Available evidence indicates that there are a multitude of neuropsychiatric syndromes that occur after a stroke. Cognitive impairment occurs in approximately one-third of patients. These neuropsychiatric manifestations often impede the recovery of motor functioning, reduce social functioning, and decrease the overall quality of life.
The goals for this activity are to understand the epidemiology and neurobiology of poststroke depression, to learn how to complete an appropriate assessment, and to be able to provide comprehensive treatment for these individuals.
1. To discuss the epidemiology of poststroke depression
2. To describe the risk factors for poststroke depression
3. To elaborate on the assessment of individuals with poststroke depression
4. To enumerate the treatments for poststroke depression
This continuing medical education (CME) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.
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It is estimated that in the United States alone, approximately 795,000 individuals have a stroke annually. The prevalence of stroke is greater among men than women, but the stroke incidence doubles among postmenopausal women. Furthermore, stroke was rated as the third most common cause of disability adjusted life-years worldwide in 2010.1 In the United States, stroke has been established as the most burdensome of all neurological disorders.2 One study3 found that among the long-term (15 year) survivors of stroke, 33.8% have mild disability, 14.3% have moderate disability, and 15.0% have severe disability (Figure 1). The prevalence of disability increased with time, but 10% of these individuals had lived with moderate-severe disability since their stroke.
Available evidence indicates that there are a multitude of neuropsychiatric syndromes that occur after a stroke (Figure 2).4 Poststroke bipolar disorder, mania, and psychotic symptoms are rare sequelae to stroke. Cognitive impairment occurs in approximately one-third of individuals post stroke.5 These neuropsychiatric manifestations often impede the recovery of motor functioning, reduce social functioning, and decrease the overall quality of life.4
A recent meta-analysis found that the prevalence of any depressive disorder post stroke is approximately 33.5%.6 In this study, the point prevalence of major depression was 17.7% with the prevalence for minor depression being 13.1%. Prevalence of dysthymia and adjustment disorder was 3.1% and 6.9%, respectively. An earlier meta-analysis found that the frequency of poststroke depression was approximately 31%.7 The proportion of those with depression between 1 and 5 years after stroke was 25%, and the proportion of those with depression at 5 years after stroke was 23%.
In the DSM-5, poststroke depression (PSD) is classified under the criteria for “Depressive Disorder Due to Another Medical Condition”8 (Figure 3). To meet the DSM-5 criteria, individuals should present with a prominent and persistent period of depressed mood or markedly diminished interest or pleasure in all or almost all activities. The history, physical examination, or laboratory findings should show that the depressive symptoms are due to the direct pathophysiological consequence of a stroke. Furthermore, the presence of depressive symptoms should not be better explained by another mental disorder, including an adjustment disorder, nor should the depressive symptoms occur exclusively during the course of a delirium. In addition, these symptoms should cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
PSD symptoms can be further subclassified as presenting with (1) depressive features when all criteria for a major depressive episode are not met, (2) a major depressive-like episode when the criteria for a major depressive episode are met, and (3) mixed features when symptoms of mania or hypomania are also present but do not predominate in the clinical presentation.
PSD phenomenology is similar to, but not the same as, that described by other individuals with depression.9 For example, individuals with PSD are less likely to report “inability to feel” or “disturbed sleep.” In addition, individuals with PSD may be less likely to report anhedonia and apathy when compared with other individuals who have depression. In one study, researchers compared symptoms in (1) poststroke patients with and without depression, (2) individuals who were being seen in general practice, and (3) patients with symptomatic atherosclerotic diseases.10 They found that although the 3 cohorts demonstrated broadly similar symptom profiles, as well as comparable levels of individual symptom prevalence, the individuals with PSD had more severe symptoms than individuals in the other 2 groups.
A recent meta-analysis by Shi et al indicated that a history of mental illness (depression/anxiety) was the highest-ranking risk factor for PSD (odds ratio [OR] 2.93).11 Other risk factors for PSD were family history of mental illness (OR = 1.95), age (< 70 years, OR = 1.94), female sex (OR = 1.77), level of handicap (OR = 1.52), severity of stroke (OR = 1.12), and neuroticism (OR = 1.08). The investigators also found that education (> 8 years) and social support (OR = 0.93) were protective factors for PSD. Brain damage in the left frontal lobe and left basal ganglia was associated with PSD, and specified levels (< 10.2 ng/ml) of brain-derived neurotrophic factor and leptin (> 20.7 ng/ml) were risk factors for PSD. Biochemical factors, including interleukin-1b (IL-1b) and intercellular cell adhesion molecule-1 (ICAM-1), hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and myocardial infarction were not found to be associated with PSD.
