Cerebrovascular Disease and Depression

7/30/2019 Cerebrovascular Disease and Depression

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Cerebrovascular Diseasesand 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: [email protected] Psychiatry Reports 2003, 5:231 238Current Science Inc. ISSN 1523-3812Copyright 2003 by Current Science Inc.

Introduction: Historical Perspective The relationship between depression and cerebrovascular diseases (CVD) has been studied extensively for more thantwo decades [14,5]. Cerebrovascular diseases constitutea leading health hazard in terms of the effect on the quality of life of the individual and the economic burden on soci-ety [6]. Stroke is the third leading cause of mortality inadults [6]. The relationship between depression and CVDis complex and influenced by multiple factors.

The occurrence of mood disorders associated withbrain injury (predominantly CVD) has been known for over a century. In 1826, Bayle and Calmeil (discussed in[7]) described the psychiatric symptoms in general paraly-sis of the insane, which provided one of the earliest exam-ples 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 etio-logic role of CVD in producing states of depression. Morerecently, epidemiologic studies by Kay [11] demonstratedthe frequent association between stroke and first episodesof 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 depres-sion has been recognized for many years, the nature of therelationship is less certain. Post [12] postulated that ath-erosclerotic diseases and affective disorders share the sameunderlying etiology. Roth [13] and Meyer [8] suggestedthat injuries to certain brain areas produce depression.Most clinicians, however, have assumed that depression isreactive to the impairments produced by stroke [8,1215].Fisher [14] stated that the brain was the most cherishedorgan in the body and injury to this organ would under-standably 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 describean emotional disorder that was uniquely associated withbrain diseasethe catastrophic reaction. This is an emo-tional outburst involving various degrees of anger, frustra-tion, 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 emotionalabnormality characteristic of brain injury. The indifferencereaction, associated with right hemisphere lesions, consistsof symptoms of indifference toward failures, lack of inter-est in family and friends, enjoyment of foolish jokes, andminimization of physical difficulties. A third emotionaldisorder that has historically been associated with braininjury, such as cerebral infarction, is pathologic laughter or crying. Ironside [19] described the clinical manifestationsof this disorder. Parikh et al. [4] devised a scale to measurepathologic laughter and crying. The emotional displays arecharacteristically unrelated to the inner emotional state.Folstein et al. [20] compared 20 patients who suffered astroke with 10 orthopedic patients. Although the func-tional disability in the groups was comparable, the patients

Cerebrovascular diseases constitute a leading health haz-ard. The association between stroke and depression hasbeen recognized for many years. Depression is the mostcommon psychiatric disorder associated with cerebrovas-cular diseases, most episodes of post-stroke depressionoccur in the first 2 years after a cerebrovascular accident.Studies have found an association between lesion location,physical impairment, cognitive impairment, aphasia, andpost-stroke depression. The location of the lesion in termsof proximity to the left frontal pole of the brain has a pro-found impact on the frequency and severity of post-strokedepression. Treatment modalities include pharmacotherapy,psychotherapy, electroconvulsive therapy, and rehabilita-tion. Understanding the psychologic and physical morbidityof post-stroke depression, as well as its timely, comprehen-sive treatment, are important for effective management.


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232 Medicopsychiatric Disorders

who had suffered a stroke were more depressed [20]. Theauthors concluded, mood disorder is a more specific com-plication of stroke than simply a response to motor dis-ability. Finkelstein et al. [21] found that depression andfailure to suppress serum cortisol after dexamethasoneadministration were more common among 25 randomly selected patients who had suffered a stroke than among agroup of 13 control patients with equally disabling medi-cal illnesses [21].

To summarize, there are two primary schools of thought in the study of emotional disorders that are associ-ated with CVD. One attributes emotional disorders to anunderstandable psychologic reaction to the associatedimpairment; the other is based on a lack of associationbetween severity of impairment and severity of emotionaldisorder, which suggests a direct causal connectionbetween CVD and neuropsychiatric disorder.

