Two-year longitudinal study of post-stroke mood disorders: dynamic changes in correlates of depression at one and two years

As part of a prospective study of 103 stroke patients, we have analyzed the relation between depression and associated variables at 3 months, 6 months, 1 year, and 2 years after stroke. At all intervals up to and including 1 year poststroke, patients with left hemisphere strokes showed a strong relation between severity of depression and distance of the lesion on computed tomography scan from the frontal pole. At 2 years poststroke, this relation was no longer significant. The correlation between depression and impairment in activities of daily living peaked at 6 months and thereafter fell but remained significant at 1 and 2 years poststroke. The correlation between depression and cognitive impairment and between depression and social functioning fluctuated--with most correlations at 1 and 2 years follow-up nonsignificant. Although the conclusions that can be drawn from this study are limited by the fact that less than half of the original patients were followed up at each time, these declining correlations between depression and associated variables at 1 and 2 years follow-up may reflect the natural course of major depression which spontaneously remits between 1 and 2 years after stroke. The persisting significant association of impairment in activities of daily living with depression may reflect the effect of severe depression in sustaining and possibly retarding recovery from physical impairment.     

Mood disorders in left-handed stroke patients

Thirty left-handed patients hospitalized for stroke were examined for mood disorders. Patients with left hemisphere lesions and nondominant hand impairments had significantly higher depression scores and more depressive diagnoses than patients with right hemisphere lesions and dominant hand impairments. Major depression was strongly associated with left anterior brain injury, and depression severity was significantly correlated with proximity of the lesion on CAT scan to the left frontal pole. These findings are almost identical to previously reported results from right-handed patients and suggest that cerebral lateralization of poststroke mood disorders may be independent of cerebral motor dominance and language dominance.     

A two year longitudinal study of poststroke mood disorders: prognostic factors related to one and two year outcome

In a prospective study of mood disorders in 103 stroke patients, we examined the predictive value of affective, cognitive, social and neurologic variables obtained in-hospital and at six months poststroke in terms of outcome as determined by the same measures at one and two years follow-up. The following factors were found to have prognostic significance: 1) Lesion Location: proximity of the lesion on CT scan to the frontal pole in patients with left anterior infarcts showed a strong positive relationship with severity of depression at one year but not at two years poststroke. 2) Affective Status: depression (in-hospital and at 6 months) strongly predicted depression at one year but not at two years poststroke. Additionally, in-hospital depression significantly correlated with physical impairment at two years, while depression at six months bore a moderate relationship to physical impairment at one year. 3) Physical Impairment: impairment in activities of daily living in-hospital bore a modest relationship to depression at one year while such impairment at six months correlated strongly with depression at both one and two years. These findings may reflect the natural course of major depression which remits between one and two years poststroke. Although stroke lesion location is the strongest predictor of subsequent depression, there appears to be a reciprocal relationship between physical impairment and depression (i.e., depression predicts impairment and impairment predicts depression). Since poststroke depressions are amenable to therapeutic intervention, these prognostic factors may have implications for the treatment and rehabilitation of stroke patients.     

A two-year longitudinal study of poststroke mood disorders. In-hospital prognostic factors associated with six-month outcome

In a prospective study of mood disorders in stroke patients, variables obtained during the acute hospitalization were examined for their relationship to outcome at either 3- or 6-month follow-up. Distance of the lesion on computerized axial tomography scan from the frontal pole in patients with left anterior infarcts was significantly associated with severity of depression at 3 and 6 months poststroke. In addition, intellectual and functional physical impairment in-hospital were significantly correlated with severity of depression and social functioning scores at 3 and 6 months poststroke. Thus, patients who develop depression during the first 6 months poststroke may be responding to the severity of their impairment whereas the patients who develop depressions during the acute poststroke period may have a neuroanatomical and neurophysiological basis for their depression. Although other explanations might be proposed, the dynamic nature of the relationship between depression and associated variables during the first 6 months poststroke indicates that etiology of poststroke depression may be different depending upon the time of onset of the depression after brain injury.     

