basketball. Two nights later he had a thromboembolism that produced a large, right middle cerebral artery infarct with left hemiparesis and sensory deficit. Within a few days after stroke, he developed a depressive syndrome with symptoms of anxiety, sadness, tension, restlessness, worry, low energy, and loss of interest in activities that he previously enjoyed, such as eating out and shopping. He also complained of insomnia and loss of appetite. This syndrome lasted for 3 months, when the patient was started on antidepressant medication (nortriptyline). There was a progressive mood improvement, and the patient was euthymic 3 weeks after starting antidepressant medication.

Biological basis

Etiology and pathogenesis

Major poststroke depression is associated with lesions involving left cortical (mainly frontal) and subcortical (mainly basal ganglia) regions. Moreover, there is a correlation between the distance of the lesion from the frontal pole and depression scores: the closer the lesion is to the frontal pole, the more severe the depression. On the other hand, minor (dysthymic) depression is associated with both right and left posterior (mainly parietal) lesions (92).

In a study that included a consecutive series of 193 patients participating in the multicenter Stroke Data Bank, Morris and colleagues found a significant association between poststroke depression and small left hemisphere lesions (76). Astrom and colleagues reported that 12 of 14 patients (86%) with left anterior stoke lesions had major depression, as compared to only 2 of 7 patients (28%) with left posterior lesions, and 1 of 7 patients (14%) with right hemisphere lesions (p less than .001) (06). Singh and colleagues reported that lesions to the inferior frontal region, irrespective of side, predicted high 3-month depression scores (101). Single lesions to the lateral prefrontal cortex were reported to predict a higher prevalence of depression and anxiety disorders at 3 months postinjury (83). The neuropsychiatric features after acute insular stroke were evaluated by Manes and colleagues. Lesions to the right insula were reported to be significantly related to more subjective anergia, underactivity, and tiredness as compared to left insular lesions (68). The Cardiovascular Healthy Study included 3657 people 65 years or older who underwent brain MRI and a modified version of the Centers for Epidemiological Studies-Depression scale; the researchers found that lesions in the basal ganglia were associated with greater scores than lesions in other brain areas (111). Beblo and colleagues analyzed lesion configuration in 20 consecutive patients with postacute single unilateral strokes and found that 9 of 10 patients with left hemisphere strokes exhibited major depression, whereas 7 of the 10 subjects with right hemisphere infarcts exhibited minor depression. For both major and minor depression, the maximal overlap of lesions was found in subcortical areas, including parts of the caudate nucleus, posterior parts of the putamen, and the deep white matter (11). In a series of 109 consecutive patients with ischemic stroke and depressive disorders, Vataja and colleagues found a strong correlation between severity of depression and a higher number and larger volume of infarcts in the caudate, pallidum, and genu of internal capsule, predominantly on the left side (117). In a study that included 45 patients with single lesions, Starkstein and colleagues found that 44% of patients with left cortical lesions and 39% of patients with left subcortical lesions were depressed, as compared to 11% of patients with right cortical lesions and 24% of patients with right subcortical lesions (108). Carson and colleagues carried out a metaanalysis study that did not demonstrate a strong association between poststroke depression and lesion location. The analysis included studies that used different criteria for depression, different psychiatric instruments, and different evaluations of lesion location (21).

Moreover, correlations between depression scores and the distance of the lesion from the frontal pole were significant for both patients with left cortical (r = -0.52, p less than .05) and left subcortical (r=-0.68, p less than .05) lesions. A similar correlation between distance of the lesion from the frontal pole and depression scores among patients with left hemisphere lesions was reported by Eastwood and colleagues (r = -0.74, p less than .01) (30), Morris and colleagues (r = -0.87, p less than .0001) (78), and Herrmann and Wallesch (r = -0.44, p less than .05) (46). These findings demonstrate that lesion location along the anterior-posterior brain axis is an important variable in the severity of depression following stroke. Although some authors could not replicate the laterality findings (50; 20), important methodological differences such as time since stroke, referral pattern, and severity of stroke may explain these differences (Shimoda and 92; 21).

