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REVIEWS AND OVERVIEWS

Mechanisms of Psychiatric Illness

Post-Stroke Depression: A Review
Robert G. Robinson, M.D., Ricardo E. Jorge, M.D.

Poststroke depression (PSD) has been recognized by psy- treatment of PSD have demonstrated the efficacy of anti-
chiatrists for more than 100 years, but controlled system- depressants. Similarly, randomized controlled trials for pre-
atic studies did not begin until the 1970s. Meta-analyses vention of PSD have shown that antidepressants significantly
addressing almost all major clinical issues in the field have decrease the incidence of PSD compared with placebo. Early
emerged because of the relatively small number of patients antidepressant treatment of PSD appears to enhance both
included in some stroke studies. In order to build large physical and cognitive recovery from stroke and might in-
databases, these meta-analyses have merged patients with crease survival up to 10 years following stroke. There has also
rigorously assessed mood disorders with major depressive been progress in understanding the pathophysiology of PSD.
features with patients scoring above arbitrary cutoff points Inflammatory processes might be associated with the onset
on depression rating scales, thus missing important findings of at least some depressive symptoms. In addition, genetic
such as cognitive impairment associated with major but not and epigenetic variations, white matter disease, cerebro-
minor depression. Nevertheless, PSD occurs in a significant vascular deregulation, altered neuroplasticity, and changes in
number of patients and constitutes an important compli- glutamate neurotransmission might be relevant etiological
cation of stroke, leading to greater disability as well as in- factors. Further elucidation of the mechanism of PSD may
creased mortality. The most clinically important advances, ultimately lead to specific targeted treatments.
however, have been in the treatment and prevention of PSD.
Recent meta-analyses of randomized controlled trials for the AJP in Advance (doi: 10.1176/appi.ajp.2015.15030363)

Stroke is defined as a sudden loss of blood supply to the brain patients with left anterior strokes compared with strokes in
leading to permanent tissue damage caused by thrombotic, other locations. In addition, in 1984, the first randomized,
embolic, or hemorrhagic events. Almost 85% of strokes double-blind placebo-controlled treatment trial demonstrated
are ischemic, while 12% are hemorrhagic. The incidence of that nortriptyline was effective in treating PSD (6).
stroke varies dramatically over the life course, with incidence The present review will address identification of PSD, as
rates between 10 and 20 per 10,000 individuals in the age well as its prevalence, risk factors, relationship to physical
range of 55–64, while incidence rates increase to 200 per impairment, cognitive impairment, and mortality. We will
10,000 individuals for those aged over 85. There are 700,000 also review treatment of PSD, prevention of PSD, etiology,
strokes annually in the United States and 163,000 stroke- and suggestions for future research.
related deaths according to the latest statistics of the
American Heart Association (1).
METHOD
The association of neuropsychiatric disorders with
cerebrovascular disease includes depression, anxiety disorder, We conducted a literature search using the following data-
apathy, cognitive disorder, mania, psychosis, pathological af- bases: MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO,
fective display, catastrophic reactions, fatigue, and anosognosia. PsycBITE, Cochrane Central Register of Controlled Trials,
The first empirical studies of post-stroke depression (PSD) Internet Stroke Center (www.strokecenter.org/trials),
included studies conducted by researchers such as Martin Ovid Central Register of Controlled Trials database, and
Roth (2), who demonstrated the association between ath- ClinicalTrials.gov.
erosclerotic disease and depression, and Folstein et al. (3), who Our keywords included “poststroke depression,” “depres-
demonstrated that depression was significantly more common sion AND cerebrovascular disorders,” “vascular depression,”
in patients with stroke compared with patients with com- “stroke AND antidepressant,” “stroke AND antidepressant
parable physical impairments due to orthopedic injuries. AND depression,” “poststroke depression AND randomized
The first systematic longitudinal study of PSD found that clinical trial,” as well as “poststroke depression AND trial.”
severity of impairment in activities of daily living, social Reference lists of each article utilized were searched by
functioning, and cognitive function were all associated with hand to identify additional citations not identified by the
the existence of PSD (4). databases. This is primarily a narrative review that did not
A 1984 study published in Brain (5) first identified a sig- utilize the Preferred Reporting Items for Systematic Reviews
nificant increase in both major and minor depression among and Meta-Analysis [PRISMA] because of the limitations of

ajp in Advance ajp.psychiatryonline.org 1

Thus. and greater disability compared with non. (7). Meta-analyses idated such diagnosis on the basis of the presence of sub. The Prevalence of Depression in Various Clinical Settings section on incidence and prevalence of PSD. a single cerebral other forms of depressive disorders occurring after stroke. The existing evidence. major depressive- Percent of Patients 20 like episode. a Patients were examined using a standardized mental status examination Clinically defined vascular depression was proposed in and DSM-IV diagnostic criteria for depression following stroke with 1997 by Alexopoulos et al. Incidence and Prevalence of PSD We conducted a pooled analysis of studies published prior to The frequency of PSD has been studied in many countries of 2003 (18) using only studies that used structured interviews the world. However. Patients with vascular depression have later age at onset. major depressive-like features or minor depression defined as more than two but less than five symptoms of major depression. or mixed-mood features.108 Hospitals N=2. and infarct may trigger the same pathophysiological changes of many did not examine the time since stroke. The results are shown in Figure 1 and horts including 25. 10–12). and greater physical impairment than found that the cumulative percent of patients who developed geriatric patients with nonvascular depression. (8) val. databases (14. and/or patients who show progression of white matter The contributions by Ayerbe et al.org ajp in Advance . such as lower frequency of family scale. these ischemia and PSD usually is related to large-vessel infarction meta-analyses have included many studies that have defined (except lacunar infarcts).293 patients and reported that the differences in the prevalence and incidence of PSD has been pooled prevalence of PSD was 29% at any time point within lost in the existing meta-analyses of aggregated data. Thus. and diagnostic criteria to identify major and minor depression cidence of PSD have utilized meta-analysis to create large in community-based settings. These scales provide information about the frequency and personal history of depression. which is also related to the following stroke. N=192 DSM-5 that is specific for cerebrovascular disease is major or 15 minor vascular neurocognitive disorder. In addition. (14) and Hackett and hyperintensities over time have a poor response to treatment Pickles (15) are significant because they 1) establish that with antidepressants and a more chronic and relapsing poststroke depression is a frequent and important compli- clinical course (9). Community-based Acute or Outpatient pressive features must have depressed mood or loss of in. of depression should be ascertained based on a structured ence of cardiovascular risk factors and the severity of de. On the microvascular geriatric depression (7. scans. acute or rehabilitation hospitals. all of which may affect the prevalence of depression. mental state examination and should meet established di- pression observed in vascular depression is not present in agnostic criteria for a specific depressive disorder (17). our knowledge of important clinical lished in 2013 included 20. the clinical setting depression as slowly evolving vascular ischemia.POST-STROKE DEPRESSION existing meta-analyses in this field discussed under the FIGURE 1. the investigators tory of depression.g. diagnostic instrument has rarely been validated. most studies have found similarities PSD based on arbitrary cut-off scores on a depression rating between these conditions. cation of stroke and 2) refute prior assertions that the fre- Although vascular depression is related to small-vessel quency of PSD has been exaggerated (16). Setting Rehabilitation Populations N=2. In addition. or outpatient clinics. stating that the prevalence of poststroke depression is 31% miss these cortical pathology and white matter hyperintensities in MRI important clinical variables. or the severity of stroke.psychiatryonline. Following Strokea 30 Major Depression Diagnosis of PSD N=526. one or more depressions within the first 5 years following patients with vascular depression with executive dysfunction stroke ranged from 39% to 52% (14). severity of stroke. it has been clearly established that the existence reported that the significant association between the pres. however. PSD (13). 5 years following stroke (14). (e. A prior meta-analysis of 43 studies pub. 2 ajp. suggests that PSD these meta-analyses did not distinguish major depression from is one form of vascular depression. less family and personal his. N=524 25 Minor Depression The DSM-5 defines poststroke mood disorders as mood dis- N=598. N=553 orders due to stroke with depressive features.. One study other hand. A patient with a diagnosis of mood disorder due to stroke 10 with a major depression-like episode must have depressed 5 mood or loss of interest or pleasure along with four other symptoms of depression lasting 2 or more weeks. The only disorder in N=297. while Krishnan et al. community or hospitalized patients). but their use as a dysfunction. The most recent meta-analysis of 61 co. The most-quoted studies of prevalence and in. 15).769 symptoms of major depression lasting 2 weeks or longer. Thus.488 patients (15) reported that 31% of demonstrate that the frequency of PSD depends on the clinical patients developed depression at any time point up to 5 years settings where the patients are seen.191 terest or pleasure along with at least two but less than five N=2. greater cognitive impairment. Patients 0 with a diagnosis of mood disorder due to stroke with de. prominent executive and severity of depressive symptoms.