Common Cerebrovascular DiseasesCerebrovascular diseases usually present as an abrupt onset of focal neurologic deficit. The deficit may remain fixed,gradually worsen or improve. Cerebrovascular diseases aremainly caused by an ischemic or hemorrhagic phenome-non. The ischemic injuries may or may not lead toinfarction, for example, in transient ischemic attacks. Hem-orrhages cause parenchymal injury by direct damage andextravasation 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

AgeDepression is seen in approximately 1% to 2 % of the eld-erly population. The elderly are prone to depression for a

variety of neuroanatomic, neurophysiologic, psychologic,and social reasons.

Gender The lifet ime prevalence of major depressive disorder is10% to 25% for women and 5% to 12% for men. Thishigher prevalence among women is because of various fac-tors, including hormonal differences, stress, and structuraldifferences in the brain [6]. A study by Duff [22] reportedthat after a stroke, women have twice the incidence of major depression compared with men. It showed that apast diagnosis of psychiatric disorder and cognitive impair-ment was associated with increased severity of depressionin women, and it was associated with greater impairment in daily activities and social functioning in men.

Race There is no significant difference in the prevalence of mood disorders across different ethnic groups [6]. How-ever, the occurrence of depression post-CVD is higher in

African-Americans compared with whites [6]. This may berelated to the higher prevalence of resistant essential hyper-tension among the African-Americans, which predisposesto 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 healthcare that is required to prevent depression after stroke [6].

Previous history of psychiatric illness and personality traitsStudies have suggested that depressed individuals are morelikely to suffer from stroke [23]. One study showed that middle-aged men are three times more likely to suffer fromstroke if they suffer from psychologic distress, such asdepression and anxiety. Although these men had other risk

factors associated with stroke such as age, smoking, obe-sity, and hypertension, they also had significant symptomsof anxiety and depression [23]. One theory suggests that increased sympathetic activity in depression leads to vaso-constriction because of the release of norepinephrine. Theimmunologic theory suggests that there is a higher chanceof 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 onthe magnetic resonance imaging (MRI) [2426]. Whitematter lesions are frequently associated with hyperten-sion, atherosclerosis, and atrial fibrillation. This iscalled vascular depression, and is associated with dif-fuse subcortical involvement. One study attempted toassess the relationship between white matter densitiesseen on the MRI and depression [5]. Comparing 20elderly patients with depression with 20 elderly controlindividuals, the study concluded that deep white matter densities are more frequently caused by cerebralischemia, and ischemic lesions are more frequently located in the dorsolateral prefrontal cortex indepressed subjects [5]. The study supported thehypothesis of vascular depression as a cause of late-lifedepression. Another study trying to assess the relation-ship between white matter lesions in dementia withLewy bodies, Alzheimers disease, vascular dementia,and normal aging showed that there is an important link between white matter densities in the frontal areasand depression [24].


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Cerebrovascular Diseases and Depression Ghoge et al. 233

Epidemiology Depression is the most common psychiatric disorder asso-ciated with CVD [6]. Approximately 15% to 25% of com-munity based samples of patients with acute stroke and30% to 40% of patients hospitalized with acute stroke havea clinically diagnosable major or minor depressive disor-der [6] that is likely to last for over a year without treat-ment [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 beenattributed to a variety of reasons, such as the relapse of acyclical depressive disorder, recurrence of stroke, deteriora-tion of a medical condition, or withdrawal of social sup-port. In ischemic episodes, though, they are seen moreoften in the chronic phase of the disease [3].

One study found that the incidence of depression washighest in infarcts of cardiac origin (71%) followed by ath-erosclerotic infarcts (52%), and was least seen in lacunar

infarcts [25]. Patients with silent cerebral infarcts andmajor depression present with more marked neurologic symptoms and more severe depressive symptoms thanthose without silent cerebral infarcts [26].

Relationship of Mood to Other Variables Although the exact mechanism is unclear, several factorsare implicated in the etiology of post-stroke depression.

