Cerebrovascular Diseases and Depression

Himani Ghoge, MBBS, Santvana Sharma, MBBS, DPM, Shamash Sonawalla, MD, and Rajesh Parikh, MD, DPM, DipNBE*

Address *Neuropsychiatry Clinic, Jaslok Hospital and Research Centre, 15 Dr. B. G. Deshmukh Marg, Bombay 400 026, India. E-mail: rajeshparikh@vsnl.com Current Psychiatry Reports 2003, 5:231238 Current Science Inc. ISSN 1523-3812 Copyright 2003 by Current Science Inc.

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.

Introduction: Historical Perspective

The relationship between depression and cerebrovascular diseases (CVD) has been studied extensively for more than two decades [14,5]. Cerebrovascular diseases constitute a leading health hazard in terms of the effect on the quality of life of the individual and the economic burden on society [6]. Stroke is the third leading cause of mortality in adults [6]. The relationship between depression and CVD is complex and influenced by multiple factors. The occurrence of mood disorders associated with brain injury (predominantly CVD) has been known for over a century. In 1826, Bayle and Calmeil (discussed in [7]) described the psychiatric symptoms in general paralysis of the insane, which provided one of the earliest examples of brain disease associated with mood disorder. Meyer [8] described traumatic insanity and postulated that there was a relationship with specific locations of brain injury. Bleuler [9] reported persistent and refractory depression

after stroke, and Kraeplin [10] discussed the possible etiologic role of CVD in producing states of depression. More recently, epidemiologic studies by Kay [11] demonstrated the frequent association between stroke and first episodes of severe depression in elderly individuals, and Post [12] reported that, in geriatric patients, mood disorders after stroke were frequently responsive to electroconvulsive treatment (ECT). Although the association between stroke and depression has been recognized for many years, the nature of the relationship is less certain. Post [12] postulated that atherosclerotic diseases and affective disorders share the same underlying etiology. Roth [13] and Meyer [8] suggested that injuries to certain brain areas produce depression. Most clinicians, however, have assumed that depression is reactive to the impairments produced by stroke [8,1215]. Fisher [14] stated that the brain was the most cherished organ in the body and injury to this organ would understandably lead to depression. Bleuler [9] suggested that melancholic moods after stroke may last for months and, sometimes, longer. Kraeplin [10] stated that CVD may accompany manic-depressive psychosis or may endanger states of depression. Goldstein [16] was the first to describe an emotional disorder that was uniquely associated with brain diseasethe catastrophic reaction. This is an emotional outburst involving various degrees of anger, frustration, depression, tearfulness, refusal, shouting, swearing, and, sometimes, aggressive behavior. The indifference reaction, described by Hecaen et al. [17] and Brown et al. [18], was the second emotional abnormality characteristic of brain injury. The indifference reaction, associated with right hemisphere lesions, consists of symptoms of indifference toward failures, lack of interest in family and friends, enjoyment of foolish jokes, and minimization of physical difficulties. A third emotional disorder that has historically been associated with brain injury, such as cerebral infarction, is pathologic laughter or crying. Ironside [19] described the clinical manifestations of this disorder. Parikh et al. [4] devised a scale to measure pathologic laughter and crying. The emotional displays are characteristically unrelated to the inner emotional state. Folstein et al. [20] compared 20 patients who suffered a stroke with 10 orthopedic patients. Although the functional disability in the groups was comparable, the patients

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who had suffered a stroke were more depressed [20]. The authors concluded, mood disorder is a more specific complication of stroke than simply a response to motor disability. Finkelstein et al. [21] found that depression and failure to suppress serum cortisol after dexamethasone administration were more common among 25 randomly selected patients who had suffered a stroke than among a group of 13 control patients with equally disabling medical illnesses [21]. To summarize, there are two primary schools of thought in the study of emotional disorders that are associated with CVD. One attributes emotional disorders to an understandable psychologic reaction to the associated impairment; the other is based on a lack of association between severity of impairment and severity of emotional disorder, which suggests a direct causal connection between CVD and neuropsychiatric disorder.

