Clinical manifestations

Presentation and course

	• Stroke survivors experience both major and minor depression.
	• Only a minority of patients have depression symptoms without having major depression.

Up to 33% of stroke survivors experience depression, with a cumulative incidence of 39% to 52% within 5 years of stroke (10). By comparison, the 12-month prevalence of major depression in the United States is 6.7% (57). Both major and minor (dysthymic) depression have been reported after stroke. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders defines poststroke major depression as a "prominent and persistent period of depressed mood or markedly diminished interest or pleasure in all, or almost all, activities that predominates in the clinical picture." 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. In poststroke depression, the prevalence of these symptoms is similar to that in patients with primary depression (in absence of brain injury). Only 2% to 3% of stroke patients have symptoms without a depressed mood and suggested that these criteria do not over diagnose major depression among stroke patients (88). Depression interferes with rehabilitation by causing physical and cognitive function impairment (97; 105; 90). Older adults are more likely than younger ones to mask depression with somatic rather than psychiatric symptoms (62).

Apathy occurs in more than 20% of first-ever stroke patients and may impair functional recovery (101). Although apathy and depression share some correlations, it has been suggested that they may require different treatment approaches (78; 70). Mild to severe poststroke depression in the elderly is associated with increased mortality and may last for at least 7 years poststroke (83; 52). Other morbidities include dependency, risky behaviors including drug and alcohol abuse, increase in suicide rate, poor compliance with treatment, and self-care (55).

Table 1. Criteria for Major Depressive Episode

(A) 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 one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
	(1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observation made by others (eg, appears tearful). (Note: In children and adolescents, can be irritable mood.)
	(2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either 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. (Note: In children, consider failure to make expected weight gain.)
	(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 (which 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.
(B) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
(C) The episode is not attributable to the physiological effects of a substance or to another medical condition.
Note: Criteria A to C represent a major depressive episode.
(D) The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.
(E) There has never been a manic episode or a hypomanic episode.
Note: Responses to a significant loss (eg, bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of loss.

Table 2. Criteria for Major Depressive Episode Due to Another Medical Condition*

(A) A prominent and persistent period of depressed mood or markedly diminished interest or pleasure in all, or almost all, activities that predominates in the clinical picture.

(B) There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct pathophysiological consequence of another medical condition.

(C) The disturbance is not better explained by another mental disorder (eg, adjustment disorder, with depressed mood, in which the stressor is a serious medical condition).

(D) The disturbance does not occur exclusively during the course of a delirium.

(E) The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.

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 one, but fewer than four, 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 two years. Because waiting for two 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 3. 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, 5th edition (05).

Poststroke depression rating scale distinguishes two depression profiles: (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 (39). Both catastrophic reaction and hyperemotionalism (also known as "pathological affective display") were significantly associated with depression (95). However, the lack of these symptoms in many depressed stroke patients call into question the "endogenous" and "reactive" categories.

A small study suggests that patients with poststroke depression exhibit no melancholia and have fewer cyclic and ideational disturbances, but they have more physical signs than those with primary depression (13). Early-onset major depression, within 3 to 6 months of stroke, was associated with a higher frequency of vegetative symptoms and larger lesion volume than late-onset (12 to 24 months later) major depression. At the same time, 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 (121).

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, 5th Edition, Revised Diagnosis, are useful in assessing depression. However, none of these instruments clearly stood apart from the others. 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 (16).

Proxies tended to score the patients as more severely affected than the patients scored themselves (131; 49).

Comorbidities and psychiatric distress associated with aging complicates the diagnosis and treatment of depression. Moreover, depression causes additional stress on caregivers (06).

Prognosis and complications

Major depression is diagnosed in 60% of patients at one year after stroke but resolves by the 2-year evaluation (96). Of those with dysthymia, 60% were still depressed at the 2-year evaluation. However, most patients with minor depression were not depressed 3 to 6 months after the acute event (50). During the first year after stroke, there was an increasing frequency of major depression and a decreasing frequency of minor depression. Patients with aphasia were more severely affected (56). Depression following cortical stroke appears to last longer than after subcortical stroke (116). Patients who recovered from depression had improved cognitive recovery and overall function (61; 25).

Independent outcomes of depression after stroke include lower quality of life, disability, and mortality (10).

Psychological well-being, social functioning, and quality of life are adversely affected by depression (28; 72; 23).