374 stroke ization of emotion (30) and that focal brain stimulation using patients (23). however. ROBINSON AND JORGE Risk Factors of PSD had a significantly higher frequency of major or minor de- Few prospective studies have examined risk factors to de. patients with PSD PSD requires the formulation of a new pathophysiological might be more likely to have a history of diabetes mellitus model of the disorder to integrate these disparate findings. 18 studies reviewed by Hackett and Pickles (15) and in 24 out dence strongly suggests a significant association between of 30 studies reviewed by Johnson et al. The findings.. most consistently associated with PSD. Age was not associated first clinical stroke. degree of disability. Epigenetic modifications of recent and largest meta-analysis analyzed 43 studies in- 5-HTTLPR have also been implicated in the onset and se. pression than patients with other lesion locations. only a few of these prospective more. However. factor for PSD in 13 out of 21 studies that examined this as. On the other hand. thrombotic. Initial studies have demonstrated that stroke patients sistent.e. In addition. However. This conclusion is also supported by the with PSD in 16 of these 21 studies. left frontal cortical versus left anterior). Subsequent analysis by this in the literature include genetic factors. have been incon. 0. gene methylation status was associated with incident PSD and the different neuroimaging methods used to determine and more severe symptoms at 12 months follow-up (21).88–1. However. transient phenomenon restricted to the first 2 months fol- lowing stroke. Furthermore. type and severity of stroke.99 (95% confidence interval [CI]50. a finding association is hardly surprising given the heterogeneity in the that was only observed in the presence of the 5-HTTLPR s/s way in which depression was assessed in these studies. repetitive transcranial magnetic stimulation is only effective when it is administered to the left dorsolateral prefrontal Medical and psychiatric history. ischemic or hemorrhagic) or mechanism about 10% of the variance of severity of PSD (32).11) for the asso- creased methylation status was independently associated ciation of stroke location and depression risk (28). The most PSD in stroke survivors (19).507 stroke patients and reported an odds ratio of verity of PSD. higher brain-derived neurotrophic factor (BDNF) lesion location (e. Further- velop PSD. recent strength of the correlation between PSD and impairment in systematic reviews argue against an association between PSD activities of daily living is relatively weak. In a recent study of 286 stroke patients. gender. and social support.psychiatryonline. Major cardiovascular risk cortex in patients with vascular depression (31). 26). subsequent meta- candidate genes have been examined as risk factors for PSD. one-third of these studies identified left frontal or left basal ganglia lesions within 2 months of a female sex as a risk factor for PSD (22). The severity of dis- ability was found to be significantly related to PSD in 16 out of Stroke characteristics and lesion location. believe that identifying the role that lesion location plays in pear to have no relation to PSD. A few the first 6 months after a stroke. A family history of depression was associated with stroke impairment in activities of daily living is the factor PSD in the few studies that examined this association (25). and none of the distance of the anterior border of ischemic lesion from the these models were replicated in an independent population of left frontal pole and severity of depression for both cortical stroke patients (14). lesion location. explaining only and the type (i. volving 5. two studies led by Robinson (5. the genotype (20). age.g. medical research group (27) found that the association of PSD with and psychiatric history. The severity of post- (22–24). lesion left frontal and left basal ganglia lesions appears to be a location.) of stroke (22–24). We also factors such as hypertension and hypercholesterolemia ap. 26) reported that acute State Examination scores than nondepressed patients with stroke patients with left frontal or left basal ganglia lesions similar background characteristics who were matched for ajp in Advance ajp. (18). However. 23). In spite of conflicting results. The available evi. We still believe there is an association between PSD and sociation. (i. (24). etc. A personal history of depression or anxiety or both was also consistently identified as a risk factor for PSD Functional and cognitive impairment. both studies found a significant correlation between studies proposed a specific predictive model. embolic. Utilizing separate populations of patients in 1984 and with major depression had significantly lower Mini-Mental 1987. Common genetic variations might confer distance of the anterior border of the lesion from the frontal vulnerability or resilience to develop psychiatric illness when pole in the left hemisphere remains significant only during an individual faces an unusual stressful challenge. The relationship between PSD and cognitive impairment Lesion location has been extensively investigated as a risk (especially executive dysfunction) has been well established factor for PSD. This lack of with PSD at 2 weeks and at 1 year following stroke. 23). the different definitions of patients. in. and the correlation of depression severity with Genetic factors. among the same group of stroke diverse timing of the assessments.e. A systematic review of 24 studies of with left frontal hemisphere lesions and with proximity to stroke patients reported that gender was not a significant risk the frontal pole (29). analysis of data from stroke patients who were either acute or The 5-HTTLPR and the STin2 VNTR polymorphisms of the chronic and had one or more stroke lesions reported no serotonin transporter gene (SERT) have been associated with significant association with lesion location (14. These findings were fact that there is strong scientific evidence of brain lateral- replicated in a review of 23 studies including 18. (22–24). there are studies that have continued to report the association of PSD Demographic factors... The risk factors that have been examined and subcortical regions (5.org 3 . the stroke severity and PSD (14.