Race There is no significant difference in the prevalence of mood disorders across different ethnic groups [6]. However, the occurrence of depression post-CVD is higher in African-Americans compared with whites [6]. This may be related to the higher prevalence of resistant essential hypertension among the African-Americans, which predisposes to a hemorrhagic stroke. It may also be related to the lower socioeconomic status of the African-Americans, which would hinder their access to the medication and health care that is required to prevent depression after stroke [6]. Previous history of psychiatric illness and personality traits Studies have suggested that depressed individuals are more likely to suffer from stroke [23]. One study showed that middle-aged men are three times more likely to suffer from stroke if they suffer from psychologic distress, such as depression and anxiety. Although these men had other risk factors associated with stroke such as age, smoking, obesity, and hypertension, they also had significant symptoms of anxiety and depression [23]. One theory suggests that increased sympathetic activity in depression leads to vasoconstriction because of the release of norepinephrine. The immunologic theory suggests that there is a higher chance of getting an affective disorder if there is a previous history of depression. Family history There is a higher incidence of post-stroke depression if there is a family history of mood disorder [3]. Lesions on magnetic resonance imaging There is an increased risk of suffering from depression when there are subcortical white matter lesions seen on the magnetic resonance imaging (MRI) [2426]. White matter lesions are frequently associated with hypertension, atherosclerosis, and atrial fibrillation. This is called vascular depression, and is associated with diffuse subcortical involvement. One study attempted to assess the relationship between white matter densities seen on the MRI and depression [5]. Comparing 20 elderly patients with depression with 20 elderly control individuals, the study concluded that deep white matter densities are more frequently caused by cerebral ischemia, and ischemic lesions are more frequently located in the dorsolateral prefrontal cortex in depressed subjects [5]. The study supported the hypothesis of vascular depression as a cause of late-life depression. Another study trying to assess the relationship between white matter lesions in dementia with Lewy bodies, Alzheimers disease, vascular dementia, and normal aging showed that there is an important link between white matter densities in the frontal areas and depression [24].

Common Cerebrovascular Diseases

Cerebrovascular diseases usually present as an abrupt onset of focal neurologic deficit. The deficit may remain fixed, gradually worsen or improve. Cerebrovascular diseases are mainly caused by an ischemic or hemorrhagic phenomenon. The ischemic injuries may or may not lead to infarction, for example, in transient ischemic attacks. Hemorrhages cause parenchymal injury by direct damage and extravasation of blood in the tissue around it. The four major categories of CVD are the following: atherosclerotic thrombosis, cerebral embolism, lacunae, and intracranial hemorrhage. Ischemia and infarction constitute 85% to 90% of the total group.

Risk Factors for Cerebrovascular Disease and Depression

Age Depression is seen in approximately 1% to 2 % of the elderly population. The elderly are prone to depression for a variety of neuroanatomic, neurophysiologic, psychologic, and social reasons. Gender The lifetime prevalence of major depressive disorder is 10% to 25% for women and 5% to 12% for men. This higher prevalence among women is because of various factors, including hormonal differences, stress, and structural differences in the brain [6]. A study by Duff [22] reported that after a stroke, women have twice the incidence of major depression compared with men. It showed that a past diagnosis of psychiatric disorder and cognitive impairment was associated with increased severity of depression in women, and it was associated with greater impairment in daily activities and social functioning in men.

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Epidemiology
Depression is the most common psychiatric disorder associated with CVD [6]. Approximately 15% to 25% of community based samples of patients with acute stroke and 30% to 40% of patients hospitalized with acute stroke have a clinically diagnosable major or minor depressive disorder [6] that is likely to last for over a year without treatment [3]. Most episodes of depression occur in the first 2 years after a cerebrovascular accident. After the initial 2 years post-stroke, the prevalence of depression decreases, but there is an increase again after 10 years. This has been attributed to a variety of reasons, such as the relapse of a cyclical depressive disorder, recurrence of stroke, deterioration of a medical condition, or withdrawal of social support. In ischemic episodes, though, they are seen more often in the chronic phase of the disease [3]. One study found that the incidence of depression was highest in infarcts of cardiac origin (71%) followed by atherosclerotic infarcts (52%), and was least seen in lacunar infarcts [25]. Patients with silent cerebral infarcts and major depression present with more marked neurologic symptoms and more severe depressive symptoms than those without silent cerebral infarcts [26].