Both subcortical atrophy that may precede the stroke lesion and a family or personal history of psychiatric disorder are relevant risk factors for poststroke depression (92). Starkstein and colleagues compared 13 patients with major poststroke depression and 13 patients without poststroke depression matched for lesion site and location (109). Eleven pairs had left hemisphere lesions and the remaining 2 pairs had right hemisphere lesions. Although there were no significant between-group differences in demographic variables and severity of physical impairment, patients with major poststroke depression had significantly larger third and lateral ventricles than patients without poststroke depression.

In a study that included a consecutive series of 93 patients with acute right hemisphere lesions, Starkstein and colleagues found that patients with poststroke depression had a significantly higher frequency of family history of psychiatric disorders than nondepressed patients with right hemisphere lesions or patients with major depression after left hemisphere lesions (107).

In their study to determine the association between the neuro-radiological characteristics of stroke lesions and post-stroke major depression among survivors, Ojagbemi and colleagues found that lesion characteristics documented in the acute phase of stroke could not predict the occurrence of major depressive disorder during rehabilitation (81). No differences were noted with hemispheric lateralization or intra-hemispheric lesion location. Female gender showed strong association with post-stroke major depressive disorder.

Bushnell and associates reported that women have worse quality of life (QOL) than men up to 12 months after stroke, even after adjusting for the incremental impact of demographic, socioeconomic, clinical, and stroke-specific effects including disability on longitudinal QOL (18). Women fared worse in the dimensions of mobility, pain/discomfort, and anxiety/depression at 3 and 12 months.

Dysfunction of biogenic amines may play an important role in the mechanism of poststroke depression. The cell bodies of noradrenergic and serotonergic neuron, located in the brainstem (locus coeruleus and raphe nuclei, respectively), send ascending projections through the median forebrain bundle to the frontal cortex and arc posteriorly running longitudinally through the deep layers of the cortex. Lesions that disrupt these pathways near the frontal pole and the basal ganglia may affect more biogenic amine fibers. Laboratory investigations in rats have demonstrated that right, but not left, hemisphere lesions produce cortical depletions of norepinephrine and locomotor hyperactivity (91). In humans, Mayberg and colleagues reported that stroke lesions in the right hemisphere produced a significantly higher ratio of ipsilateral-to-contralateral spiperone binding (primarily to serotonin receptors) in uninjured temporal and parietal cortex as compared to patients with comparable left hemisphere strokes (71). On the other hand, patients with left hemisphere strokes showed a significant inverse correlation between the amount of spiperone binding in the left temporal cortex and depression scores. In conclusion, a greater depletion of biogenic amines in patients with right hemisphere lesions could result in a compensatory upregulation of serotonin receptors. This lack of upregulation after left hemisphere lesions may lead to left temporal lobe dysfunction and ultimately result in depression. A higher incidence of typical depression in asymmetric left hemisphere-predominant cases of frontotemporal dementia supports the left laterality of strokes resulting in depression (31).

Kim and colleagues reported that delayed depression and anxiety after ischemic stroke were related to the severity of deep white matter hyperintensities (DWMH) and unfavorable outcomes at 3 months, regardless of anti-anxiety treatment, suggesting that WMH might play a role in the pathomechanism of delayed depression and anxiety (57). Ayerbe and colleagues concluded that depression pre-stroke, cognitive impairment, stroke severity, and anxiety are the major predictors of depression after stroke (07). Independent outcomes of depression after stroke include lower quality of life, mortality, and disability.

Epidemiology

Most studies reported a prevalence of poststroke depression of about 40%. Although half of these depressions meet the criteria for a major depression, the remaining half meets the criteria for a minor (dysthymic) depression. The number of patients admitting to depressive symptoms but not meeting criteria for major or minor depression also may be high. As much as a third of stroke survivors suffer from depression during the first year after the onset of stroke (43).