脑卒中后抑郁与部位的相关性研究

目的：探讨急性期脑卒中患者影像学改变在脑卒中后抑郁（PSD）患者中的相关性和临床意义,期望早期发现PSD患者并为及时干预提供帮助。方法：对329例急性脑卒中后1个月内患者采用系统的神经心理评估和MRI检查。所有患者均常规行汉密尔顿抑郁量表（HAMD）评分,根据头颅MRJ结果分析病变部位。结果：PSD的发病率以左侧半球脑卒中患者明显高于双侧和右侧半球脑卒中患者,且左侧额叶和基底节尤为突出。不同病灶数目组间比较,PSD的发生率以多灶患者明显高于单灶患者（P〈0．01）。结论：急性脑卒中后PSD与病变部位在左侧半球尤其是左侧额叶、颞叶和基底节区具有显著相关性。完全前循环梗死也是易患PSD的危险因素。     

A two-year longitudinal study of post-stroke mood disorders: dynamic changes in associated variables over the first six months of follow-up

We are prospectively studying a group of 103 stroke patients over the first 2 years after infarction to determine the variables which are associated with the development of depression. At both 3 and 6 months post-stroke, patients with left hemisphere infarcts showed a strong relationship between severity of depression and distance of the lesion on CT scan from the frontal pole. The strength of this association was unchanged from the immediate post-infarction period. In contrast, the correlation between degree of functional physical impairment and severity of depression steadily increased over the 6 month follow-up. The correlation between severity of depression and Mini-Mental score or between depression and social functioning score dropped between in-hospital and 3 months but then increased significantly between 3 and 6 months post-stroke. Age did not correlate with depression beyond the acute post-stroke period. Whether the increasing strength of the relationships between impairment and depression over the first 6 months post-stroke indicates that continued depression led to delayed recovery or whether continued severe impairments led to depression is not known, however, this issue will be addressed in further data evaluation from this prospective study.     

Mood changes in stroke patients: Relationship to lesion location

During the past several years we have been studying mood changes in stroke patients.^1–9 We have reported recently in a follow-up study of 103 outpatients that the duration of untreated post-stroke depression was at least 7–8 mo in two-thirds of the patients.¹ We also found that during the period from 6 mo to 2 yr post-stroke, there was a significant increase in the prevalence and severity of depression as compared to other post-stroke time periods.¹ In addition, we are presently conducting a 2 yr longitudinal study on a separate group of 103 stroke patients and have reported during the acute stroke period that severity of depression was significantly correlated with the severity of the patient's intellectual and functional physical impairment as well as their age and the quality of their social supports.²However, the most consistent finding from our studies is the importance of lesion location.^1–5,9 For instance, we have shown that patients with left hemisphere lesions have higher depression scores than those with right hemisphere lesions. However, intrahemispheric lesion location seems to have as great an impact as interhemisphere lesion location. Patients with left anterior lesions were significantly more depressed than patients with left posterior lesions^2–4 even if the patient had bilateral lesions.⁹ In addition, we have shown that the closer the lesion was to the left frontal pole the greater the depression score^3,4 even in the presence of bilateral hemisphere strokes.⁹ Thus, although multiple factors including severity of impairment and quality of social supports contribute to the development of post-stroke depression,² lesion location seems to be one of the most important variables. Therefore, in the present study we wanted to examine the role of lesion location by selecting a group of stroke patients with single stroke lesions and no prior history of psychiatric disorder to determine what clinical symptoms develop in the acute post-stroke period, and we wanted to analyze what relationship these symptoms might have to size or location of the brain lesion.     

Poststroke depression in acute phase after stroke.

We studied factors associated with acute poststroke depression in 100 patients, aged 27-70, 2 weeks after their first clinically significant stroke. Depressive symptoms were relatively common (27% Beck Depression Inventory > or =10), but the prevalence of major depression was only 5.6%. Older patients were most vulnerable to poststroke depression. Patients with left hemisphere lesion had no more depression than other patients, but when the lesion was in the left hemisphere or in the brainstem, stroke severity was associated with depression.     

Mood change following left hemispheric brain injury

Eighteen patients with left hemispheric strokes were compared to 11 patients with traumatic brain injury for frequency and severity of depression, using several mood scales. More than 60% of the stroke patients had clinically significant depressions as compared with about 20% of the trauma patients, even though the two groups had comprable impairments in their activities of daily living and global cognitive functions. Analyses of brain CT scans revealed that the two groups had similar-sized lesions, but the areas of ischemic injury were more anterior than the traumatic lesion. When the results were controlled for lesion location, there were no significant differences in mood between the two groups. The severity of depression was directly correlated with the closeness of the lesion to the frontal pole. These results suggest that depression following left hemispheric brain injury may not be a nonspecific neurological or psychological response, but rather may be a symptom of injury to specific pathways, such as the catecholamine-containing ones, as they pass through the frontal cortex.     