et al. [28] examined a consecutive series of patients with stroke lesions who had been admitted to a rehabilitation center. They found that, among patients with left hemisphere lesions, scores on a depression rating scale significantly correlated with lesion location. However, among patients with right hemisphere lesions, depression scores did not significantly correlate with lesion location. Similarly, Morris et al. [29] found that, after controlling for family history of mood disorder, patients with single left hemisphere lesions showed a significant inverse correlation between distance of the lesion from the frontal pole and severity of depression. In summary, studies conducted by different investigators support the hypothesis that the closer the lesion is to the frontal pole, the greater is the severity of depression and that left frontal lesions are the most likely lesions to show this relationship. The location of the lesion along the anterior-posterior dimension is an important variable in the severity of post-stroke depression. Cortical and subcortical lesions In a study of 45 patients with single lesions restricted to cortical or subcortical structures in the left or the right hemisphere, Starkstein et al. [30] found that 44% of patients with left cortical lesions were depressed, whereas 39% of patients with left subcortical lesions, 11% of patients with right cortical lesions, and 14% of patients with right subcortical lesions were depressed. Although the frequency of depression between patients with left cortical versus left subcortical or right cortical versus right subcortical lesions was not significantly different, patients who had lesions in the left hemisphere had significantly higher rates of depression than patients with right hemisphere lesions, regardless of the cortical or subcortical location of the lesion [30]. When patients were further subdivided into those with anterior lesions and those with posterior lesions, all five patients with left cortical lesions involving the frontal lobe had depression compared with two of the 11 (18.1%) patients with left subcortical posterior lesions. These relationships were not significant for patients with right hemisphere lesions. A study by Starkstein et al. [31] examined the relationship between lesions of specific subcortical nuclei and depression. Basal ganglia lesions produced post-stroke major depression in seven of eight (87.5%) patients with left-sided lesions, in one of seven (14.2%) patients with right-sided lesions, and in none of the patients with left or right thalamic lesions. A recent study by Lind et al. [32] among patients with dementia found that the subcortical syndrome correlated with depressed mood and suggested that patients with dementia with a clinically established subcortical dysfunction appeared more susceptible to depressive symptomatology [32]. This in agreement with findings of anterior lesion location corresponding to depression in patients with stroke. A number of recent MRI studies found an associa-

Relationship of Mood to Other Variables

Although the exact mechanism is unclear, several factors are implicated in the etiology of post-stroke depression. Relationship to lesion location In a study of consecutive patients admitted to a hospital after the acute onset of stroke, Robinson et al. [1] found that major or minor depression occurred in 14 of 22 (63.6%) patients with a left hemisphere injury, but in only two of 14 (14.3%) patients with a right hemisphere lesion. The intrahemispheric location of the lesion was also an important determinant of the presence of depressionsix of 10 (60%) patients with left anterior frontal lesions had depression compared with one of eight (12.5%) patients with left posterior lesions. There was also a significant correlation between the distance of the anterior border of the lesion from the frontal pole and severity of depression. They found that the closer the lesion is to the frontal pole, the more severe the depression. Three other investigators have also systematically examined the association between lesion location and post-stroke depression. Sinyor et al. [27] found a significant inverse correlation between depression severity and distance of the lesion from the frontal pole for right and left hemisphere lesions [27]. Although smaller, the correlation was in the same direction as that of the Robinson et al. [1] study, but was not specific to patients with left hemisphere lesions. Differences in demographic characteristics of the sample, the time since stroke, and the lack of standardized diagnosis in the Sinyor et al. [27] study may underlie the difference in results between the studies [27]. In more recent studies, Eastwood