Relationship to lesion locationIn a study of consecutive patients admitted to a hospitalafter 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 animportant determinant of the presence of depressionsix of 10 (60%) patients with left anterior frontal lesions haddepression compared with one of eight (12.5%) patients

with left posterior lesions. There was also a significant cor-relation between the distance of the anterior border of thelesion 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 investigatorshave also systematically examined the association betweenlesion location and post-stroke depression. Sinyor et al.[27] found a significant inverse correlation betweendepression severity and distance of the lesion from thefrontal pole for right and left hemisphere lesions [27].

Although smaller, the correlation was in the same directionas that of the Robinson et al. [1] study, but was not specific to patients with left hemisphere lesions. Differences indemographic characteristics of the sample, the time sincestroke, and the lack of standardized diagnosis in the Sinyor et al. [27] study may underlie the difference in resultsbetween the studies [27]. In more recent studies, Eastwood

et al. [28] examined a consecutive series of patients withstroke lesions who had been admitted to a rehabilitationcenter. They found that, among patients with left hemi-sphere lesions, scores on a depression rating scale signifi-cantly correlated with lesion location. However, among patients with right hemisphere lesions, depression scoresdid not significantly correlate with lesion location. Simi-larly, Morris et al. [29] found that, after controlling for fam-ily history of mood disorder, patients with single left hemisphere lesions showed a significant inverse correla-tion between distance of the lesion from the frontal poleand severity of depression.

In summary, studies conducted by different investiga-tors support the hypothesis that the closer the lesion is tothe frontal pole, the greater is the severity of depressionand that left frontal lesions are the most likely lesions toshow this relationship. The location of the lesion along theanterior-posterior dimension is an important variable inthe severity of post-stroke depression.

Cortical and subcortical lesionsIn a study of 45 patients with single lesions restricted tocortical 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, whereas39% of patients with left subcortical lesions, 11% of patients with right cortical lesions, and 14% of patients

with right subcortical lesions were depressed. Although thefrequency of depression between patients with left cortical

versus left subcortical or right cortical versus right subcorti-cal lesions was not significantly different, patients who hadlesions in the left hemisphere had significantly higher rates

of depression than patients with right hemisphere lesions,regardless of the cortical or subcortical location of thelesion [30].

When patients were further subdivided into those with anterior lesions and those with posterior lesions, allfive patients with left cortical lesions involving the frontallobe had depression compared with two of the 11(18.1%) patients with left subcortical posterior lesions.

These relationships were not significant for patients withright hemisphere lesions. A study by Starkstein et al. [31]examined the relationship between lesions of specific subcortical nuclei and depression. Basal ganglia lesionsproduced 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 dementiafound that the subcortical syndrome correlated withdepressed mood and suggested that patients with demen-tia with a clinically established subcortical dysfunctionappeared more susceptible to depressive symptomatology [32]. This in agreement with findings of anterior lesionlocation corresponding to depression in patients withstroke. A number of recent MRI studies found an associa-


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tion between depressive symptoms and frontal (espe-cially dorsolateral prefrontal cortex) white matter hyperintensities, the volume of the white matter hyperin-tensities, 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 hemi-sphere lesions. When other confounding factors areaccounted for ( eg, prior lesions and family or personal his-tory of mood disorder), left dorsolateral frontal corticaland left basal ganglia lesions produce a similar high fre-quency of major depression that is greater than that for any other lesion location.

Middle cerebral circulation versus posterior circulation lesionsStarkstein 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 wasfound 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 post-stroke follow-up revealed that the frequencies of depres-sion were 68% and 0%, respectively. Thus, patients withlesions in the cerebellar or brain stem region had a signifi-cantly shorter course of depression compared with those

with middle cerebral arterial lesions. These findings sug-gest that the mechanism of depression after middle cere-bral artery lesions may differ from the mechanism of depression after cerebellar or brain stem lesions. Starksteinet al. [36] speculated that the shorter duration of depres-sion after cerebellar or brain stem lesions may be related totheir 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 lessfrequently and are shorter in duration than depressionassociated with middle cerebral artery lesions. This may indicate differences in the mechanism of depression asso-ciated with these two lesion locations.