The prevalence of poststroke depression varies depending on the sample characteristics. Although the prevalence of poststroke depression in persons with acute stroke ranges from about 40% to 50%, the prevalence of poststroke depression in rehabilitation centers was reported to range between 49% and 54%, and the prevalence in community-based studies was reported to be around 23% (17; 92). In a rural Chinese community, as many as 62.2% (28 of 45) of stroke survivors met the criteria for depression. The mood disorder correlated with loss of daily living activities (36). A Finnish study found major depression in 26% and minor depression in 14% of a consecutive series of 486 patients with ischemic stroke (87). In an 18-month follow-up study of 100 stroke patients, Berg and coworkers observed that 46% of patients that were depressed during the first 2 months were also depressed at 12 and 18 months poststroke (14). Poststroke depression affects approximately one third of ischemic stroke survivors (43).

De Wit and associates, in their longitudinal multicenter study, document the prevalence, severity, and time course of anxiety and depression in stroke rehabilitation patients in 4 European countries at 2, 4 and 6 months poststroke in 532 consecutively recruited patients using the Hospital Anxiety and Depression Scale (28). Despite differences in patient profiles and intensity of rehabilitation, no significant differences occurred in prevalence and severity of both disorders between centers. Anxiety was almost as common as depression and additional patients became anxious or depressed at each time point. Prevalence of anxiety ranged between 22% and 25%; depression ranged between 24% and 30%. Median severity ranged between 4 and 5. Some 11% and 7% of those initially not anxious became anxious at 4 or 6 months after stroke, respectively. Depression showed a similar pattern.

Women were reported to have a significantly higher prevalence of poststroke major depression as compared to men (47; 85). In men, major depression was associated with greater impairments in activities of daily living and worse social functioning. In women, more severe depression was significantly associated with a prior diagnosis of a psychiatric disorder and more severe cognitive impairment (85).

A significant association between female sex, long-lasting disability, living alone after stroke, and age more than 70 years and depression after stroke was reported by (45). Aben and colleagues performed a prospective study in 190 patients to evaluate psychological factors related to depression after stroke. They found that neuroticism (the tendency to experience negative mood states) was an important predictor of poststroke depression (01).

Eriksson and colleagues noted that the rate of suicide attempts and completed suicides in poststroke patients were double the rate of the general population under their study (32). They concluded that both clinical and socioeconomic factors including lower education or income and living alone increase the risk of poststroke suicide attempts. Other factors included male sex, young age, severe stroke, and poststroke depression, and the risk was highest during the first 2 years after stroke.

Prevention

The role of intervention for preventing depression after stroke remains unclear. The possibility that depression may be associated with subsequent strokes was examined by Ohira and colleagues in a study that included 901 individuals in a rural Japanese community (80). The main finding was that after controlling for several confounding variables, depressive symptoms were a significant predictor of stroke. Only 1 study evaluated the use of an antidepressant drug to prevent poststroke depression.

The antidepressant mianserin was evaluated in an 18-month, randomized, double-blind, placebo-controlled study that included 100 patients with acute stroke (82). Patients received either mianserin (up to 60 mg per day) or placebo during a 12-month period and were evaluated at baseline and at 2, 6, 12, and 18 months follow-up. Both the mianserin and placebo groups showed a similar prevalence of depression during the follow-up period (6% and 4% at baseline; 4% and 10% at 2 months; 8% and 6% at 6 months; 10% and 11% at 12 months; and 16% and 15% at 18 months, respectively), thus, failing to demonstrate a significant efficacy for mianserin to prevent poststroke depression.

A double-blind study by Narashima and coworkers compared nortriptyline, fluoxetine, and placebo to prevent poststroke depression. During the 3-month treatment period, nortriptyline and fluoxetine appeared to be better than placebo in preventing depression. However, when nortriptyline was discontinued, patients were more likely to develop depression during the following 6 months (79).