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tion between depressive symptoms and frontal (especially dorsolateral prefrontal cortex) white matter hyperintensities, the volume of the white matter hyperintensities, lesions in the basal ganglia, and subcortical white matter lesions [5,3335]. In summary, the evidence suggests that the frequency of depression is higher among patients with left anterior hemisphere lesions than among patients with right hemisphere lesions. When other confounding factors are accounted for (eg, prior lesions and family or personal history of mood disorder), left dorsolateral frontal cortical and left basal ganglia lesions produce a similar high frequency of major depression that is greater than that for any other lesion location. Middle cerebral circulation versus posterior circulation lesions Starkstein et al. [36] compared 37 patients with posterior circulation lesions with 42 patients with middle cerebral artery lesions. Patients with posterior circulation lesions were further subdivided into those with hemispheric lesions (temporo-occipital) and those with cerebellar or brain stem lesions [36]. Major or minor depression was found in 48% of patients in the middle cerebral artery lesion group and in 35% of patients with cerebellar or brain stem lesions. Frequency of depression among patients with in-hospital depression was 82% and 20%, respectively, at 6-month follow-up. One to 2 years poststroke follow-up revealed that the frequencies of depression were 68% and 0%, respectively. Thus, patients with lesions in the cerebellar or brain stem region had a significantly shorter course of depression compared with those with middle cerebral arterial lesions. These findings suggest that the mechanism of depression after middle cerebral artery lesions may differ from the mechanism of depression after cerebellar or brain stem lesions. Starkstein et al. [36] speculated that the shorter duration of depression after cerebellar or brain stem lesions may be related to their smaller size and to the possibility that the cerebellar or brain stem lesions produce less injury to the biogenic amine pathways [36]. In summary, depression associated with cerebellar or brain stem lesions appear somewhat less frequently and are shorter in duration than depression associated with middle cerebral artery lesions. This may indicate differences in the mechanism of depression associated with these two lesion locations. Right hemisphere lesions Starkstein et al. [3], in a series of 93 patients with acute right hemisphere lesions, reported that of 54 patients with positive computed tomography scans, six of nine patients (66%) with major depression and five of eight patients (63%) with minor depression had lesions that involved the parietal lobe, compared with nine of 25 patients (36%) without mood changes and one of 12 patients with undue cheerfulness. Similar results were

reported by Finset [37], who found that patients with parietal white matter lesions had a higher frequency of depression compared with patients with lesions in any other location in the right hemisphere. Relationship with physical impairment Robinson et al. [38] and Eastwood et al. [28] have reported a low, but significant, correlation between depression and functional physical impairment (ie, activities of daily living [ADL]). This association can be construed as the functional impairment producing depression or depression influencing the severity of functional impairment. Two studies lend support to the latter suggestion. Sinyor et al. [27] reported that although patients with stroke who were not depressed showed a slight increase or no change in functional status over time, patients with depression had significant decreases in function during the first month after stroke. Parikh et al. [4] compared a consecutive series of 63 patients with stroke with major or minor depression with patients with stroke without depression during a 2-year period after stroke. Although the groups had similar impairments in ADL during their hospital stay, patients with depression had significantly less improvement at 2year follow-up than the patients without depression. This finding held true after controlling for various variables, such as the type and extent of in-hospital and rehabilitation treatment, the size and location of the lesion, the patients demographic characteristics, nature of the stroke during the follow-up period, and medical history [4]. Although the correlation between depression and physical impairment after stroke is not strong, the two variables do appear to interact. There is little evidence to support that physical impairment is a major cause of post-stroke depression. However, if depression develops, the patients physical recovery tends to be delayed for 2 years or more. Also, the negative effect of depression on physical recovery, especially on ADL, lasts even after the depression has subsided (ie, major depression tends to resolve in approximately 1 year). Relationship with cognitive impairment Studies have suggested that elderly patients with functional major depression have intellectual deficits that improve with treatment of depression [39]. This was first examined by Robinson et al. [38]. Patients with major depression after a left hemisphere infarct had significantly lower scores on the Mini-Mental State Examination than a comparable group of patients without depression [38]. The size of the lesion and depression scores independently correlated with the severity of cognitive impairment. Another study by Starkstein et al. [41] found that even when patients were matched for lesion size and location, depressed patients were more cognitively impaired. By administering a comprehensive neuropsychologic battery, Bolla-Wilson et al. [42] found that those patients with major depression and left hemisphere