Right hemisphere lesionsStarkstein et al. [3], in a series of 93 patients with acuteright hemisphere lesions, reported that of 54 patients

with positive computed tomography scans, six of ninepatients (66%) with major depression and five of eight patients (63%) with minor depression had lesions that involved the parietal lobe, compared with nine of 25patients (36%) without mood changes and one of 12patients with undue cheerfulness. Similar results were

reported by Finset [37], who found that patients withparietal 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 reporteda low, but significant, correlation between depression andfunctional physical impairment ( ie, activities of daily living [ADL]). This association can be construed as the functionalimpairment producing depression or depression influenc-ing the severity of functional impairment. Two studies lendsupport to the latter suggestion. Sinyor et al. [27] reportedthat although patients with stroke who were not depressedshowed a slight increase or no change in functional statusover time, patients with depression had significant decreases in function during the first month after stroke.Parikh et al. [4] compared a consecutive series of 63patients 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 2- year follow-up than the patients without depression. Thisfinding held true after controlling for various variables,such as the type and extent of in-hospital and rehabilita-tion treatment, the size and location of the lesion, thepatients demographic characteristics, nature of the strokeduring the follow-up period, and medical history [4].

Although the correlation between depression and phys-ical impairment after stroke is not strong, the two variablesdo appear to interact. There is little evidence to support

that physical impairment is a major cause of post-strokedepression. However, if depression develops, the patientsphysical 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 sub-sided ( ie, major depression tends to resolve in approxi-mately 1 year).

Relationship with cognitive impairment Studies have suggested that elderly patients with functionalmajor depression have intellectual deficits that improve

with treatment of depression [39]. This was first examinedby Robinson et al. [38]. Patients with major depressionafter a left hemisphere infarct had significantly lower scores on the Mini-Mental State Examination than a com-parable group of patients without depression [38]. The sizeof the lesion and depression scores independently corre-lated with the severity of cognitive impairment. Another study by Starkstein et al. [41] found that even whenpatients 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 thosepatients with major depression and left hemisphere


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lesions had significantly greater cognitive impairment compared with patients without depression with com-parable left hemisphere lesions. These cognitive deficitsprimarily involved tasks of temporal orientation, lan-guage, executive motor, and frontal lobe functions.However, among patients with right hemisphere lesions,patients with major depression did not differ frompatients without depression on any of the measures of cognitive impairment. To summarize, major depressionassociated with a left hemisphere stroke appears to pro-duce significant cognitive impairments. Whether thesecognitive impairments will improve with treatment of the depression remains to be determined.

Relationship with aphasiaRobinson and Benson [43] found that patients with non-fluent aphasia had a significantly higher frequency of depression compared with patients with fluent or globalaphasia. 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 apha-sia. Kay [11] reported that lesion location was the impor-tant variable in the association between post-strokedepression and nonfluent aphasia. To conclude, patients

with left hemisphere lesions that produce aphasia have afrequency of depression similar to that of patients with left hemisphere lesions that do not produce aphasia.

Although nonfluent aphasia and post-stroke depres-sion do not appear to be causally related, they are pro-duced by lesions of similar anatomic location (anterior areas of the left hemisphere). Thus, patients with non-fluent aphasia are at a higher risk of developing post-

stroke depression compared with patients with other types of aphasia.

Mechanisms of Post-Stroke Depression The exact mechanism of post-stroke depression is not known. Dysfunction of the biogenic amine system hasbeen implicated. The noradrenergic and serotonergic cellbodies are located in the brain stem and send ascending projections through the median forebrain bundle to thefrontal cortex. The ascending axons arch posteriorly andrun longitudinally through the deep layers of the cortex,sending terminal projections into the superficial corticallayers [45]. Lesions that disrupt these pathways in the fron-tal cortex or the basal ganglia may affect many downstreamfibers. Based on these neuroanatomic facts and the clinicalfindings that the severity of depression correlates with theproximity of the lesion to the frontal pole, Robinson et al.[1] suggested that post-stroke depression may be the con-sequence of severe depletions of norepinephrine or seroto-nin produced by frontal or basal ganglia lesions. Studies inrats have demonstrated that the biochemical response toischemic lesions is lateralized whereby a greater depletionof biogenic amines is found in patients with right hemi-