Depression is an important negative factor in the recovery from impairments in activities of daily living and is also associated with a higher mortality among stroke patients. Several investigators demonstrate a significant correlation between depression and physical impairment. A study by Singh and colleagues demonstrates that more severe deficits in activities of daily living (as measured with the Functional Independence Measure) predicted a more severe depression 3 months later (101). However, depression was also found to influence the severity of functional impairment. Parikh and colleagues examined the severity of functional impairments in 63 stroke patients with or without depression during a 2-year follow-up period (86). Although both groups were comparable in terms of physical disability while in the hospital, depressed patients showed significantly less recovery after 2 years compared to nondepressed patients. In a study that included consecutive admission to a regional stroke center, Herrmann and colleagues found significant correlations between depression and both functional outcome and handicap at 3 months and 1 year (47). Ramasubbu and colleagues examined the association of poststroke depression and deficits in activities of daily living in 626 patients (88). They found that depressed stroke patients had greater impairments in activities of daily living than nondepressed patients. Besides depression, other factors associated with more severe impairments were neurologic signs, greater age, poor prestroke physical activity, and prestroke disturbances in sexual functioning. Clark and Smith confirmed the significant association between poststroke depression and worse social functioning, and Lofgren and coworkers demonstrated a significant negative correlation between depression and psychological well-being after stroke (25; 62). Carod-Artal and colleagues examined quality of life in a series of 90 stroke survivors 1 year after the acute event. They found that depression was among the main predictors of quality of life among stroke patients (19).

Depression may also increase the mortality of stroke. Morris and colleagues determined the vital status of 91 patients out of 103 who had been examined after an acute stroke 10 years before (75). Forty-eight (53%) of the patients had died during the 10-year follow-up period, and patients with poststroke depression were 3.4 times more likely to have died during the follow-up period than were nondepressed stroke patients. House and colleagues examined mortality in a 12 and 24-month follow-up study that included 448 stroke patients. They found that mood symptoms on a self-reported rating scale were associated with 12-and 24-month mortality after stroke and after adjusting for stroke-related factors (51). Everson and colleagues examined the association between depression symptoms and stroke mortality in a prospective study of behavioral, social, and psychological factors related to health and mortality in a community sample (33). They confirmed a significant relationship between depressive symptoms and stroke mortality.

Patients with major depression after left hemisphere lesions also demonstrated significantly more severe cognitive impairments than nondepressed stroke patients, and poststroke depression may have a negative influence on the recovery of cognitive impairment. Robinson and colleagues reported that patients with major poststroke depression had significantly lower scores on the Mini-Mental State Exam than nondepressed stroke patients, but no significant differences were found between patients with minor depression and nondepressed stroke patients (94).

Because lesion variables may account for a significant proportion of cognitive deficits, Starkstein and colleagues matched stroke patients with or without major depression for lesion size and location. They found that patients with major poststroke depression had significantly lower Mini-Mental State Exam scores than patients without depression (110). Because the Mini-Mental State Exam is a crude measure of cognitive functions, Bolla-Wilson and colleagues examined depressed and nondepressed stroke patients with a comprehensive neuropsychological battery (16). They found that although patients with major poststroke depression and left hemisphere lesions (n=10) had significantly more severe cognitive impairments than nondepressed patients with left hemisphere lesions (n=16), there were no significant differences in cognitive function between depressed (n=8) and nondepressed patients with right hemisphere lesions (n=19). Among patients with major depression and left hemisphere lesions, deficits were most severe on tasks of verbal memory, language, visuoconstructional ability, executive motor functions, and frontal lobe-related tasks.