Cognitive dysfunction, as measured by the Mini Mental Status Examination, often follows stroke (54). Major depression after stroke had an additional impact on cognitive dysfunction. This may impair recovery (97; 116).

Cognition was affected more by left side lesions. The domains most affected were verbal memory, language, visuo-constructional ability, executive motor functions, and frontal lobe-related tasks (20). Cognitive impairment due to major depression after left-side stroke persisted for up to 1 year after stroke (32).

Suicidal thoughts may occur in the acute phase of stroke, mostly in patients with a lower educational level or a preexistent mood disorder (102). The increased vulnerability of these patients underscores the importance of psychiatric evaluation.

Fatigue Severity Scale was significantly higher in the suicidality group and remained a significant predictor, with an odds ratio of 1.5, suggesting that prompt management of fatigue might reduce suicide risk (120).

Depression not only follows stroke, but it is also a significant predictor of stroke (86). Depression correlates with recovery, functional outcome, and handicap (90; 48; 92).

Moreover, at 10-year follow-up, depression increased mortality by 3.4 times (83). This may be due to decreased medication compliance in patients with depression (122). Mood symptoms on a self-reported rating scale were also associated with death at 12 and 24 months after stroke (52). The relationship between depressive symptoms and stroke mortality was confirmed in a prospective study of behavioral, social, and psychological factors related to health and mortality in a community sample (35). However, it is the persistently high level of depression that is associated with increased risk of stroke, not depression, that improves over time (107).

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

	• Dysfunction of biogenic amines may play an important role in the mechanism of poststroke depression.
	• No clear relationship between the location of the stroke and depression has been found.
	• Left hemisphere lesions are associated with depression in the acute inpatient phase.
	• Right hemisphere lesions are associated with depression in the chronic outpatient phase.
	• Other risk factors for poststroke depression are family history of mental illness or preexisting depression, anxiety, preexisting cerebral atrophy, cognitive dysfunction, and severity of stroke.

Etiology and pathogenesis

The pathophysiology of post-stroke depression is multifactorial, with biological and psychological components. Depression after stroke is more than just a reaction to the disability caused by stroke, as it may occur in patients with anosognosia, in animal models, and in patients with transient ischemic attack or small stroke.

The main biological factors that trigger depression after stroke include genetic predisposition, location of stroke, and disruption of cortico-striato-pallido-thalamic-cortical projections. Additionally, multiple humoral factors were associated with depression following stroke causing increased inflammation, alteration of the neurotrophic factors, and disruption of the serotonergic, noradrenergic, and dopaminergic pathways.

According to a systematic review and metaanalysis of 50 studies, prestroke depression, cognitive impairment, stroke severity, and anxiety are the major predictors of depression after stroke (10). A cohort study of 1221 patients showed that persistent depression was also associated with being married or partnered (RR = 3.94, 95% CI 2.42-6.41). The risk of depression was higher in Australia and New Zealand than in Vietnam, suggesting a cultural component (04).

Multiple observational studies have suggested an effect of lesion location on depression (114; 08; 84; 14; 76; 87; 117; 126). However, the correlation between depression scores and the distance of the lesion from the left frontal pole found in earlier studies has not been replicated (51). Moreover, a metaanalysis did not demonstrate a strong association between poststroke depression and lesion location (24).

A systematic review found that patients with left hemisphere lesions are depressed in the acute inpatient phase, whereas those with right-side lesions are more depressed in the chronic outpatient phase (18). Voxel-based lesion behavior mapping (VLBM) is a novel approach of mapping the brain lesions and their functional consequences. An analysis of 270 patients has revealed that stroke in the right basal ganglia increases the risk of depression at 6 months follow-up (63).

Neuroimaging studies suggest an association between white matter hyperintensities and both motor and neuropsychological poststroke deficits (26). Subcortical atrophy that precedes the stroke lesion and a family or personal history of psychiatric disorder are risk factors for poststroke depression (115; 113). Delayed depression and anxiety after ischemic stroke were related to the severity of deep white matter hyperintensities and unfavorable outcomes at 3 months, despite treatment of anxiety (60). Lobar cerebral microbleeds may also play a role (119).

Poststroke depression has been associated with decreased levels of biogenic amines: serotonin, noradrenaline, and dopamine (66). Positron emission tomography has shown that right hemisphere lesions may result in a compensatory upregulation of serotonin receptors, which is lacking after left hemisphere lesions, leading to depression (79). Genetic factors related to serotonin transmission confer an increased susceptibility of developing depression after stroke (64; 36; 58).