a prospective study has been demonstrated to play an etiological role in mor- found that lack of social support at admission was associated tality associated with depression and myocardial infarction with the onset of PSD at 3-months follow-up (35).007) (41). was associated with increased mortality as early as 1 year after With regard to disability.. In this et al. This finding held when nortriptyline.6% for patients Consistent with the previous findings. The available evidence concerning PSD and analysis on which this assertion is based does not include all social support is conflicting. was also associated with PSD (47). p50. in a cohort of 51. while the recent meta. (42). a secondary analysis of the re- stroke. patients with PSD given a placebo [adjusted odds ratio53. 9-year follow-up compared with similar patients given pla- pression severity was an independent predictor of severity of cebo (N528) (i. This finding was A recent study of 1. Chollet views to diagnose PSD was published in 1993 (41).4.POST-STROKE DEPRESSION both lesion location and lesion volume (33). Five of six nortriptyline (100 mg/day) or fluoxetine (40 mg/day) for studies that examined whether severity of depression after 12 weeks (N553) showed that patients receiving active acute stroke predicted severity of impairment in activities of treatment had an increased probability of survival at the daily living at 1 year or more of follow-up found that de. The first motor. was the Numerous studies have examined the relationship between relationship of mortality following PSD to treatment with depression at the initial examination (which may range from a antidepressants (Figure 2) (48). Patients who developed at 12 weeks assessed using the Fugl-Meyer Motor Disability PSD during the acute poststroke period had significantly Scale. Similarly. subjects with minor depression. 95% CI51.77. (51) reported that among a group of higher mortality rates than similarly impaired stroke pa.e. However.7 at 3 months analyses did not distinguish between subjects with major (44. result of an increase in cardiovascular mortality (44). The investigators also reported increased mortality depression. 45). 95% escitalopram (5 mg–10 mg/day) enhanced cognitive per- CI51. (46). A 9-year follow-up study of few weeks following stroke to 6 or more months following patients with or without PSD who had been treated with stroke) and functional and motor recovery (36–38). this was not a randomized trial. and the Effects of Antidepressants Perhaps the most provocative finding.1–12. For instance.03]) (48). heterogeneity in the definition and evaluation of social and the effect of comorbid medical conditions (44).354 patients that used the Hospital replicated in an independent study of stroke patients with left Anxiety and Depression Scale to assess PSD found that at hemisphere lesions who were assessed during the first year the 5-year follow-up. mortality compared with patients with scores .7. and disability outcomes among non- study to report this phenomenon using standardized inter. which associated with PSD (24). Jorge et al.4–8.119 veterans hospi. sults of our previous randomized controlled trial on the ef- talized because of an ischemic stroke. nortriptyline or fluoxetine compared with 34. probably because of significant the relevant confounders such as disability. 59. A similar finding was reported by formance at 12 months assessed by the Repeatable Battery House et al. depressed patients during 12 months following stroke. patients with a Hospital Anxiety and after stroke (34). Thus. hibitor (SSRI) antidepressants in the 3 months after stroke. or subjects with among patients started on selective serotonin reuptake in- depressive symptoms.and showed significantly better improvement in activities of daily fluoxetine-related survival was examined separately and living than patients with PSD who did not respond to active was independent of whether the depression responded to treatment or placebo (39). depression severity.2% survival for patients treated with impairment in activities of daily living (18).psychiatryonline. (50) found that 12 weeks of fluoxetine (20 mg/day) was study. nondepressed stroke patients 4 ajp. A beneficial effect of antidepressants on or fluoxetine over 12 weeks leads to improved cognitive long-term survival after stroke was also observed in a function to the level seen in nondepressed stroke patients that group of 790 veterans with stroke followed over a 7-year lasts for more than 2 years (40). it is important to keep in mind the Depression Scale score $7 at 3 months after stroke had a strong association existing between major depression and the hazard ratio of 1. However. a longitudinal study has treatment or whether the patient was depressed or not shown that response to treatment of PSD with nortriptyline prior to treatment. and the data Social support. disruption of autonomic system function in patients with PSD might The Impact of PSD on Stroke Recovery and Mortality contribute to cardiovascular mortality. p50.2. those who developed ficacy of fluoxetine (20 mg–40 mg/day) and nortriptyline PSD had a higher 3-year mortality risk than veterans without (100 mg/day) to treat PSD showed that when compared a mental health diagnosis (43). however. Increased mortality associated with PSD is perhaps the Three studies analyzed the effect of antidepressants on most dramatic clinical phenomenon following PSD.41 (95% CI51.4. nondepressed patients with acute stroke.02) of increased presence of cognitive deficits (34). period (49). 12 months of tients with no in-hospital depression (odds ratio53. who responded to treatment with nortriptyline or fluoxetine p50. Furthermore.org ajp in Advance . who showed that even mild severity of PSD for the Assessment of Neuropsychological Status. living situation and marital status have not been consistently We reported that decreased heart rate variability. However. with those receiving placebo. support.13–1. 103 patients were followed up 10 years after their index more efficacious than placebo to improve motor recovery stroke to determine mortality rates. cognitive. although the number of social ties was The association of PSD with mortality appears to be the shown to be inversely correlated with the severity of PSD (18).