In a prospective observational study of individuals who were post stroke and in the emergency department or admitted to acute care in designated stroke centers, individuals with PSD had more severe strokes, greater functional handicap, and longer hospital stays and were less likely to be discharged home following acute hospitalization (all P < .001) than patients without PSD.12 One systematic review indicated that individuals with PSD tend to experience a moderate increase in the risk of poor functional outcome (OR = 2.16) when compared with stroke patients without depression.13 This association did not seem to be caused by poor rehabilitation and functional improvement among individuals with PSD.
Suicidal ideation is also a consequence of PSD. A meta-analysis by Bartoli et al found the pooled proportion of suicidal ideation among stroke survivors was 11.8%.14 Current (OR = 11.50; P < .001) and past (OR = 6.96; P < .001) depression, recurrent stroke (OR = 1.77; P < .001), disability (P = .01), and cognitive impairment (P = .03) were all associated with suicidal ideation. Suicidal ideation was less likely to occur in stroke survivors who were married (OR = 0.63; P < .001), employed (OR = 0.57; P = .02), and had higher education levels (OR = 0.55; P = .002). A meta-analysis by Cai et al found that PSD was associated with significantly increased risk for mortality among stroke survivors (HR = 1.59).15
The pathogenesis of PSD involves complex interactions between neuroanatomical and neurochemical factors.16 It is thought that the processes involved in development of PSD include reduced levels of monoamines, abnormal neurotrophic response to the occurrence of stroke, increased inflammation in the brain, dysregulation of hypothalamic-pituitary-adrenal (HPA) axis, and glutamate-mediated excitotoxicity.17,18 Available studies indicate that large lesions in critical areas of the brain, including the left frontal lobe and basal ganglia or the accumulation of silent cerebral lesions beyond a critical threshold, may interrupt the pathways of monoamine neurotransmitters or pathways that control mood regulation.16 Cytokines that are produced post stroke increase glutamate-induced excitotoxicity, resulting in neuronal death in critical areas of the brain. This may also lead to the enlargement of cerebral infarctions. This process, coupled with hypercortisolism induced by stress or inflammation after the stroke, may reduce intracellular serotonin transporters, resulting in depression. Additionally, hippocampal neurogenesis may be inhibited by the interaction among cytokines, glucocorticoid, and neurotrophin. Available evidence indicates that these neurobiological processes, seen among individuals who develop PSD, may differ from individuals who do not develop depression after a stroke, but the details regarding these complex mechanisms are only emerging.17,18
Although fairly common, PSD is often underdiagnosed.19 Differential diagnosis is difficult, as many of these individuals who are post stroke may present with cognitive impairment and may not be able to report their symptoms accurately (Table). In addition, some symptoms of stroke and depression (eg, loss of appetite, difficulty concentrating, and sleep disorders) may be indistinguishable from one another. In these situations, the presence of nonsomatic symptoms including guilt, depressed mood, hopelessness, or worthlessness is more suggestive of PSD.20
In one study, PSD was diagnosed in only 4.8% of the patients, and only 6.7% of these individuals were treated with a new antidepressant.12 However, compared with patients admitted to standard units, individuals admitted to specialized stroke units were more likely to be diagnosed with depression (5.2% vs 4.0%, P < .014) and were more likely to receive a new prescription for an antidepressant (7.8% vs 4.5%, P < .001). These results indicate that there should be routine screening post stroke for PSD. Additionally, specialized stroke unit care may improve the detection and treatment of PSD.
A number of tools may be helpful in identifying PSD. One meta-analysis found that the Center of Epidemiological Studies-Depression Scale (CES-D) (sensitivity, 0.75 and specificity, 0.88), the Hamilton Depression Rating Scale (HDRS) (sensitivity, 0.84 and specificity, 0.83), and the Patient Health Questionnaire (PHQ)-9 (sensitivity, 0.86 and specificity, 0.79) were optimal screening tools.21 The PHQ-2 performed less well than other measures. However, the investigators found that the clinical utility of these tools was modest for case-finding. They cautioned that these screening tools should not be used in isolation; a more detailed clinical assessment to detect PSD should also be used.