Neurogenesis may play an important role in recovery from ischemia and depression (68). Neurotrophins are molecules that promote the development and survival of neurons. One of these molecules, brain-derived neurotrophic factor, has an antidepressant role and confers resilience to chronic stress. It not only protects against ischemic injury and hypoglycemia in cultured neurons but also plays a central role in hippocampal neurogenesis and functional recovery after stroke (73).

The inflammatory response following stroke may disrupt the hypothalamic-pituitary axis, with increased glucocorticoid levels and decreased production of neurotrophic factor (85).

Epidemiology

	• Almost one third of patients develop depression after stroke, but more patients may have depressive symptoms without meeting the criteria for depression.
	• Chronic disability, female sex, lack of support, and advanced age are the main risk factors.
	• Young patients are also susceptible to depression due to increased stress related to family and early career demands.
	• Anxiety and depression may occur at the same time.
	• The suicide risk is twice that of the general population.

As many as one third of stroke survivors suffer from depression during the first year after the onset of stroke (45). Half of these cases 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.

A significant association was found between depression after stroke and long-lasting disability, female sex, living alone after stroke, and age over 70 years (47).

The prevalence of poststroke depression ranges from 40% to 50% in the acute phase, between 49% and 54% in rehabilitation centers, and around 23% in the community (21). A Finnish study found major depression in 26% and minor depression in 14% of a consecutive series of 486 patients with ischemic stroke (91). In an 18-month follow-up study of 100 stroke patients, 46% of patients who were depressed during the first two months were also depressed at 12 and 18 months poststroke (17). Data from the South London Stroke Register including 3689 patients found a frequency of depression of 30% at 5 years after stroke. Although some patients recovered from depression, new ones were diagnosed, suggesting the need for regular screening for depression after stroke (09).

Women tend to have a higher prevalence of poststroke major depression as compared to men (48; 89). They have a worse quality of life than men up to 12 months after stroke in the dimensions of mobility, pain and discomfort, and anxiety and depression (22). In women, more severe depression was significantly associated with a prior diagnosis of a psychiatric disorder and more severe cognitive impairment (89).

The elderly are not the only ones vulnerable to poststroke depression; younger patients are also vulnerable due to an increased level of stress related to career and family (74).

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%. Some 11% and 7% of those initially not anxious became anxious at 4 or 6 months after stroke, respectively. Depression showed a similar pattern (31).

Neuroticism, the tendency to experience negative mood states, was found to be an important predictor of poststroke depression (01).

The rates of suicide attempts and completed suicides in poststroke patients were double the rate of the general population (33). 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 two years after stroke.

Prevention

	• Because of high prevalence, it is reasonable to attempt prevention of poststroke depression.
	• Despite several studies that have demonstrated prevention of depression after stroke with antidepressant medications, the level of certainty is very low.

Little is known about preventing depression after stroke. Severity of deficits in activities of daily living predicted severity of depression at three months. Conversely, depression impairs recovery from stroke and is associated with a higher mortality among stroke patients (104).

In a metanalysis of 14 trials, depression after stroke was prevented slightly by psychotherapy, but the effect of treatment was small and did not improve other outcomes. Antidepressant medication did not prevent depression (44). A Cochrane review of 19 clinical randomized trials suggests that antidepressant medication may prevent poststroke depression, but with a very low certainty (03).

Differential diagnosis

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

Apathy manifests as lack of feeling, emotion, interest, or concern. Apathy may occur independently or associated with depression. 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 (110).

The catastrophic reaction is expressed as anxiety, tears, aggressive behavior, swearing, displacement, refusal, renouncement, and compensatory boasting (42). This reaction was seen in 19% of patients with acute stroke lesions, and 66% of patients with the catastrophic reaction also had major depression (111).

Emotional lability is characterized by sudden, easily provoked episodes of crying or laughing, which may or may not be appropriate to the context. No significant correlations were found between emotional lability and depression, social functioning, activities of daily living, and cognitive level, suggesting that poststroke depression and pathological emotions may be independent phenomena (98). A prospective study of 148 patients with single unilateral stroke found depression in 18% of the patients and emotional lability in 34% (59). Anterior cortical lesion location was significantly associated with depression, whereas lenticulo-capsular strokes were significantly associated with emotional lability.

Severe fatigue occurred in about half of the stroke patients, as compared to 16% of the healthy controls (124).

Psychological factors like helplessness and passive coping revealed an increased association with depression, whereas acceptance revealed a decreased association with depression (125).