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lesions had significantly greater cognitive impairment compared with patients without depression with comparable left hemisphere lesions. These cognitive deficits primarily involved tasks of temporal orientation, language, executive motor, and frontal lobe functions. However, among patients with right hemisphere lesions, patients with major depression did not differ from patients without depression on any of the measures of cognitive impairment. To summarize, major depression associated with a left hemisphere stroke appears to produce significant cognitive impairments. Whether these cognitive impairments will improve with treatment of the depression remains to be determined. Relationship with aphasia Robinson and Benson [43] found that patients with nonfluent aphasia had a significantly higher frequency of depression compared with patients with fluent or global aphasia. Signer et al. [44] also reported similar findings; depression was present in 63% of patients with nonfluent aphasia compared with 16% of patients with fluent aphasia. Kay [11] reported that lesion location was the important variable in the association between post-stroke depression and nonfluent aphasia. To conclude, patients with left hemisphere lesions that produce aphasia have a frequency of depression similar to that of patients with left hemisphere lesions that do not produce aphasia. Although nonfluent aphasia and post-stroke depression do not appear to be causally related, they are produced by lesions of similar anatomic location (anterior areas of the left hemisphere). Thus, patients with nonfluent aphasia are at a higher risk of developing poststroke depression compared with patients with other types of aphasia.

sphere lesions compared with those with left hemisphere lesions [2]. The greater depletion with right hemisphere lesions could lead to a compensatory upregulation of receptors, which may protect against depression; however, patients with left hemisphere lesions may have moderate depletions of biogenic amines, but without a compensatory upregulation of dopamine receptors and, therefore, a dysfunction of biogenic amine systems in the left hemisphere. This dysfunction may eventually lead to the clinical symptoms of depression.

Treatment
Cerebrovascular disease takes its toll on the patient, as well as family and friends. Understanding the psychologic and physical morbidity of the disease is important and helps realize the value of treatment and, more importantly, timely treatment. The treatment modalities include pharmacotherapy, psychotherapy, electroconvulsive therapy, and rehabilitation. Pharmacotherapy One of the first trials in treating post-stroke depression was conducted using nortryptiline. This randomized double blind study was conducted among 34 patients; 14 of these patients were given the drug and 20 were given a placebo over 6 weeks. The drug doses were started at 25 mg at bedtime and increased to approximately 100 mg. Eleven of the 14 patients showed significant improvement in their scores on the Hamilton Depression Rating Scale compared with 15 of the 20 patients treated with a placebo [46]. A randomized controlled trial by Dam et al. [47] studied the effect of fluoxetine on patients with post-stroke depression for 3 months [46]. The study showed that patients treated with fluoxetine had a better functional outcome compared with those treated with placebo; however, there was no difference in depressive symptomatology. A randomized control trial by Robinson and Benson [43] of 104 patients over 12 weeks using fluoxetine and nortryptiline showed that 77% of patients who received nortryptiline showed improvement, 14% of those treated with fluoxetine showed improvement, and 33% of those treated with a placebo showed improvement. In this trial, the dose of fluoxetine was increased gradually from 10 mg to 40 mg, which had a positive correlation only in terms of the side effects. Anderson et al. [48] assessed the effects of citalopram on 66 patients with post-stroke depression, 2 to 52 weeks after stroke, using 10 to 20 mg per day of the drug for 6 weeks. A decreased rate of depression was found in the treatment group. Another recent double blind, randomized, controlled study using citalopram found that Hamilton Depression Rating Scale scores improved significantly over 6 weeks in patients receiving citalopram (n=27) compared with placebo (n=32). At 3 and 6 weeks, the active