A meta-analysis by Hackett et al evaluated interventions for preventing PSD. The investigators included data from 10 pharmaceutical trials (12 comparisons) and 4 psychotherapy trials. 22 Most of the participants were recruited within 1 month of acute stroke, and the duration of treatment ranged from 2 weeks to 1 year. The proportion of participants meeting the study criteria for depression was lower in the antidepressant‐treated group; however, meta‐analysis was not performed, as the study methods and end point measured varied among studies. There was no evidence of benefit of antidepressants on the mean depression scores at the end of treatment or change in mean scores from baseline. Additionally, there was no evidence of pharmacotherapy improving cognitive function or activities of daily living (ADL) or reducing disability. There was no clear evidence of harm demonstrated in the analysis of adverse events. The investigators noted benefit of psychotherapy in the pooled proportion of participants who met the study criteria for depression at the end of treatment (OR = 0.64) and a reduction in psychological distress scores from baseline on the 28-item General Health Questionnaire (mean difference [MD] = ‐1.37). There was no evidence of benefit or harm either in ADL or social activities. There were also fewer adverse events noted in the intervention group (OR = 3.73).
In a meta-analysis that included data from 10 randomized placebo-controlled trials (RCTs) that evaluated the prophylactic effects of antidepressants in nondepressed individuals with stroke to prevent PSD, Chen et al found the pooled occurrence rates of newly developed PSD cases in the intervention and control groups were 12.54% (41 of 327 participants) and 29.17% (91 of 312 participants), respectively.23 Both selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) were associated with reductions in the incidence of PSD. The reductions in the incidence of PSD were not related to the interval between stroke onset and the administration of an antidepressant (P = .47), and the prophylactic effects of antidepressants were not related to duration of their use (P = .11).
In a recent meta-analysis, Gu et al included data from 12 studies that evaluated the use of prophylactic antidepressants to prevent the occurrence of PSD.24 The investigators found antidepressants following acute stroke reduced PSD incidence (relative risk [RR] = 0.33, P < .001). There were no differences detected in efficacy noted between the SSRIs, TCAs, and serotonin norepinephrine reuptake inhibitors (SNRIs) in the subgroup analysis. When compared with the control group, the RR of PSD recurrence during the follow-up period in the treatment group was 0.51 (P < .001). The pooled mean difference in reduction of depression severity on the HDRS between the antidepressant and control groups was 5.73 (P < .001). Additionally, there were improvements in the motor function (weighted mean difference [WMD] = 12.56, P < .001) and neurological function (WMD = 1.13, P < .001) between the antidepressant and the control groups. There were no differences between the 2 groups with regard to mortality rates (RR = 1.63, P = .377) or incidence of adverse events (RR = 0.93, P = .806).24
In a cross-sectional study of data from the National Ambulatory Medical Care Survey and its outpatient department, Bhattacharjee and colleagues found that only 47.32% of the participants with PSD received treatment, which was mainly driven by the use of antidepressant alone. In this study, men were approximately 3 times more likely to receive depression treatment compared with women.25 Additionally, individuals who were Caucasian were almost 4 times more likely to receive depression treatment compared with other races or ethnicities. This study also found that an increase in number of chronic diseases was associated with a lower likelihood of receiving any depression treatment.
In a meta-analysis of 28 RCTs that evaluated cognitive behavioral therapy (CBT) for PSD, the investigators found that CBT had positive effects on PSD when compared with control groups (P < .001).26 Both CBT alone (P = .001) and CBT in combination with antidepressants (P < .00001) improved depressive symptoms in PSD. CBT resulted in significantly higher remission rates (P < .00001) and response rates (P < .00001), improving anxiety, neurological functional deficits, and ADL. Data from 8 studies showed no significant relationship between CBT effects and the mean duration after stroke (P > .05).