middle whether there are biological factors related to brain damage cerebral artery occlusion produced delayed degeneration that contribute to the bidirectional relationship between of dopaminergic neurons in the left ventral tegmental area. tion of prefrontal-subcortical circuits (58). there is evidence sup.7 32 Untreated 87.org 5 . hypothalamic.004. which resulted in reduced dopamine concentrations in the The association between PSD and biological factors striatum. starting 1 week after of PSD through a “reactive” psychological mechanism or middle cerebral artery occlusion.psychiatryonline. The attempts to model PSD in experiments with rodents. 30-minute middle cerebral artery occlusion that limits impairment (23).4 41. Survival Rate for Patients Who Were Depressed and Nondepressed at 3 Months Followed Over 9 Yearsa Probability of survival for Probability of survival for nondepressed patients depressed patients 100 100 80 80 * Percent Survival Percent Survival * 60 60 40 40 20 20 0 0 1 5 9 1 5 9 Treated 96 68 64 Treated 100 82. or placebo for 3 months. and biological factors In recent years.e. middle cerebral artery ligation. there has been a renewed interest in in the mechanism of PSD (55). social. A subgroup of impairment is etiologically associated with the development these mice was given citalopram. integrate these changes into a coherent explanatory ing impairment. there have been several independent of PSD or their effects on mood (50–52). as well as hyperactivity and other Treatment in Acute Stroke [TALOS] study) is currently behavioral changes not seen in rats given sham ligations underway (54). Further experiments using this animal model dem- onstrated that the biogenic amine and behavioral effects Etiological Mechanisms were lateralized. artery ligation. (61).4 73. disrup- by the modified Rankin Scale at the 12-month follow-up (52). * p=0. (63) used a model of mild stroke in mice severity and the degree of functional physical and cognitive (i.1 57. although two of the factors most consistently neuroplasticity and in glutamate neurotransmission (59). disability and depression. How- impairment. the stroke literature is that PSD is associated with stroke Kronenberg et al. Left. indicating that SSRIs following stroke may enhance recovery From a translational approach. porting the role of psychological. a multicenter randomized controlled trial of the cerebral artery ligation produced significant bilateral de- efficacy of citalopram to reduce disability and cardiovascular pletions of norepinephrine and dopamine in both the mortality following stroke (The Efficacy of Citalopram cortex and brainstem.. a pathophysiological hypothesis of PSD that can impairment influencing depression and depression influenc.9 Untreated 92 55. fluoxetine (40 mg/day). findings of a recent meta-analysis of studies assessing the effect We conducted the earliest studies using a rat model of of SSRIs on stroke outcomes support this conclusion (53). despair assessed by the sucrose consumption test and forced ajp in Advance ajp. The most consistent finding in modeling the neuropsychiatric consequences of stroke. associated with PSD are functional disability and cognitive and an excess of proinflammatory cytokines (60). However. receiving antidepressants had decreased disability measured pituitary-adrenal (HPA) axis abnormalities (57). The behavioral correlates of these neurodegenerative has included empirical evidence suggesting alterations and neurochemical changes were anhedonia and behavioral in ascending monoamine systems (56). ROBINSON AND JORGE FIGURE 2. The survival rate of patients given antidepressants was almost twice that of those given a placebo. there is rapidly growing literature model has yet to be formulated.9 a Patients were randomly assigned to nortriptyline (100 mg/day). alterations in In summary. it is uncertain whether the level of the ischemic damage to the basal ganglia). there is clearly a reciprocal relationship with ever. and lasted up to 4 weeks (62). In addition. but not right. Right hemisphere middle Finally. not occurring after left middle cerebral Like many disorders in psychiatry.

655 patients found a 6 ajp. increased levels of of psychotherapy) that included 1. disorders due to abnormal modulation of frontal and cin. given a placebo. and also acute ischemia can unveil the presence of vascular depression their effects may vary at different times after the stroke.psychiatryonline. a number reduction in Hamilton Depression Rating Scale (HAM-D) of studies have provided support for the role of proin. Thus. resting connectivity patterns revealed by functional MRI appear to be similar in vascular depression and PSD. respectively. BDNF levels. there appears to be a threshold by be described as a bio-psycho-social disorder. Decreased compared with nondepressed control subjects. may best presentation. there was a significantly of somatic symptoms of PSD (67). 216 patients with acute ischemic stroke reported the results creased exploratory behavior and sucrose consumption. Additionally. artery occlusion with a 14-day chronic mild stress protocol have been shown to be reduced in PSD (68). 60). Among 33 poststroke patients given interleukin-6 (Il-6) were associated with increased severity citalopram (10 mg–20 mg/day). Furthermore. triggers the onset of clinical depression. and/or multiple) of the neural circuits that connect the Thus. inflammatory cytokines by which high cortisol levels induce A meta-analysis of 16 randomized controlled trials an inflammatory response that. in 1994 (72). Chronic citalopram treatment inflammatory cytokines reduce the synthesis and availability initiated 7 days after stroke. believe future studies should attempt to identify the mecha- pression independently of the presence of widespread nism of specific symptoms or clinical characteristics of PSD cerebrovascular pathology. however. The first randomized Earlier studies also examined the occurrence of HPA axis double-blind treatment trial was reported in 1984 by deregulation in PSD. prevented the de. although there are numerous possible physiological prefrontal cortex. There is a bidirectional re. will result in further (12 using antidepressants and four evaluating the efficacy HPA axis deregulation. Patients randomly assigned to nortrip- elevated cortisol levels and abnormal negative feedback tyline (50 mg–100 mg/day) had a significantly greater control of cortisol secretion (57).org ajp in Advance . The recent emphasis on neuroplasticity as a critical There have also been animal studies that combined ex. (59) based on 33 studies reported Unfortunately. scores over 6 weeks of treatment compared with patients flammatory cytokines in the development of PSD (56. It has also been hypothesized that ischemic lesions of decrease the neuroplasticity of the prefrontal cortex con- ascending monoamine pathways may result in depressive tributing to the onset and perpetuation of PSD (70). More recently. (6). more salient roles in some forms or symptoms of PSD. this which the confluence of multiple etiological factors or further general theoretical framework does little to help us elucidate damage to specific white matter tracts. with increased activation of the default TREATMENT OF PSD mode network and limbic structures and decreased activation of task-related networks and the dorsolateral aspects of the The randomized double-blind controlled treatment prefrontal cortex (66). behavioral phenotype (63). HPA axis deregulation and increased levels of proinflammatory however. We (58). a preliminary study using magnetic resonance gulate regions involved in mood regulation (18). such as the cingulate pathophysiological mechanisms leading to specific symptoms. greater reduction in HAM-D scores over 6 weeks com- lationship between HPA axis deregulation and the levels of pared with 33 similarly depressed patients given placebo. there have been relatively few studies of that lower serum BDNF was found in patients with PSD the mechanisms of PSD in clinical populations. or a strategically located stroke might produce de. the uncinate fasciculus. were significantly associated with severity of PSD cytokines may inhibit neurogenesis in the hippocampus and (65). 3-dioxygenase (56). rather than the whole syndrome. like most of the major psy- regulation and executive function leading to a similar clinical chiatric disorders not associated with stroke. A recent study of produced a depressive phenotype characterized by de. a of a multivariate analysis showing that lower serum levels of behavioral effect that was reversed by the administration of BDNF at admission were an independent predictor of PSD at citalopram and a 5-HT1A antagonist along with evidence of the 3-month follow-up (69). Furthermore. particularly the association of PSD with Lipsey et al. spectroscopy found altered glutamate levels in the anterior There is a growing consensus that ischemic lesions (single cingulate cortex of depressed stroke patients (71). neurobiological substrate for depressive disorders suggests perimental ischemic lesions with social isolation or chronic that synaptic alterations in the prefrontal cortex and hip- mild stress protocols implemented during the recovery pocampus may be etiologically implicated in PSD. In sup- process after stroke (64). From a network standpoint.POST-STROKE DEPRESSION swimming test. of serotonin through their enhancing effect on the activity of generation of dopaminergic neurons and reversed the the enzyme indolamine 2. many investigators have con- (independently of their lateralization) may disrupt mood cluded that this complex disorder. one of the regulators of these processes. Furthermore. bundle. Permanent left middle cerebral port. trials of PSD are shown in Table 1. The first double-blind controlled trial to This hypothesis has been supported by recently published examine the efficacy of SSRIs was reported by Andersen studies in which increased serum concentrations of et al. and superior longitudinal These different etiological factors described above may have fasciculus. CSF levels of serotonin or norepinephrine metabolites. However. performed by Noonan et al. a meta-analysis increased neurogenesis in the hippocampus (64). thalamus. Finally. in turn. and amygdala mechanisms related to PSD. basal ganglia.