sphere lesions compared with those with left hemispherelesions [2]. The greater depletion with right hemispherelesions could lead to a compensatory upregulation of receptors, which may protect against depression; however,patients with left hemisphere lesions may have moderatedepletions of biogenic amines, but without a compensa-tory upregulation of dopamine receptors and, therefore, adysfunction of biogenic amine systems in the left hemi-sphere. This dysfunction may eventually lead to the clinicalsymptoms 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 andhelps realize the value of treatment and, more impor-tantly, timely treatment. The treatment modalitiesinclude pharmacotherapy, psychotherapy, electroconvul-

sive therapy, and rehabilitation.Pharmacotherapy One of the first trials in treating post-stroke depression

was conducted using nortrypt iline. This randomizeddouble blind study was conducted among 34 patients;14 of these patients were given the drug and 20 weregiven a placebo over 6 weeks. The drug doses werestarted at 25 mg at bedtime and increased to approxi-mately 100 mg. Eleven of the 14 patients showed signifi-cant improvement in their scores on the HamiltonDepression Rating Scale compared with 15 of the 20patients treated with a placebo [46].

A randomized controlled trial by Dam et al. [47] stud-ied the effect of fluoxetine on patients with post-strokedepression for 3 months [46]. The study showed that patients treated with fluoxetine had a better functionaloutcome compared with those treated with placebo; how-ever, there was no difference in depressive symptomatol-ogy. A randomized control trial by Robinson and Benson[43] of 104 patients over 12 weeks using fluoxetine andnortryptiline showed that 77% of patients who receivednortryptiline showed improvement, 14% of those treated

with fluoxetine showed improvement, and 33% of thosetreated with a placebo showed improvement. In this trial,the dose of fluoxetine was increased gradually from 10mg to 40 mg, which had a positive correlation only interms of the side effects.

Anderson et al. [48] assessed the effects of citalopramon 66 patients with post-stroke depression, 2 to 52 weeksafter stroke, using 10 to 20 mg per day of the drug for 6

weeks. A decreased rate of depression was found in thetreatment group. Another recent double blind, random-ized, controlled study using citalopram found that Hamil-ton Depression Rating Scale scores improved significantly over 6 weeks in patients receiving citalopram ( n=27) com-pared with placebo ( n=32). At 3 and 6 weeks, the active


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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 depressedpatients taking trazodone showed greater improvement inBarthel 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 indepressive 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 diag-nosed with minor or major depression according to Diag-nostic and Statistical Manual of Mental Disorders . This was a6-week open trial, and severity of depression was assessedusing 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 effectivetreatment for post-stroke depression [52].

Tricyclic antidepressantsNortryptiline is the tricyclic antidepressant of choice usedto treat post-stroke depression [46]. Nortryptiline causesless orthostatic hypotension and usually only a mildamount of anticholinergic and sedative side effects. It alsohas a well-documented therapeutic range of serum levels.

This is important because some patients, especially the eld-erly, may develop higher than usual blood levels on a given

dosage regimen. To minimize any orthostatic hypotensionor 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 oncethe 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 dosesby 25 mg per day per week. Most patients will respond

within 4 to 6 weeks of reaching adequate dose. The drug isgiven for a period of 6 months and then tapered off. Other side effects include dry mouth, mild sedation, and consti-pation. Nortryptiline may have some quinidine-like effectsand should be used carefully in patients with cardiac arrhythmias. A baseline echocardiogram should beobtained before the treatment is started. A relative con-traindication to the use of the drug is a recent myocardialinfarction, urinary obstruction, and narrow angle glau-coma. Poorly controlled seizures could get exacerbated.Untreated depression has life-threatening effects of itsown; thus, before deciding on whether or not to treat withthe 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 nortryp-tiline and fluoxetine showed that nortryptiline producedan increased vulnerability to depression for more than 6months after it was discontinued, which suggests theneed for extending the prophylactic treatment and moni-toring patients carefully after the discontinuation of nortryptiline [53].