Diagnostic workup

	• Most cases of depression after stroke are not diagnosed by physicians who do not specialize in psychiatry.
	• Patients with stroke should be screened for depression.

Symptoms of depression are either masked by the patient’s cognitive impairment due to aphasia, agnosia, or memory loss or overlap, such as anxiety, emotional lability, abulia, apathy, and disorders of sleep, fatigue, concentration, or appetite (34). Due to diagnostic challenges, depression after stroke is not identified by physicians who are not psychiatrists in 50% to 80% of cases (108), or, if diagnosed, depression is inadequately treated. Patients should be systematically screened for depressive symptoms using a structured psychiatric interview, such as the Present State Exam or the Structured Clinical Interview.

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 biological markers of poststroke depression. The dexamethasone suppression test has a sensitivity of 45% to 60%, but a low specificity, as many patients without depression fail to suppress serum cortisol (112). However, post-dexamethasone cortisol level at three months predicted major depression at three years (08). Also, growth hormone response was significantly blunted in patients with poststroke depression (12), 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 (80). Gao and colleagues suggest that plasma serotonin levels may be used to represent the CSF serotonin levels in depressed and nondepressed patients following stroke (40). 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 one of the factors leading to depression following stroke. Decreased heart rate variability was associated with poststroke depression, raising the question whether this leads to increased long-term mortality through changes in heart rate variability (100).

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 (46) Montgomery Esberg Depression Rating Scale (82) Geriatric Depression Scale (43) Beck Depression Inventory (15) Hospital Anxiety and Depression Scale (132)
Anxiety
	Hamilton Anxiety Scale Beck Anxiety Inventory Hospital Anxiety and Depression Scale (132)
Psychological distress
	Scales such as the General Health Questionnaire (41)
General health
	Nottingham Health Profile (53)
Cognition
	Mini-Mental State Examination (37)
Social activities
	Frenchay Activities Index (127)
Activities of daily living
	Barthel Index (75)
Disability
	Hemispheric Stroke Scale (02)
Dependence in self-care activities of daily living
	Modified Rankin Scale (93)
Health-related quality of life
	36-item short questionnaire (SF-36) (129)

In a cross-sectional study of the Rasch analysis of the Beck Depression Inventory-II (BDI-II) in stroke survivors, 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 (69). They found that five 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 five 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.

Oxidative damage of proteins correlates with poststroke depression severity, whereas nitrative changes do not. 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 (27).

Management

	• Poststroke depression may be treated with a combination of pharmacological, psychosocial, and stroke-focused treatments.
	• Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have been successfully used to treat depression.
	• Although effective, tricyclic antidepressants have more side effects.
	• The role of cognitive behavioral therapy is not clear yet.
	• Initial studies of neuromodulation with transcranial magnetic stimulation have shown promising results.

Several studies have shown that poststroke depression may be adequately treated with antidepressant drugs.

Nortriptyline, trazodone, fluoxetine, citalopram, and venlafaxine have been tried treatments of depression after stroke (71; 94; 30; 130; 07; 99; 38). Delirium, confusion, drowsiness, and agitation occurred in some patients.

The Cochrane review found a small potential benefit of pharmacotherapy on treating depression and reducing depressive symptoms, as well as a significant increase in adverse events (03).

Psychosocial therapies have been explored for the management of depression after stroke. A metaanalysis found inconclusive effects of cognitive behavioral therapy on poststroke depression (128). Family support significantly increased social activities and improved quality of life for carers, with no significant effects on patients (77). In a small study of 60 patients with subacute aphasia, intensive social interaction had a small-to-medium effect in reducing depression severity (109).

Task-specific treadmill training designed to improve gait speed may potentially provide secondary benefits by positively impacting depression, mobility, and social participation for people after stroke (106).

Sexuality is an important issue in poststroke rehabilitation. Because preferences for the timing of this counseling vary, an ongoing exploration of the need for such counseling is essential for the ideal time of delivery of such services and optimal poststroke recovery (118).

Very early mobilization may reduce depressive symptoms in stroke patients at 7 days poststroke (29). However, very early high-dose rehabilitation therapy is associated with a worse outcome (67).

Transcranial direct current stimulation has shown promise in the treatment of poststroke depression (123). A meta-analysis including 22 randomized controlled studies of repetitive transcranial magnetic stimulation suggests a beneficial effect on poststroke depression. However, because of the heterogeneity and potential biases found, the result should be treated with caution (103).