and family support can be beneficial to treat or prevent PSD in Furthermore. fluoxetine5placebo 77%. 61%. that SSRIs are associated with increased risk for stroke. (84) 21 Methylphen.org 7 . 100%. 10 mg Scale placebo. 75% 24 of 26 placebo fluoxetine5placebo placebo (N526) Rampello et al. psycho-education. etine. Intent to treat: Completers: 26 of 33 (N533. ajp in Advance ajp. mg/day) Scale Nortriptyline. methylphenidate. 14%. mg/day).placebo citalopram. 29% for patients . mg/day). 62%. 13. (87) 54 Fluoxetine 12 weeks Beck Depression HAM-D score .placebo placebo. 40 nortriptyline. mg/day). 20 Inventory fluoxetine.15. (85) 56 Fluoxetine 12 weeks HAM-D Intent to treat: Fluoxetine. (N516. NR5not reported. ROBINSON AND JORGE TABLE 1.psychiatryonline. placebo Depression 15 of 15 (N515) Rating Scale placebo Fruehwald et al. Brief psychosocial therapies. 13 of 16 nor- nortriptyline 31% triptyline. 10 of 11 placebo placebo (N511) Robinson et al. (83) 27 Trazodone Mean 32 Zung Efficacy: trazodone. 14 of 23 (N523. fluoxetine. Double-Blind Placebo-Controlled Treatment Studies of Poststroke Depressiona Medication (N and Maximum Daily Evaluation Completion Study N Dose) Duration Measure Results Response Rate Rate Lipsey et al. (72) 66 Citalopram 6 weeks HAM-D. complications and increased risk of falls in the elderly (76). 69%. (SD=6) Scale Activities of Daily placebo (N59) Living Index for patients with abnormal dexamethasone suppression test Andersen et al. placebo (N533) Grade et al. fluoxetine. Zung Intent to treat Completers: 11 of 14 (N514. nortriptyline. nortriptyline. 200 days Depression placebo on Barthel mg/day). (86) 31 Fluoxetine 6 weeks Montgomery Intent to treat: Fluoxetine. day). placebo. HAM-D score #13: 26 of 28 fluox- (N528. 100 13 of 17 mg/day). for intellectually day). (88) 31 Reboxetine 16 weeks Beck Depression Reboxetine. placebo placebo (N517) Wiart et al. 12 of 76 placebo placebo (N576) a HAM-D5Hamilton Depression Rating Scale. 20 Inventory. 75). placebo HAM-D challenged (N515) depressed patients Choi-Kwon et al. 14 of 16 (N516. 4 mg/ Inventory. 20 mg/ Åsberg fluoxetine. It should be acknowledged that treatment with anti- whereas psychotherapy was not more effective than a control depressants is not without risk.65 years).placebo NR NR (N516. significant beneficial effect of antidepressant medication. other epidemiological studies have reported combination with antidepressant treatment (74. fluoxetine5placebo. 152 Fluoxetine 3 months Beck Depression Fluoxetine5placebo NR 15 of 76 (89) (N576. placebo. citalopram mg/day. HAM-D HAM-D scores . methylphen- 30 mg/day). 15 of 20 Placebo (N520) placebo 33%. however. 20 Melancholia citalopram. (6) 34 Nortriptyline 6 weeks HAM-D. 3 weeks HAM-D Intent to treat: NR 9 of 10 idate (N510. placebo idate. For example. NR (N57. placebo Reding et al. that been associated with an increased risk of hemorrhagic place emphasis on care management. placebo. SSRI use has intervention (73). 100 Depression and efficacy: nortriptyline. 33% fluoxetine.

4–8. orders resulting from stroke (81).org ajp in Advance . Randomized Controlled Trials for Evaluation of Preventative Treatments for Poststroke Depressiona Percent of Original Sample Developing Depression 30 Escitalopram (10 mg <65 years. (82) (52 weeks) (52 weeks) (24 weeks) (12 weeks) (52 weeks) Completers 134 67 56 88 56 Randomized 176 137 92 113 111 a Although the trials show very similar results in the percent of patients developing depression with placebo or pharmacological treatment. (79) et al. as well as suggesting that neurotrophic times greater than the risk for patients treated with esci. and all-cause mortality (77. has been first statistically significant randomized controlled trial of substantial. (90) et al. as the demonstration of preventive treatment (Figure 3). PSD was regarded as a psychological after recovery for at least 6 months (32). The well as the treatment and prevention of PSD. and perhaps inevitable reaction to stroke-related disability. diarrhea. Pooled analyses mechanism by which antidepressants enhance physical and revealed that the likelihood of developing PSD was reduced cognitive recovery after stroke even in the absence of PSD. the risk of may lead to identification of how specific symptoms of PSD onset of depression for placebo patients was more than four may be mediated. the American Heart Association recommends the use of antidepressants for PSD. There were no significant active and placebo group The effect of these antidepressants may be due to inter. progress in ascertaining the diagnosis and Prevention of PSD prevalence of PSD. and with the use of an mechanism. Since that time. the Robinson et al. the risk factors for PSD. it seems to us that identifying additional prevention of PSD was conducted by Robinson et al. 10 mg/day for patients ages 65 and under) over the association of Il-6 with somatic symptoms of depression 1 year had an incidence of PSD of 8. (82). and severity of impairment. Other urgent areas for future research include deter- marized the findings of eight randomized controlled trials mining the mechanisms of increased mortality extending assessing the efficacy of preventive interventions among 776 over at least 7 years following PSD and elucidating the initially nondepressed stroke patients (80). 78).POST-STROKE DEPRESSION FIGURE 3. cognitive recovery. differences in the frequency of side effects of nausea. Tsai et al. 8 ajp.2. Thus. The neurogenesis induced by SSRIs is a likely potential especially following a 1-year treatment. the effect of PSD Perhaps the major advance in the treatment of PSD has been on physical recovery. 95% CI52. aspects of the mechanism of PSD is the most urgent need published in 2008. actions with other variables such as depression. (50) trials had sufficient power to demonstrate statistical significance. Controlling for age. which should be continued As recently as the 1970s. or preventing not only PSD but other neuropsychiatric dis- p. (50) et al. and mortality.0. in which 58 nondepressed acute stroke for future research because it may lead to a more specific patients treated with escitalopram (5 mg/day for patients therapeutic intervention. SSRI. 3 months following stroke (69) are intriguing findings that severity of stroke.4% hours after stroke with the development of depression after for 59 patients receiving placebo. For example. (79). and Chollet et al. myocardial infarction. gender. disability.5% compared with 11. and anti-inflammatory agents may be effective in treating talopram (adjusted hazard ratio54. among subjects receiving active pharmacologic treatment. 25 5 mg >65 years) Problem solving therapy Sertraline (63 mg Rasmussen. fatigue. (79).psychiatryonline. and dizziness.5. and comorbid medical conditions that require further elucidation. FUTURE DIRECTIONS Finally.9% (67) and the association of low levels of serum BDNF within for 59 patients receiving problem solving therapy and 22. studies of the role of over age 65. 20 50 mg Almeida) Fluoxetine (20 mg) Milnacipran 15 Placebo 10 5 0 Robinson Rasmussen Almeida Chollet Tsai et al. The most recent meta-analysis of prevention trials sum. (91) et al.001).