Mechanisms of Post-Stroke Depression

The exact mechanism of post-stroke depression is not known. Dysfunction of the biogenic amine system has been implicated. The noradrenergic and serotonergic cell bodies are located in the brain stem and send ascending projections through the median forebrain bundle to the frontal cortex. The ascending axons arch posteriorly and run longitudinally through the deep layers of the cortex, sending terminal projections into the superficial cortical layers [45]. Lesions that disrupt these pathways in the frontal cortex or the basal ganglia may affect many downstream fibers. Based on these neuroanatomic facts and the clinical findings that the severity of depression correlates with the proximity of the lesion to the frontal pole, Robinson et al. [1] suggested that post-stroke depression may be the consequence of severe depletions of norepinephrine or serotonin produced by frontal or basal ganglia lesions. Studies in rats have demonstrated that the biochemical response to ischemic lesions is lateralized whereby a greater depletion of biogenic amines is found in patients with right hemi-

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group had significantly lower Hamilton Depression Rating Scale scores than the placebo group. A study by Reding et al. [49] found that depressed patients taking trazodone showed greater improvement in Barthel ADL index than the placebo-treated individuals. A more recent randomized controlled study done by Raffaele et al. [50] in 22 patients with acute stroke using 300 mg of trazodone also found an improvement in depressive symptoms, with trazodone in comparison with placebo. One of the only studies on milnacipran, a serotonin noradrenergic reuptake inhibitor, by Kimura et al. [51] was conducted in 12 patients aged 53 to 88 years diagnosed with minor or major depression according to Diagnostic and Statistical Manual of Mental Disorders. This was a 6-week open trial, and severity of depression was assessed using Hamilton Depression Rating Scale. The total daily dose of milnacipran was in the range of 30 and 75 mg twice daily; 58.3% of the total patient population and 70% of the patients completing the study were in remission of their depressive symptoms (Hamilton Depression Rating Scale), which suggests that milnacipran may be an effective treatment for post-stroke depression [52]. Tricyclic antidepressants Nortryptiline is the tricyclic antidepressant of choice used to treat post-stroke depression [46]. Nortryptiline causes less orthostatic hypotension and usually only a mild amount of anticholinergic and sedative side effects. It also has a well-documented therapeutic range of serum levels. This is important because some patients, especially the elderly, may develop higher than usual blood levels on a given dosage regimen. To minimize any orthostatic hypotension or any sedative effects, the drug is administered at bedtime. The drug dosage is started at 25 mg at bedtime for a week, and increased by 25 mg. The blood levels are assessed once the patient has been on 50 mg per day of the drug for 1 week. The therapeutic level is aimed at 50 to 140 ng/mL. Most patients require 100 mg per day to get to this level. The side effects can be minimized by increasing the doses by 25 mg per day per week. Most patients will respond within 4 to 6 weeks of reaching adequate dose. The drug is given for a period of 6 months and then tapered off. Other side effects include dry mouth, mild sedation, and constipation. Nortryptiline may have some quinidine-like effects and should be used carefully in patients with cardiac arrhythmias. A baseline echocardiogram should be obtained before the treatment is started. A relative contraindication to the use of the drug is a recent myocardial infarction, urinary obstruction, and narrow angle glaucoma. Poorly controlled seizures could get exacerbated. Untreated depression has life-threatening effects of its own; thus, before deciding on whether or not to treat with the drug, the risk-benefit ratio should be evaluated [46]. For patients who cannot tolerate nortryptiline, desipramine may be used.