Downhill and Robinson examined the longitudinal evolution of cognitive deficits in 309 patients with acute stroke lesions (29). At the in-hospital assessment, patients with major depression after a left hemisphere stroke had significantly lower Mini-Mental State Exam scores than nondepressed patients. This association persisted for up to 1 year after stroke. A study by Kase and colleagues showed a significant decline in Mini-Mental State Examination scores for both depressed and nondepressed stroke patients as compared to a group of normal controls (53). Whether the decline was most marked for the depressed group was not examined. Well-designed clinical trials are needed to test the best strategies against depression across all survivors of stroke.

Santos and colleagues reported that suicidal thoughts may develop soon after the onset of acute stroke and are more frequent in patients with a lower educational level or a previous mood disorder (99). Those who develop depressive symptoms in the acute phase of stroke are more vulnerable, making the assessment of suicidal behavior in this patient group paramount.

Tang and colleagues reported that the Fatigue Severity Scale (FSS) was significantly higher in the SI (Suicidality) group and remained as a significant predictor, with an odds ratio of 1.5, suggesting that early identification and treatment of fatigue in poststroke patients might reduce suicide risk (113).

Differential diagnosis

Poststroke depression should be differentiated from poststroke apathy, the catastrophic reaction, and pathological laughing and crying (emotional lability).

Apathy is the absence or lack of feeling, emotion, interest, or concern. Starkstein and colleagues found that 11% of 80 patients with acute stroke lesions showed apathy as their only psychiatric disorder, and another 11% had both apathy and depression (104). Patients with apathy (without depression) showed a significantly higher frequency of lesions involving the posterior limb of the internal capsule as compared to patients with no apathy.

The catastrophic reaction was described by Goldstein and is expressed by anxiety, tears, aggressive behavior, swearing, displacement, refusal, renouncement, and compensatory boasting (40). Starkstein and colleagues found the catastrophic reaction in 19% of patients with acute stroke lesions, and 66% of patients with the catastrophic reaction also had major depression (105). Thus, the catastrophic reaction may characterize a specific type of poststroke major depression.

Emotional lability is characterized by sudden, easily provoked episodes of crying or laughing, which may or may not be appropriate to the context. Robinson and colleagues found no significant correlations between scores of emotional lability and scores of depression, social functioning, activities of daily living, and cognitive level, suggesting that poststroke depression and pathological emotions may be independent phenomena (95). Kim and colleagues prospectively studied 148 patients with single unilateral stroke at 2 to 4 months poststroke and correlated lesion location with depression and emotional lability. They found depression in 18% of the patients and emotional lability in 34%. Anterior cortical lesion location was significantly associated with depression (p less than .05), whereas lenticulocapsular strokes were significantly associated with emotional lability (p less than .01) (56).

Van der Werf and colleagues assessed the frequency of severe fatigue in a series of 90 stroke patients and 50 healthy controls (115). About half of the stroke patients complained of severe fatigue, as compared to 16% of the healthy controls.

In their study van Mierlo and colleagues found that psychological factors comprising of neuroticism, pessimism, passive coping, and helplessness showed increased association with poststroke depression, whereas factors including extraversion, optimism, self-efficacy, acceptance, perceived benefits, and proactive coping revealed decreased association (116). All the above factors were found to be bivariately associated with the presence of poststroke depressive symptoms. Multivariate logistic regression analysis revealed increased association of helplessness and passive coping and decreased association with acceptance. Perceived benefits were independently significantly associated with the presence of poststroke depressive symptoms.

Diagnostic workup

Depression after stroke often goes undetected, or if diagnosed, is inadequately treated. Patients should be assessed specifically for the presence of depressive symptoms using a structured psychiatric interview such as the Present State Exam or the Structured Clinical Interview from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. Several depression scales, such as the Hamilton Depression Scale and the Center for Epidemiological Studies Scale for Depression, may be used to rate the severity of depressive disorder and may also be used as screening instruments to determine the likelihood of the existence of depression. However, the diagnosis of depression should always be based on diagnostic criteria elicited through clinical interview.