Pathological correlates of poststroke depression in elderly patients.

OBJECTIVE: The authors examined the relationship between poststroke depression and location of stroke. METHODS: They performed a clinicopathological analysis of 95 consecutively autopsied elderly initial-stroke survivors. RESULTS: The severity of brain vessel arteriosclerosis and frequency of brain vascular lesions were not significantly different between 21 cases with poststroke depression and 74 cases without. Earlier death was the only variable significantly associated with poststroke depression. No lesion pattern characterized the depression group. CONCLUSIONS: Neuropathological data confirm that depression is associated with worse prognosis in elderly stroke patients and lend support to the hypothesis that psychological rather than neurological factors are the main determinants of poststroke depression.     

Functional and neuroanatomic correlations in poststroke depression: the Sunnybrook Stroke Study

BACKGROUND AND PURPOSE: The purpose of our study was to determine the functional and neuroanatomic correlates of poststroke depressive symptoms. METHODS: Patients with consecutive admissions to a regional stroke center for new-onset unilateral hemispheric stroke who met World Health Organization and National Institute of Neurological and Communicative Disorders and Stroke criteria were eligible for inclusion in a longitudinal study. Acutely, patients underwent CT scanning, and at 3 months and 1 year after stroke, depressive symptoms were assessed by using both the Montgomery-Asberg Depression Rating Scale and the Zung Self-Rating Depression Scale. The Functional Independence Measure (FIM) served as an indication of functional outcome and was obtained at 1 month, 3 months, and 1 year after stroke, along with other demographic information. The Talairach and Tournoux stereotactic atlas was used for the primary determination of CT lesion localization. Lesion proximity to the anterior frontal pole was also measured. RESULTS: Eighty-one patients participated in the longitudinal study. Stepwise linear regression analyses generated a highly significant model (F(3,76)=9.8, R(2)=28%, P<0.0005), with lower 1-month total FIM scores, living at home, and damage to the inferior frontal region predicting higher depression scores at 3 months. Similarly, lower 3-month total FIM scores correlated with higher 3-month depression scores, and lower 1-year total FIM scores correlated with higher 1-year depression scores. CONCLUSIONS: Functional measures correlated with poststroke depression across time and, together with neuroanatomic measures, predicted depressive symptoms longitudinally. Although inferior frontal lesion location, irrespective of side, appeared to play a role as a risk factor in this study, the degree of functional dependence after stroke imparted the greatest risk.     

Repetitive transcranial magnetic stimulation as treatment of poststroke depression: a preliminary study.

BACKGROUND: Depression has a significant impact on poststroke recovery and mortality. There are a proportion of patients with poststroke depression (PSD) who do not respond to antidepressants. Repetitive Transcranial Magnetic Stimulation (rTMS) might be a safe and effective alternative in these refractory cases. METHODS: We conducted a randomized, parallel, double-blind study of active versus sham left prefrontal rTMS in patients with refractory PSD. After discontinuing antidepressants, patients were randomly assigned to receive 10 sessions of active (10 Hz, 110% of the motor threshold, 20 trains of 5 seconds duration) or sham left prefrontal rTMS. Efficacy measures included HAM-D scores, response and remission rates. Patients completed a neuropsychological battery at baseline and after completing the protocol. RESULTS: When compared with sham stimulation, 10 sessions of active rTMS of the left dorsolateral prefrontal cortex were associated with a significant reduction of depressive symptoms. This reduction was not influenced by patient's age, type or location of stroke, volume of left frontal leukoaraiosis or by the distance of the stimulating coil to the prefrontal cortex. However, there was a significant positive correlation between the percentage of reduction of Ham-D scores and frontal gray and white matter volumes. There were no significant changes in cognitive functioning between the active and the sham stimulation groups. In addition, there were few and mild adverse effects that were equally distributed among groups. CONCLUSIONS: Taken together, these preliminary findings suggest that rTMS may be an effective and safe treatment alternative for patients with refractory depression and stroke.     