A study comparing the long-term efficacy of nortryptiline and fluoxetine showed that nortryptiline produced an increased vulnerability to depression for more than 6 months after it was discontinued, which suggests the need for extending the prophylactic treatment and monitoring patients carefully after the discontinuation of nortryptiline [53]. Selective serotonin reuptake inhibitors One study found that fluoxetine improved the functional outcome, but no improvement in depressive symptomatology in patients with post-stroke depression [47]. However, certain randomized control trials have shown fluoxetine to be efficacious in treating post-stroke depression [52]. Citalopram has proved effective in treating post-stroke depression [48]; recommended dose is 10 to 20 mg per day. Side effects include nausea, vomiting, abdominal pain, somnolence, and sexual dysfunction. There are no specific contraindications for its use. Other selective serotonin reuptake inhibitors may be helpful in post-stroke depression, but require further study. Selective serotonin noradrenaline reuptake inhibitors Milnacipran has side effects such as weight gain, sexual dysfunction, tachycardia, and hypertension, and anticholinergic effects such as constipation. In one study, this drug was used in the dose range of 30 to 75 mg twice daily, and 70% of the patients completing the study were in remission, which suggests that milnacipran may be an effective treatment for post-stroke depression [51]. Trazodone A dopamine reuptake inhibitor and dopamine 2a and 2c antagonist, trazodone has been particularly effective in improving sleep time and in decreasing night awakenings in patients with post-stroke depression. It has alpha-blocking effects, and can cause gastrointestinal side effects and also priapism. The overdose attempts are also benign. No fatalities were reported when the drug was taken alone. It also lacks the anti-arrhythmia effects of nortryptiline. The recommended dose is up to 300 mg per day. Other drugs, such as monoamine oxidase inhibitors and methylphenidate, could also be helpful in post-stroke depression, but they require further research. Electroconvulsive therapy Murray et al. [53] reported that electroconvulsive therapy is effective in treating post-stroke depression. It had fewer side effects than drugs, and is not associated with neurologic deterioration [53]. Psychotherapy Oradei and Waite [54] and Watziawick and Coyne [55] reported that group and family therapy are beneficial in terms of faster recovery. Controlled studies for these treatment modalities are still under way [54,55].

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Rehabilitation Psychosocial adjustment is an important issue in patients after stroke. Thompson et al. [56] examined 40 patients, as well as their caregivers, for an average of 9 months for psychosocial adjustment after stroke. They found that a lack of meaningfulness in life and overprotection by the caregiver were independent predictors of depression. They also found that psychosocial factors could predict motivation and depression in patients with stroke. The authors suggested that therapeutic approaches using cognitive adaptation and social support might be useful toward understanding peoples ability to cope after stroke. Dennis et al. [57] showed that introduction of a stroke family care worker improved the patients satisfaction with the services and may have had some effect on the psychologic and social outcome, but did not improve the physical well being. This could be because a family care worker could make the patient more dependent, helpless, socially less well adjusted, and more depressed [57].

Conclusions
The relationship between CVD and depression is complex, and is influenced by various factors. Studies have found that left frontal lesions and more anterior lesions correlate with depressive symptoms in the post-stroke period. Left dorsolateral frontal cortical and left basal ganglia lesions also show a positive correlation with severity of depression in patients in the post-stroke period. Studies have also found an association between physical impairment, cognitive impairments, aphasia, and post-stroke depression. Various classes of antidepressants have been tested, and these range from the more conservative tricyclic antidepressants (predominantly nortryptiline) to other classes like the selective serotonin noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors, and trazodone. Monoamine oxidase inhibitors and methylphenidate may be helpful, but require further research. Electroconvulsive therapy seems to be efficacious with fewer side effects than pharmacotherapy. Psychotherapy (predominantly group and family therapy) and rehabilitation measures improve the prognosis of patients with post-stroke depression. Therefore, a comprehensive approach in the management of post-stroke depression can enhance recovery and improve outcome in patients with post-stroke depression.