et al: A two-year longitudinal 35. Acion L. Gen Psychiatry 2008. Arch Gen Psychiatry 1988. 47:1222–1227 committee meeting sponsored by Avanir Pharmaceuticals. 131:e29–e322 25. Benjamin EJ. Br J Psychiatry 2013. Arch Gen Psy- intensity progression and late-life depression outcomes. J Neuropsychiatry Clin Neurosci 2003. Taylor WD. Robinson RG: A reappraisal of post- study of post-stroke mood disorders: findings during the initial stroke depression. Hackett ML. and he receives royalties from 22. Am J Psychiatry 1997. Tenev VT. J Nerv Ment Dis 2001. Kohen R. dementia of depression in stroke patients. Starr LB. Roth M: The natural history of mental disorder in old age. Rabins PV. 1: 29. 1018–1020 Brain 1987. affective style. Am J 33. et al: Association of serotonin Houston. et al: One-year follow-up in 15. Koçer A. MacNeill SE. Kutlubaev MA. 2015. ROBINSON AND JORGE AUTHOR AND ARTICLE INFORMATION 18. Parikh RM. Arndt S. Robinson RG. Eur J Phys Rehabil Med 2008. Maiberger R. J Gerontol A Biol Sci Med Sci 2004. et al: Risk factors for geriatric cation of lesion. et al: Poststroke depression 1. et al: Mood disorders in stroke 422–430 patients: importance of location of lesion. et al: Risk factors for poststroke Cambridge University Press. Spencer WC. 29:618–624 510–517 36. 47:785–789 Geriatr Psychiatry 2004. Nyström KV. Robinson has received compensation for participation in an advisory Res 2013. Stewart R. Geurden M. 158:83–92 randomized treatment study. 60:1090–1096 32. 28. MacNeill SE. et al: The impact of poststroke 13. J Neu- stroke statistics–2015 update: a report from the American Heart rosci Nurs 2006. University of York. J Ment Sci risk factor for poststroke depression? meta-analysis. 149:93–99 consultant to Otsuka Pharmaceuticals. Kosier JT: Treatment of cognitive im- nosed in patients with stroke? Acta Psychiatr Scand 2010. Price TR: Comparison of cortical and complication of stroke. Robinson RG. Starr LB. Jorge RE. 65:268–276 Psychiatry 2003.and inter-hemispheric lesion location evaluation. 202:14–21 38. Robinson RG. Hackett ML. 3:11–21 pression. Lipsey JR. he has served as a J Affect Disord 2013. Hackett ML: Part II: predictors of depression after accepted Aug. DNA promoter methylation and poststroke depression. using repetitive transcranial magnetic stimulation. Robinson RG. 2006. 12:84–92 37. depression on recovery in activities of daily living over a 2-year defined vascular depression in geriatric rehabilitation patients. Int J Stroke 2014. Carver College of Medicine. et al: Phenomenological com. Robinson (robert-robinson@uiowa. Iowa. Wei N. Int J Stroke 2014. et al: Treatment of vascular depression 9. J Neurol Neurosurg Psychiatry 1977. De Ryck A. 13:525–534 parison of poststroke depression and functional depression. the Michael E. et al: The Sunnybrook Stroke study of post-stroke mood disorders: dynamic changes in associated Study: a prospective study of depressive symptoms and functional variables over the first six months of follow-up. Irwin W: The functional neuroanatomy of emotion and 8. Lancet 1984. Meyers BS. Bolla-Wilson K. Pearlson GD. research funding from the Senator Financial Group. 121: pairment after poststroke depression: a double-blind treatment trial. Paolucci S. New From the Department of Psychiatry. 65:1296–1302 20. Robinson RG. Lipsey JR. Stewart R. Dr. Robinson RG: The Clinical Neuropsychiatry of Stroke. 45:247–252 depression: the importance of executive functioning within the 34. he has received 21. Koçer E. p 470 Iowa. Robinson RG. intra. McHugh PR: Mood disorder as a specific 26. Kimura M. 2nd ed. Kang HJ. et al: A longitudinal study of SLC6A4 Address correspondence to Dr. 146: 59:1290–1294 627–634 12. et al: Post-stroke depression and 297–300 lesion location: a hospital based cross-sectional study. 20. Black SE. Price TR: Comparison of patients with Psychiatry 1986. J Psychiatr Dr. Hays JC. 40: subcortical lesions in the production of poststroke mood disorders. and Aug. 19. 38(suppl):316–327 Association. Kubos KL. Kim JM. 110:1045–1059 4. Wolfe CD. Spalletta G. Arch Neurol 1990. Ayerbe L. Br J Psychiatry 1991. Cain KC. Cerebrovasc an updated systematic review and meta-analysis of observational Dis 2000. 31:1482–1486 ajp in Advance ajp. 44:13–18 analysis. et al: The effect of remission of 16. and the Department of Psychiatry and Behavioral Sciences. Kang HJ. 17:276–280 3. Stroke 1984. Yong W. Yochim B. Robinson RG. Starr LB. Lipsey JR. Indian J 7. Lichtenberg PA: Post-stroke and clinically. et al: A two-year longitudinal 27. Brain 1984. Mitchell PH. 10:25–32 studies. Köhler S. 54:915–922 30. Moser DJ. Lancet Neurol 2014. et al: Heart disease and incidence and risk factors: an integrative literature review. Bilge C. Am J follow-up. Blazer DG: MRI-defined vascular de. Trends Cogn Sci 1999.psychiatryonline. Narushima K. Arch Gen Psychiatry 1997. et al: Nortriptyline treatment cation: a systematic review. Starkstein SE. J Geriatr Psychiatry Neurol 2014. Pai K. 101:281–301 Psychiatry 2009. review. House A. Johnson JL. Grasso MG. Kosier JT. 14:736–741 using meta-analysis. Herrmann N. Pickles K: Part I: frequency of depression after stroke: stroke patients discharged from rehabilitation hospital. Folstein MF. Alexopoulos GS.edu). 40. Young RC. 401–403 Stroke 2000. he has received promoter methylation and genotype with poststroke depression. Circulation 2015. Chemerinski E. Kubos KL. Robinson RG. Arch Baylor College of Medicine. Thunga R. et al: Mood disorders in the year poststroke depression on activities of daily living in a double-blind after first stroke. et al: White matter hyper. transporter gene polymorphisms with poststroke depression. et al: Neuropsychiatric outcomes 10. covery. Mast BT. Kim JM. et al: Post-stroke depression and lesion lo- 6. et al: Natural history.org 9 . 107:81–93 28. Am J Geriatr 1955. Davidson RJ. Arch Gen chiatry 2008. Dennis M. Robinson RG. 143:527–529 and without poststroke major depression matched for size and lo- 11. Starkstein SE. 27:147–158 Received Mar. Mast BT. Lipsey JR. Rajashekaran P. et al: A longitudinal study of BDNF lecture honorarium from Xiang-Janssen Pharmaceuticals. Lawrence J. 154:497–501 31. O’Brien JT. Cambridge University Press. 262:81–90 of post-stroke depression: a double-blind study. 15: outcome. 23. revisions received July 17. et al: Lateralization of vascular depression hypothesis. Stroke 1983. 189:421–425 17. Li X. Go AS. Mogridge L. 9:1017–1025 39. MacFall JR. 15: 5. 2015. 23. 55:343–348 hypothesis. stroke and impact of depression on stroke outcome: an updated systematic review of observational studies. Mozaffarian D. Steffens DC. 9: 1026–1036 REFERENCES 24. Stroke 1998. Robinson RG: How should depression be diag. Ayis S. Antonucci G. 2015. Iowa City. of stroke. J Neurol 2015. Am J Psychiatry 1989. Minarik PA. Brouns R. predictors and after stroke: the effect of antidepressant therapy on functional re- outcomes of depression after stroke: systematic review and meta. et al: Depression and functional outcome 14. Robinson RG. Jorge RE: Is family history of depression a 2. Jorge has received lecture honoraria from depression: identification of inconsistencies based on a systematic Janssen. DeBakey VA Medical Center. Krishnan KR. et al: “Vascular depression” Psychiatry 2013. Starkstein SE. Robinson RG. Houston.