Selective serotonin reuptake inhibitorsOne study found that fluoxetine improved the functionaloutcome, but no improvement in depressive symptomatol-ogy in patients with post-stroke depression [47]. However,certain randomized control trials have shown fluoxetine tobe efficacious in treating post-stroke depression [52]. Cit-alopram has proved effective in treating post-stroke depres-sion [48]; recommended dose is 10 to 20 mg per day. Sideeffects include nausea, vomiting, abdominal pain, somno-lence, and sexual dysfunction. There are no specific con-traindications for its use. Other selective serotonin

reuptake inhibitors may be helpful in post-stroke depres-sion, but require further study.

Selective serotonin noradrenaline reuptake inhibitorsMilnacipran has side effects such as weight gain, sexualdysfunction, tachycardia, and hypertension, and anticho-linergic effects such as constipation. In one study, this drug

was used in the dose range of 30 to 75 mg twice daily, and70% of the patients completing the study were in remis-sion, which suggests that milnacipran may be an effectivetreatment for post-stroke depression [51].

Trazodone

A dopamine reuptake inhibitor and dopamine 2a and 2c antagonist, trazodone has been particularly effective inimproving sleep time and in decreasing night awakeningsin patients with post-stroke depression. It has alpha-block-ing effects, and can cause gastrointestinal side effects andalso priapism. The overdose attempts are also benign. Nofatalities were reported when the drug was taken alone. It also lacks the anti-arrhythmia effects of nortryptiline. Therecommended dose is up to 300 mg per day.

Other drugs, such as monoamine oxidase inhibitorsand methylphenidate, could also be helpful in post-strokedepression, but they require further research.

Electroconvulsive therapy Murray et al. [53] reported that electroconvulsive therapy iseffective in treating post-stroke depression. It had fewer side effects than drugs, and is not associated with neuro-logic deterioration [53].

Psychotherapy Oradei and Waite [54] and Watziawick and Coyne [55]reported that group and family therapy are beneficial interms of faster recovery. Controlled studies for these treat-ment modalities are still under way [54,55].


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RehabilitationPsychosocial adjustment is an important issue in patientsafter stroke. Thompson et al. [56] examined 40 patients, as

well as their caregivers, for an average of 9 months for psy-chosocial adjustment after stroke. They found that a lack of meaningfulness in life and overprotection by the caregiver

were independent predictors of depression. They alsofound that psychosocial factors could predict motivationand depression in patients with stroke. The authors sug-gested that therapeutic approaches using cognitive adapta-tion and social support might be useful towardunderstanding peoples ability to cope after stroke. Denniset al. [57] showed that introduction of a stroke family care

worker improved the patients satisfaction with the servicesand may have had some effect on the psychologic andsocial outcome, but did not improve the physical wellbeing. This could be because a family care worker couldmake 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 foundthat left frontal lesions and more anterior lesions correlate

with depressive symptoms in the post-stroke period. Left dorsolateral frontal cortical and left basal ganglia lesionsalso show a positive correlation with severity of depressionin patients in the post-stroke period. Studies have alsofound an association between physical impairment, cogni-tive impairments, aphasia, and post-stroke depression. Var-ious classes of antidepressants have been tested, and these

range from the more conservative tricyclic antidepressants(predominantly nortryptiline) to other classes like theselective serotonin noradrenaline reuptake inhibitors,selective serotonin reuptake inhibitors, and trazodone.Monoamine oxidase inhibitors and methylphenidate may be helpful, but require further research. Electroconvulsivetherapy seems to be efficacious with fewer side effects thanpharmacotherapy. Psychotherapy (predominantly groupand family therapy) and rehabilitation measures improvethe prognosis of patients with post-stroke depression.

Therefore, a comprehensive approach in the management of post-stroke depression can enhance recovery andimprove outcome in patients with post-stroke depression.

References and Recommended Reading Papers of particular interest, published recently, have beenhighlighted as: Of importance Of major importance

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Cerebrovascular Disease and Depression

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