Comparison of mania and depression after brain injury: causal factors

Patients who developed secondary mania after brain injury (N = 17) had a significantly greater frequency of injury to right hemisphere areas connected with the limbic system than poststroke patients with major depression (N = 31), who had injury primarily in the left frontal cortex and basal ganglia. For patients without mood disturbance after brain injury (N = 28), the location of the lesion was not significant. Secondary mania patients also had a significantly greater frequency of family history of affective disorder than did the other two groups. These results suggest that an interaction between injury to certain areas of the right hemisphere and genetic factors or other neuropathological conditions produces secondary mania.     

脑卒中患者情感障碍及生活质量研究

目的探讨脑卒中患者情感障碍的发生率,脑卒中部位与情感障碍的关系,以及对患者生活质量的影响。方法运用抑郁自评量表(SDS)、焦虑自评量表(SAS)、神经功能缺损量表(NFDS)和诺丁汉健康问卷(NHP)对191例脑卒中患者进行现状调查。结果191例患者中发生情感障碍85例(44.5%),55例(65.90%)同时出现抑郁和焦虑。情感障碍的发生与额叶、左侧大脑半球、基底节病灶有关;脑卒中伴情感障碍患者NFDS和NHP评分高。结论脑卒中后情感障碍发生率较高,与脑卒中部位相关,对患者的神经功能及生活质量有明显的影响,不利于脑卒中患者的康复。     

Treatment of cognitive impairment after poststroke depression : a double-blind treatment trial

BACKGROUND AND PURPOSE: Patients with poststroke major depression have a greater severity of cognitive impairment than nondepressed patients even when matched for size and location of stroke lesion. Prior treatment studies have consistently failed to show an improvement in cognitive function even when poststroke mood disorders responded to antidepressant therapy. We examined the response of cognitive function to treatment with nortriptyline or placebo in a double-blind trial. METHODS: Patients with major (n=33) or minor (n=14) depression participated in a double-blind treatment study with nortriptyline or placebo. They were examined for change in depressive mood, measured by the Hamilton Rating Scale for Depression (HAM-D), and change in cognitive impairment, assessed by the Mini-Mental State Examination (MMSE), after treatment with nortriptyline or placebo. Cognitive treatment response, as measured by the MMSE, was compared between patients whose depression did and did not respond to treatment. RESULTS: Patients whose poststroke depression remitted (predominantly associated with nortriptyline treatment) had significantly greater recovery in cognitive function over the course of the treatment study than patients whose mood disorder did not remit (predominantly associated with placebo treatment). CONCLUSIONS: Our findings support the contention that poststroke major depression leads to a "dementia of depression." Prior studies failed to show an effect of treatment because the effect size was too small. Successful treatment of depression may constitute one of the major methods of promoting cognitive recovery in victims of stroke.     

Sexual dysfunction following stroke

This study was undertaken to examine the prevalence of sexual dysfunction among 100 patients (75 men and 25 women) following stroke and its relationship to neuropsychiatric impairments or stroke characteristics. Forty-four men (58.6%) and 11 women (44.0%) reported dissatisfaction with their sexual functioning after stroke, as compared with only 16 men (21.3%) and five women (20.0%) before stroke. Twenty men (26.6%) and six women (24.0%) reported diminished libido after stroke as compared with eight men (10.6%) and seven women (28.0%) before stroke. Patients with sexual dysfunction had significantly more depressive symptoms among both males (P =.007) and females (P =.0005) and more impaired activities of daily living (ADL) in males (P =.0009). Based on logistic regression, the independent predictors of poststroke sexual dysfunction were Hamilton Rating Scale for Depression (HAM-D) score (odds ratio [OR] 1.55; 95% confidence interval [CI], 1.20 to 2.01), left hemisphere lesion (OR, 16.51; 95% CI, 2.34 to 116.25), and poststroke depression (OR, 8.09; 95% CI, 1.28 to 51.38). These data suggest that treatment of depression may have a significant beneficial effect on patients with sexual dysfunction. Our findings also suggest that left hemisphere lesions, for unknown reasons, play an important role in poststroke sexual dysfunction.     