Am J Geriatr factor levels in post-stroke depression. Williams LS. Tardy J. Kroenke K. Mikami K. 25:255–263 variability and the effect of depression on post-myocardial infarction 68. Jorge RE. 299:2391–2400 hypothesis: mechanisms linking vascular disease with depression. JAMA 2013. 343:d4551 multifactorial nature: results from a prospective longitudinal study. Robinson RG. J Neuropsychiatry Clin Neurosci 2014. Jorge RE. Wu CL. et al: Association of de. 79:1862–1865 hypercortisolism early versus late after stroke: a 3-year longitudinal 79. 55.org ajp in Advance . et al: Antidepressant use and J Neurol Sci 2014. Grove EL. Neuroendocrinol Lett 2014. 165:1486–1491 a review. Cochrane BB. et al: Explanatory factors for the report. Williams LS. Mikami K. Proc Natl Acad Sci USA 2010. Li W. Crewther SG: Meta-analyses indicate asso. Psy- Ann Pharmacother 2011. Robinson RG: Differential behavioral and biochemical effects of 84. Bakas T. et al: Exofocal dopaminergic pression with 10-year poststroke mortality. Taylor WD. Bossù P. randomized. 10: 76. Lassalle-Lagadec S. et al: Poststroke depression and its BMJ 2011. Ayis S. Zhao YD. Stroke 2009. Jorge RE. et al: Involvement of serotonin neu- after stroke may be associated with depressive symptoms at 1 month. Chrostowski J. Biol Psychiatry 2012. 107:2669–2674 49. Hsieh CF. Stroke 1994. et al: Low heart rate chiatry Clin Neurosci 2013. Aström M. et al: Care management of 54.POST-STROKE DEPRESSION 41. placebo-controlled study. 11:984–991 blind randomized placebo-controlled trial. double-blind. Hackett ML. Mead GE. Votypka V. Am J Geriatr Psychiatry intervention with antidepressant reduces poststroke depression 2011. 85:514–521 toms and interleukin-6 serum levels in acute stroke. Russo SJ. Arndt S. Adams HP Jr. Zhang ZJ. et al: Mortality and poststroke 70. Ayis S. et al: Systematic hypothesis for post-stroke postmenopausal women in the Women’s Health Initiative Study. Veith RC. 35:104–109 78. et al: Decreased heart rate 69. Mortensen JK. Li J. Cerebrovasc Dis 2013. et al: Prevention of poststroke depression depression: a review of the literature and a new hypothesis involving with milnacipran in patients with acute ischemic stroke: a double- inflammatory cytokines. Am J 65. et al: Antidepressant use and risk 985–987 of adverse outcomes in older people: population based cohort study. House A. Orto LA. Dhiman P. Ayerbe L. Stroke 1993. 63. Foley NC. Arch 205:707–710 Phys Med Rehabil 1998. Morris PL. 255:332–334 stroke: a double-blind trial. Starkstein SE. 347:159–166 risk of incident cardiovascular morbidity and mortality among 56. 83. Swindle RW: Depression and other mental Biochem Behav 2010. et al: Fluoxetine for motor recovery 72. Grade C. Sibon I. De Ryck A. 18:963–974 pression: Does prophylactic pharmacotherapy work? J Stroke 59. Alexopoulos GS: The vascular depression domized controlled trial. Prinz V. Koo JW. Neurology 66. et al: Mortality at 12 and 24 months 64. et al: The etiology of poststroke 82. J Neurol Neurosurg Psychiatry 2014. placebo-controlled trial to test the effects 38:998–1003 of citalopram in patients with acute stroke. Am J critical mediator of stress-impaired neurogenesis and depressive Psychiatry 2003. 160:1823–1829 behavior. J Neuropsy- 46. et al: Escitalopram and problem- study. Schlumpf M. Becker KJ. et al: Selective serotonin reuptake inhibitor 71. Spalletta G. et al: The long-term outcomes of de. Mol Psychiatry 2006. controlled trial. McHugh P. Dilharreguy B. 26:323–328 60. Cravello L. Anderson CS. 32:696–701 sponses in a rat model of post-stroke depression. Ayerbe L. Allison M. Glodzik-Sobanska L. Science 1979. degeneration as antidepressant target in mouse model of poststroke 150:124–129 depression. 79:1047–1050 10 ajp. Shoemaker WJ. Robinson RG. Am J Psychiatry 1993. depression caused inflammation and neurotransmission and resultant Arch Intern Med 2009. Lancet Neurol 2011. Chou SY. et al: Reduction of CSF Psychiatry 2004. Zhu L. et al: TALOS: a multicenter. Vestergaard K. Chollet F. House A. Kronenberg G. Wang SH. Ling S. Mrkobrada M: Selective serotonin reuptake inhibitors 57. 72:273–281 42. Aizenstein HJ. J Neuropsychiatry Clin Neurosci 1992. Crichton SL. Balkaya M. generalized anxiety disorder. pression severity. Arch Gen Psychiatry 2010. Jorge RE. et al: Prevention of post-stroke rotrophic and neuroimaging markers in depression after stroke. et al: Brief psychosocial-behavioral the course of disability following stroke. 148:111–120 50. Imperiale F. Jorge RE. Winter SW. et al: Neuropsychiatric symp- Register. Carney RM. using escitalopram or problem-solving J Stroke Cerebrovasc Dis 2013. Cochrane Database Syst Rev 2008. et al: Subacute default 2014. psychopharmacology. Radiology 2012. controlled trial. Acion L. deactivation in neu. Int J Stroke 2015. Coupland C. 16:867–873 373–379 48. JAMA 2008. poststroke recovery: a double-blind. et al: Prevention of poststroke de- Mol Psychiatry 2013. Arch Intern Med 2005. Yang Y. Neurology 2012. Tsai CS. 10:123–130 hibitor citalopram. 24:52–57 solving therapy for prevention of poststroke depression: a ran- 58. 161:1090–1095 monoamine metabolites in poststroke depression: a preliminary 44. rotransmission in hippocampal neurogenesis and behavioral re- Stroke 2001. Moser DJ. Robinson RG. et al: Methylphenidate in early right and left hemispheric cerebral infarction in the rat. Olsson T. Robinson RG. Asplund K: Different linkage of depression to and brain hemorrhage: a meta-analysis. J Affect Disord 2014. International clinical 61. et al: Single voxel proton treatment and depression are associated with poststroke mortality. et al: Effect of experi. 40:3073–3078 hibitors for stroke recovery. 26:263–267 mental cerebral infarction in rat brain on catecholamines and be. 31:904–909 47. 19:1007–1015 significantly more than usual care with antidepressant: living well 53. Ried LD. Arch Neurol 1986. Bryer JB. Cheng Q: Etiological mechanisms of post-stroke depression: mortality. poststroke depression with the selective serotonin reuptake in- controlled trial. 310:1066–1067 75. Ghose SS. 22:e124–e135 therapy. 43:763–765 62. 264:218–224 pression up to 10 years after stroke. Blumenthal JA. et al: Escitalopram and enhancement of 73. Mitchell PH. with stroke: randomized. Robinson RG. Smoller JW. Albucher JF. Nature 1975. 77. Fransen E. Freedland KE. Feng H. Jorge RE. Ciaramella A. 22:1243–1251 ciations between neuroendocrine activation. Hackett M: Selective serotonin reuptake in. Knapp P. 45:888–897 chiatry Res 2006. 83:2007–2012 mode network dysfunction in the prediction of post-stroke de- 45. Fang J. the South London Stroke 67. Morriss R. Pharmacol 43. Carey LM.psychiatryonline. Neurol Res 2009. 169:2128–2139 on possible treatments. Noonan K. Andersen G. Moser D. Bamford J. Moser DJ. Jia H. Salter KL. Spalletta G. 25:1099–1104 51. Kraglund KL. Redford B. 95:129–137 health diagnoses increase mortality risk after ischemic stroke. Int Clin Psychopharmacol 2011. 168: Psychiatry 2008. Lauritzen L: Effective treatment of after acute ischaemic stroke (FLAME): a randomised placebo. Andrzejewski P. Ferguson D. Hackam DG. et al: Serum brain-derived neurotrophic variability is associated with poststroke depression. Spalletta G. Zeng JW. Slowik A. Brouns R. et al: Interventions for treating cognitive recovery following stroke. (4): 187–196 CD003437 52. Guo YJ. 80. poststroke depression: a randomized. et al: Effect of antidepressants on 74. 67: depression after stroke. magnetic resonance spectroscopy in post-stroke depression. Stroke 2007. Reding MJ. et al: Antidepressant therapy after haviour. Crichton S. 81. et al: Nuclear factor-kappaB is a depression: a placebo-controlled trial of antidepressants. 4:440–442 increased mortality of stroke patients with depression.