References and Recommended Reading

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Eastwood MR, Rifat SL, Nobbs H, et al.: Mood disorders following cerebrovascular accident. Br J Psychiatry 1989, 154:195200. Morris PLP, Robinson RG, Raphael B: Lesion characteristics and post-stroke depression: evidence of a specific relationship in the left hemisphere. J Neuropsychiatry Clin Neurosci 1996, 8:153159. Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical lesions in the production of post-stroke mood disorders, Brain 1987, 110:10451059. Starkstein JE, Robinson RG, Berthier ML, et al.: Differential mood changes following basal ganglia vs thalamic lesions. Arch Neurol 1988, 45:725730. Lind K, Edman A, Karlsson I, et al.: Relationship between depressive symptomatology and the subcortical brain syndrome in dementia. Int J Geriatr Psychiatry 2002, 17:774778. Daniel T, Goudemand M, Ghawche F, et al.: Delusional melancholia and multiple lacunar infarcts of the basal ganglia. Rev Neurol (Paris) 1991, 147:6062. Nebes RD, Reynolds CF 3rd, Boada F, et al.: Longitudnal increase in the volume of the white matter hyperintensities in late onset depression. Int J Geriatric Psychiatry 2002, 17:526530. Steffens DC, Krishnan KR, Crump C, et al.: Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. Stroke 2002, 33:16361644. Starkstein SE, Robinson RG, Berthier ML, et al.: Depressive disorders following posterior circulation compared with middle cerebral artery infarcts. Brain 1988, 111:375387. Finset A: Depressed Mood and Reduced Emotionality After Right Hemisphere Brain Damage in Cerebral Hemisphere Function in Depression. Edited by Kinsbourne M. Washington, DC: American Psychiatric Press; 1988:4964. Robinson RG, Starr LB, Kubos KL, et al.: A 2 year follow up study of post stroke mood disorders: finding during the initial evaluation, Stroke 1983, 14:736741. Wells CE: Pseudodementia. Am J Psychiatry 1979,136:895900. Robinson RG, Bolla-Wilson K, Kaplan E, et al.: Depression influences intellectual impairment in stroke patients. Br J Psychiatry 1986, 148:541547. Starkstein SE, Robinson RG, Price TR: Comparison of patients with and without post stroke depression matched for size and location of lesion. Arch Gen Psychiatry 1988, 45:247252. Bolla-Wilson K, Robinson RG, Starkstein SE, et al.: Lateralisation of dementia of depression in stroke patients. Am J Psychiatry 1989, 146:627634.

Robinson RG, Benson DF: Depression in aphasic patients: frequency, severity and clinical pathological correlations. Brain Lang 1981, 14:282291. 44. Signer S, Cummings JL, Benson DF: Delusions and mood disorders in patients with chronic aphasia. J Neuropsychiatry Clin Neurosci 1989, 1:4045. 45. Morrison JH, Molliver ME, Grzanna R: Noradrenergic innervation of the cerebral cortex: widespread effects of local cortical lesions. Science 1979, 205:313316. 46. Lipsey JR, Robinson RG, Pearlson GD, et al.: Nortriptyline treatment of post-stroke depression: a double-blind study. Lancet 1984, 1:297300. 47. Dam M, Tonin P, De Boni A, et al.: Effects of fluoxetine and maprotiline on functional recovery in post-stroke hemiplegic patients undergoing rehabilitation therapy. Stroke 1996, 27:12111214. 48. Anderson G, Vestergaard K, Lauritsen L: Effective treatment of post-stroke depression with the selective serotonin re-uptake inhibitor citalopram. Stroke 1994, 25:10991104. 49. Reding MJ, Orto LA, Winter SW, et al.: Anti-depressant therapy after stroke: a double blind study. Arch Neurol 1986, 43:763765. 50. Raffaele R, Rompello L, Vecchio I, et al.: Trazodone therapy of post-stroke depression. Arch Gerontol Geriatr Suppl 1996, 5:217220. 51. Kimura M, Kinetani K, Imai R, et al.: Therapeutic effects of milnacipran, a serotonin and noradrenaline reuptake inhibitor on post stroke depression, Int Clin Psychopharmacol 2002, 17:121125. A good article. 52. Narushima K, Kosier JT, Robinson RG: Preventing post stroke depression: a 12 week double blind randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 2002, 190:296303. A good article. 53. Murray GB, Shea V, Conn DK: Electroconvulsive therapy for post-stroke depression. J Clin Psychiatry 1987, 47:258260. 54. Oradei DM, Waite NS: Group psychotherapy with stroke patients during immediate recovery phase. Am J Orthopsychiatry 1974, 44:386395. 55. Watziawick P, Coyne JC: Depression following stroke: brief, problem focused family treatment. Fam Treat 1980, 19:1318. 56. Thompson SC, Dobolew-Shobin A, Graham MA, et al.: Psychosocial adjustment following a stroke. Soc Sci Med 1989, 28:239247. 57. Dennis M, O'Rourke S, Staniforth T, et al.: Evaluation of the stroke family care worker: results of a randomized control trial. Br J Psychiatry 1997, 314:1071.

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