The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines

Although poststroke depression is unlikely to represent a single disorder and numerous etiologies for different kinds of poststroke depression will likely emerge as the result of future research, we believe that a number of poststroke depressive disorders are likely to be the result of specific changes in brain pathology and neurophysiology. Nevertheless, there are relatively few hypotheses about the pathophysiology of poststroke depression. This paper, therefore, proposes a new hypothesis for poststroke depression involving increased production of proinflammatory cytokines resulting from brain ischemia in cerebral areas linked to the pathogenesis of mood disorders. This paper reviews the evidence supporting the hypothesis that proinflammatory cytokines are involved in the occurrence of stroke as well as mood disorders linked to the brain damage. The increased production of proinflammatory cytokines such as IL-1beta, TNF-alpha or IL-18 resulting from stroke may lead to an amplification of the inflammatory process, particularly in limbic areas, and widespread activation of indoleamine 2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic regions such as the ventral lateral frontal cortex, polar temporal cortex and basal ganglia. The resultant physiological dysfunction may lead to poststroke depression. Future investigations may explore this hypothesis through more extensive studies on the role of proinflammatory cytokines, such as IL-1beta, TNF-alpha or even IL-18, in patients with poststroke depression.     

Research into the specificity of depression after stroke: a review on an unresolved issue

Iwo decades of research have failed to generate consistent insight into the specificity of poststroke depression (PSD). This is, at least in part, caused by methodological difficulties. Differences in symptom profile between PSD and depression with no or another medical cause were described, but no specific and unequivocal clinical picture has been established so far. Prevalence rates of PSD varied largely between studies. In community based studies using standardised diagnostic instruments for depression, relatively low prevalence rates were reported compared to inpatient or rehabilitation studies. PSD occurs most frequently in the first few months after stroke, while a new incidence peak may occur 2-3 years after stroke. Two systematic reviews on the relation between lesion location and depression did not support the claim that left hemisphere lesions are a risk factor for PSD. A new concept of vascular depression has been proposed, which relates depression in the elderly to acute or chronic damage to the cerebral vascular system. Future efforts should aim at increasing the uniformity of study designs, assessment tools should be further improved for use in cognitively impaired patients and appropriate control groups should be defined to study the characteristic features of PSD.     

Cerebrovascular diseases and depression

Cerebrovascular diseases constitute a leading health hazard. The association between stroke and depression has been recognized for many years. Depression is the most common psychiatric disorder associated with cerebrovascular diseases, most episodes of post-stroke depression occur in the first 2 years after a cerebrovascular accident. Studies have found an association between lesion location, physical impairment, cognitive impairment, aphasia, and post-stroke depression. The location of the lesion in terms of proximity to the left frontal pole of the brain has a profound impact on the frequency and severity of post-stroke depression. Treatment modalities include pharmacotherapy, psychotherapy, electroconvulsive therapy, and rehabilitation. Understanding the psychologic and physical morbidity of post-stroke depression, as well as its timely, comprehensive treatment, are important for effective management.     

Focal or generalized vascular brain damage and vulnerability to depression after stroke: a 1-year prospective follow-up study

BACKGROUND: Both the lesion location hypothesis and the vascular depression hypothesis have been proposed to explain the high incidence of depression in stroke patients. However, research studying both hypotheses in a single cohort is, at present, scarce. OBJECTIVE: To test the independent effects of lesion location (left hemisphere, anterior region) and of co-occurring generalized vascular damage on the development of depression in the first year after ischemic stroke, while other risk factors for depression are controlled for. METHODS: One hundred and ninety consecutive patients with a first-ever, supratentorial infarct were followed up for one year. CT was performed in the acute phase of stroke, while in 75 patients an additional MRI scan was also available. Depression was assessed at 1, 3, 6, 9, and 12 months after stroke using self-rating scales as screening tools and the SCID-I to diagnose depression according to DSM-IV criteria. RESULTS: Separate analyses of the lesion location hypothesis and the vascular depression hypothesis failed to reveal significant support for either of these biological models of post-stroke depression. Similar negative results appeared from one overall, multivariate analysis including variables of both focal and generalized vascular brain damage, as well as other non-cerebral risk factors. In addition, level of handicap and neuroticism were independent predictors of depression in this cohort, as has been reported previously. CONCLUSION: This study supports neither the lesion location nor the vascular depression hypothesis of post-stroke depression. A biopsychosocial model including both premorbid (prior to stroke) vulnerability factors, such as neuroticism and (family) history of depression, as well as post-stroke stressors, such as level of handicap, may be more appropriate and deserves further study.