There is no consensus regarding the sensitivity and specificity of potential biological markers of poststroke depression. The dexamethasone suppression test showed a sensitivity of about 45% to 60%, but a significant number of nondepressed patients also fail to suppress serum cortisol (ie, low specificity) (106). However, Astrom and colleagues demonstrated that postdexamethasone cortisol values at 3 months predicted major depression at 3 years, suggesting that this test may be useful as a marker of risk of major depression (06). Barry and Dinan found that growth hormone responses were significantly blunted in patients with poststroke depression (09), but other studies confirming this finding have not been carried out. Dexamethasone suppression testing on another group of patients with a neurologic disorder commonly associated with depression, Parkinson disease, has been unreliable in diagnosing depression (72). Gao and colleagues suggest that plasma serotonin levels may be used to represent the CSF serotonin levels in depressed and nondepressed patients following stroke (38). In their study they found a reduction in the plasma or CSF serotonin concentrations in patients with poststroke depression, suggesting that serotonin deficiency may be 1 of the factors leading to depression following stroke. Robinson and coworkers, in their preliminary study, have demonstrated for the first time that decreased heart rate variability was associated with poststroke depression (97). Although they concede larger longitudinal studies are needed to confirm this finding using both time-based and frequency domain measures of heart rate variability, they also raise the question whether poststroke depression leads to increased long-term mortality through changes in heart rate variability.

In clinical trials involving patients with stroke, the secondary outcomes are often studied using the following tools for various categories, as listed below:

Depression
	Hamilton Depression Rating Scale (44) Montgomery Esberg Depression Rating Scale (74) Geriatric Depression Scale (41) Beck Depression Inventory (12) Hospital Anxiety and Depression Scale (122)
Anxiety
	Hamilton Anxiety Scale Beck Anxiety Inventory Hospital Anxiety and Depression Scale (122)
Psychological distress
	Scales such as the General Health Questionnaire (39)
General health
	Nottingham Health Profile (52)
Cognition
	Mini-Mental State Examination (34)
Social activities
	Frenchay Activities Index (118)
Activities of daily living
	Barthel Index (67)
Disability
	Hemispheric Stroke Scale (02)
Dependence in self-care activities of daily living
	Modified Rankin Scale (89)
Health-related quality of life
	36-item short questionnaire (SF-36) (119)

In their cross sectional study of the Rasch analysis of the Beck Depression Inventory-II (BDI-II) in stroke survivors, Lerdal and colleagues report that a 16-item version of the BDI-II, omitting items 10, 16, 17, 18 and 21, may be more appropriate than the original 21-item BDI-II for use as a unidimensional measure of depression in patients following first-ever stroke (63). They found that 5 BDI-II items did not demonstrate acceptable goodness-of-fit to the Rasch model: items 10 (crying), 16 (changes in sleep), 17 (irritability), 18 (changes in appetite), and 21 (loss of interest in sex). After removal of these 5 items, the resulting 16-item version not only had fewer items, it also had better internal scale validity, person-response validity, and person-separation reliability than the original 21-item version in their sample of stroke survivors.

Based on their research, Cichon and associates concluded that oxidative damage of proteins is correlated with the degree of poststroke depression, whereas nitrative changes do not show any relationship (24). They were able to demonstrate a positive correlation between the concentration of carbonyl groups and the Geriatric Depression Scale and a negative correlation between the degree of depression and the concentration of -SH groups or catalase activity.