In a network meta-analysis of 23 RCTs that evaluated 9 PSD treatment interventions, the investigators found that SNRIs were associated with the highest reduction in the depression scores, followed by TCAs, psychotherapy plus antidepressant, and SSRI antidepressants.27 In a second network meta-analysis, the investigators included data from 15 RCTs in which 13 antidepressant drugs were considered.28 The investigators found that for efficacy, paroxetine was ranked the best antidepressant for reduction in depression scores at the end of treatment, followed by imipramine, reboxetine, nortriptyline, citalopram, and fluoxetine. They also found that duloxetine ranked the best for the reduction in depression scores at durations of 4 weeks and 8 weeks. For tolerability, paroxetine was ranked the best, but there was no significant difference noted between any of the comparisons. In a third network meta-analysis of 14 RCTs with 9 different antidepressant treatments, the investigators found that doxepin, paroxetine, and nortriptyline were significantly more effective than placebo (standardized mean differences: -1.93, -1.39, and -1.25, respectively) in the treatment of PSD.29
In a study that evaluated transcranial direct current stimulation (tDCS) for PSD, the investigators randomized 48 antidepressant-free individuals with PSD into 2 groups: active and sham tDCS.30 Participants received twelve 30-minute sessions of left/cathodal right dorsolateral prefrontal tDCS over a 6-week period: once daily on weekdays for 2 weeks, then 1 session every other week. The primary outcome was a change in the 17-item HDRS at 6 weeks. The investigators found that active tDCS was superior to sham at the end point (P < .001). The response and remission rates were also significantly higher in the active treatment group (37.5% and 20.8%, respectively) when compared with the sham treatment group (4.1% and 0%, respectively). The number-needed-to-treat for response and remission were 3 and 5, respectively. There were no changes in cognitive performance due to tDCS, and the frequency of adverse events was not significantly different between the active and sham groups at all time points. Additionally, no serious adverse events were reported.30 The investigators did not identify any potential predictors of response including depression onset after stroke, duration of the depressive episode, and duration of the stroke episode.
A systematic review and meta-analysis of 22 RCTs evaluated the effect of repetitive transcranial magnetic stimulation (rTMS) on PSD.31 The primary outcome was severity of depression as measured by the HDRS. The secondary outcomes were response rates, remission rates, stroke severity, and ability to perform daily activities. The investigators found that rTMS was beneficial for PSD on all of the following: HDRS (P < .001); response rates (OR = 3.46, P < .00001); remission rates (OR = 0.99, P < .00001); National Institutes of Health Stroke Scale (P < .001); ADL (P < .001); and Montgomery-Asberg Depression Scale (P = .0001). A total of 15 (1.7%) participants in the active treatment group and 6 (0.7%) participants in the control group experienced headache; 2 (0.2%) participants in the active treatment group and 9 (1.0%) participants in the control group developed gastrointestinal reactions; 3 (0.3%) participants in the active treatment group and 7 (0.8%) participants in the control group had dry mouth; 1 (0.1%) participant in the active treatment group suffered from tinnitus; 1 (0.1%) participant in the active treatment group felt weak; and 6 (0.7%) participants in the control group experienced other adverse events. The investigators did not find any statistically significant differences in withdrawals due to adverse events between the 2 groups; 0.2% (2 of 881) of patients in the control group withdrew due to gastrointestinal effects. Because of the significant heterogeneity between the different studies, the effect of frequency of treatment, site, duration of illness, type of basic treatment, type of control intervention, and total session on outcomes could not be evaluated.
PSD is a common sequela of stroke. The pathogenesis of PSD involves complex interactions between both neuroanatomical and neurochemical factors. PSD is associated with more severe strokes, greater functional handicap, longer hospital stays, lower likelihood of discharge to home following acute hospitalization, and a greater risk for mortality. Common risk factors for PSD include a history of mental illness (depression/anxiety), a family history of mental illness, age (< 70 years), female sex, level of handicap, severity of stroke, and neuroticism.
Although fairly common, PSD often remains underrecognized and poorly treated. Available evidence indicates efficacy of both nonpharmacological and pharmacological treatment strategies for the prevention of PSD. Early identification and appropriate management of PSD will reduce the morbidity and mortality due to this condition. Future research should investigate the pathophysiological underpinnings of PSD, so that more effective preventative and treatment strategies can be developed.
Dr Tampi is professor and chairman, Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General and Chief, Section for Geriatric Psychiatry, Department of Psychiatry and Psychology, Cleveland Clinic. Dr George is a research coordinator, Department of Research at Cleveland Clinic Akron General and clinical assistant professor of Obstetrics and Gynecology, Northeast Ohio Medical University.
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