40:275–285 after stroke: a placebo-controlled. Kwon SU. placebo-controlled study. Petit H. Han SW. emotional incontinence. Gatterbauer E. placebo-controlled study. Wiart L. et al: A double-blind. Robinson RG. et al: Early fluoxetine treat. 44: controlled study with an open-label long-term follow up. Psychosomatics 2003. 67:1104–1109 ajp in Advance ajp. Lunde M. J Clin safety of reboxetine in elderly patients affected by “retarded” post. Poulsen DL. 37: depression: a double-blind placebo-controlled study. Joseph PA. et al: Fluoxetine in early poststroke ness: a double-blind. Waterreus A.org 11 . Psychiatry 2006. ROBINSON AND JORGE 85. Almeida OP. 250:347–351 91. and anger prone- 86. Hankey GJ: Preventing depression after 88. J Neurol 216–221 2003. Chiechio S. of depression in stroke patients. double-blind study. 87. Rasmussen A. Arch Ger- fluoxetine in the treatment of depression and in short-term recovery ontol Geriatr 2005. Am J Psy. Alvano A. et al: Fluoxetine treatment in chiatry 2000. Fruehwald S. et al: Nortriptyline versus stroke depression: a random. 156–161 31:1829–1832 90. Castillo C. placebo-controlled study of sertraline in the prevention ment of post-stroke depression: a three-month double-blind placebo. 157:351–359 poststroke depression. Schultz SK. Rehak P.psychiatryonline. Choi-Kwon S. Rampello L. 89. Stroke 2000. et al: An evaluation of efficacy and stroke: results from a randomized placebo-controlled trial. Stroke 2006.