Management

Poststroke depression may be adequately treated with antidepressant drugs. Three randomized, double-blind, placebo-controlled studies were carried out in poststroke depressed patients. In the first study, Lipsey and colleagues examined the efficacy of nortriptyline in a randomized, double-blind, placebo-controlled study that included 11 patients treated with active drug and 15 patients given placebo (66). After 6 weeks of treatment, patients taking nortriptyline showed significantly lower Hamilton Depression scores than the placebo group. Important side effects such as delirium, confusion, drowsiness, and agitation were found in 3 patients. In the second study, Andersen and colleagues examined the efficacy of the specific serotonin reuptake inhibitor citalopram in the treatment of poststroke depression (05). They found that at both 3 and 6 weeks of treatment the active group had significantly lower Hamilton Depression scores than the placebo group. In the third study, nortriptyline, fluoxetine, and placebo were compared in the treatment of depression after acute stroke (96). Patients received either nortriptyline up to 100 mg/day, fluoxetine up to 40 mg/day, or placebo during a 12-week period. Nortriptyline produced a significantly higher response rate than fluoxetine or placebo in the treatment of poststroke depression, anxiety, and impairments in activities of daily living. There was no significant difference in depression outcome between fluoxetine and placebo (96). In a multicenter, double-blind, placebo-controlled study for the treatment of acute hemiplegic patients with poststroke major depression, Wiart and colleagues found fluoxetine to produce no major side effects and to be significantly more effective than placebo (120). Fruehwald and coworkers carried-out a 3-month double-blind, randomized, placebo-controlled trial of fluoxetine (20 mg/d) in 50 moderate to severe poststroke depressed patients. The study included an 18-month open-label extension. There were no significant differences between placebo and fluoxetine treated patients during the initial 3-month period, but between-group differences became significant at the 18-month follow-up. Although no significant differences could be observed between both groups at 4 weeks, depression increased in the placebo group at 12 weeks; the difference was evident at 18 months, when patients treated with fluoxetine showed less depression (35). Dahmen and colleagues carried out an open label study of venlafaxine in 12 stroke patients. They found a positive treatment response (reduction in Hamilton Depression scores greater than 50%) in 10 of the 12 patients after 2 weeks of treatment (27).

In a study that used trazodone as the antidepressant medication, Reding and colleagues found that depressed patients after stroke who had a positive dexamethasone suppression test had greater improvements in activities of daily living than placebo-treated patients (90). It should be noted that contemporary serotonin selective reuptake inhibitors are used more widely for antidepressant treatment than trazodone, and trazodone’s sedative side effect may be specifically undesirable in some poststroke patients. Kneebone and Dunmore reviewed the psychological management of poststroke depression and identified cognitive behavior therapy as a potentially useful treatment modality (60). However, a randomized controlled study by Lincoln and Flannaghan found no significant benefit of cognitive behavioral psychotherapy for poststroke depression (65).

Mant and colleagues carried out a randomized controlled trial of family support versus normal care in a series of 323 stroke patients and 26 carriers. The main finding was that family support significantly increased social activities and improved quality of life of careers, with no significant effects on patients (69). Smith and Thompson explored the secondary benefits of treadmill training for people in the chronic stage of recovery from stroke (103). They found that a task-specific intervention designed to improve gait speed may potentially provide secondary benefits by positively impacting depression, mobility, and social participation for people poststroke.

Hackett and coworkers, in their update of a Cochrane review first published in 2004, found a small but significant effect of pharmacotherapy (not psychotherapy) on treating depression and reducing depressive symptoms as well as a significant increase in adverse events (42). They recommend that more research is required before recommendations can be made about the routine use of such treatments. Cumming and colleagues evaluated the effect of very early mobilization after stroke on levels of depression, anxiety, and irritability (26). They found that very early mobilization may reduce depressive symptoms in stroke patients at 7 days poststroke. Stein and colleagues studied poststroke patients and established that most stroke survivors identify sexuality as an important issue in their poststroke rehabilitation (112). Because preferences for the timing of this counseling vary, an on going exploration of the need for such counseling is essential for the ideal time of delivery of such services and optimal poststroke recovery.

In poststroke patients, depression in particular has been shown to interfere significantly with physical functioning. This often results in greater reductions in their activities of daily living and physical function as a whole as well as worse rates of recovery. In poststroke patients, considerable interaction between cognitive and motor functions has been established. Neuroimaging studies suggest an association between white matter hyperintensities and both motor and neuropsychological poststroke deficits (23).