Cerebrovascular disease and late life depression: an age old association revisited

CEREBROVASCULAR DISEASE ANDLATE LIFE DEPRESSION: AN AGEOLD ASSOCIATION REVISITED

RAHUL RAO*

Guy's Hospital, St Thomas' Street, London SE1 9RT, UK

ABSTRACT

Objectives. To examine the relationship between depression and cerebrovascular disease in three distinct settings:depression in established cerebrovascular disease, cerebrovascular disease in established depression and depression invascular dementia.

Methods. Medline, EMBASE, PsychLit and PsychInfo databases were scanned to locate relevant articles. Datawere also extracted from other articles, cited by those articles generated from the above databases.

Results. Using operational criteria, the prevalence of depression is higher than controls only within the ®rst yearafter stroke, but most studies have not employed control groups. The prevalence of depression in vascular dementiacompared with Alzheimer's disease is higher in the majority of studies, but matching for sociodemographic factorsand severity of cognitive impairment has been inconsistent. An association between frontal/subcortical cerebro-vascular lesions and depression in later life has been observed, but there may be methodological ¯aws underlying thisobservation in some computerized tomography studies.

Conclusion. There is some evidence that cerebrovascular disease has an aetiopathological role in late lifedepression. The increased likelihood of damage to frontal/subcortical brain circuitry following stroke, transientischaemia and hypertension may explain the high prevalence of depression in older people with vascular risk factors.

More valid de®nitions of lesion location and the use of appropriately matched control groups would seek to clarifythis issue. The extrapolation to care settings from the high prevalence of depression accompanying cerebrovasculardisease and the prolongation of disability in depressed people with stroke, suggests closer liaison between old agepsychiatrists, neurologists and physicians caring for the elderly. Copyright # 2000 John Wiley & Sons, Ltd.

KEY WORDSÐageing; depression; stroke; prevalence; frontal lobe; brain imaging; vascular dementia

During the mid 19th century, Durand-Fardel(1843) reported irritability and depression to becommon acute sequelae of strokes. There has sincebeen a steadily increasing volume of researchexamining the relationship between depressionand cerebrovascular disease. These studies fallinto three distinct categories: depression in estab-lished cerebrovascular disease, cerebrovasculardisease in established depressive disorder anddepression in vascular dementia. This reviewcritically evaluates each of these associations inturn, intentionally excluding other disorders suchas emotionalism and apathy which, althoughclinically important consequences of stroke,

would require more extensive discussion in theirown right. Both apathy (Marin et al., 1995; Levyet al., 1998) and emotionalism (Andersen, 1997;Calvert et al., 1998) have been the subject of recentreviews.

The following review was based on a search ofMedline, EMBASE, PsychInfo and PsychLitdatabases from 1980 to December 1998. Morerecent articles were sought from monthly issues ofIndex Medicus. The following words were used toextract articles of interest: depression; cerebro-vascular disorders; stroke; vascular dementia;brain imaging; frontal lobe; rating scale. Articleswere then selected if they, in part of whole,examined the relationship between cerebrovasculardisease and depression. Further articles of interestwere then selected on the basis of the aboveselection criterion.

Copyright # 2000 John Wiley & Sons, Ltd. Received 2 August 1999Accepted 29 August 1999

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY

Int. J. Geriat. Psychiatry 15, 419±433 (2000)

*Correspondence to: Dr R. Rao, Senior Lecturer in Old AgePsychiatry, Job Ward, Thomas Guy House, Guy's Hospital,St Thomas' Street, London SE1 9RT, UK. Tel: �44-171-232-0148. Fax: �44-171-394-1097. e-mail: [email protected]

DEPRESSION ACCOMPANYINGCEREBROVASCULAR DISEASE

In the context of mood disorders associatedwith cerebrovascular disease, depression followingstroke (commonly referred to as `post-strokedepression') has commanded the largest volumeof research over the past three decades. Depressionis more likely to occur after a stroke than in othermedical disorders with similar levels of disability(Folstein et al., 1977) and compared with age- andsex-matched community residents (House et al.,1991; Dam et al., 1989; Andersen et al., 1994).

A number of studies have found high sensitivitiesand speci®cities when validating established depres-sion rating scales against diagnostic instruments fordepression in stroke populations. These scalesinclude the Hamilton Rating Scale for Depression(HRSD) (Ng et al., 1995), General Health Ques-tionnaire (Robinson and Price, 1982), GeriatricDepression Scale (Johnson et al., 1995), Zung Self-rating Scale for Depression (Agrell and Dehlin,1989) and the Centre for Epidemiological StudiesÐDepression Scale (Shinar et al., 1986). The HRSDhas been used most frequently in screening for post-stroke depression. However, rating scales fordepression used in stroke may be sensitive, butoften lack speci®city when compared with diag-nostic instruments (Schramke et al., 1998).

The prevalence of post-stroke depression indi�erent populations has been subject of a numberof studies, but few have used standardized diag-nostic instruments at speci®c time periods afterstroke. Table 1 outlines the characteristics ofstudies that have used such instruments. A studyexcluded from this table assessed 103 stroke clinicattenders over an 18 month period using DSM IIIcriteria for major depression, but its sample washeterogeneous, with a wide variation in the timeinterval since the last stroke (more than 10 years in18% of the group).

However, 45% of those people who had su�eredtheir last stroke between 6 months and 2 yearspreviously were given a diagnosis of DSM IIImajor depression (Robinson and Price, 1982). Onlytwo of the studies shown in Table 1 used strokeregisters (House et al., 1991; Burvill et al., 1995),and only one of these studies patients followingtheir ®rst stroke (House et al., 1991). Most studiesdo not, however, include a control group, which isproblematic when interpreting the prevalence ofpost-stroke depression. However, this cannotdetract from the observation that the prevalence

of post-stroke depression during the ®rst monthranges from 11 to 50%, declining only after 2 yearsfollowing stroke. It is striking that communitysamples show comparatively lower prevalence ratesfor depression.

It is possible that patients with less severe strokes(and probably less neurological and functionalde®cit) not requiring hospital admission have lesssevere depressive symptomatology. The applicationof these studies to clinical practice suggests thatpatients should be screened for major depressionfor at least 2 years after their stroke. Clearly, thereis large variation between studies in the prevalenceof post-stroke depression, depending on methodo-logical di�erences such as restriction to certainstroke sub-types, diagnostic criteria, and demo-graphy of the study population (e.g. in-patientsversus community residents). However, in spite ofthe high prevalence of post-stroke depression in themajority of studies, a diagnosis of depressionfollowing stroke may be missed during routineclinical practice.

Risk factors for post-stroke depression

Several factors in¯uence both the course andseverity of post-stroke depression, including age(Robinson et al., 1984a; Morris et al., 1992), timesince stroke (Robinson et al., 1987; House et al.,1991), severity of intellectual impairment (Houseet al., 1990a; Andersen et al., 1995, 1996), socialsupport (Shima et al., 1994; Morris et al., 1991;Astrom et al., 1992), and past history of depression(Andersen et al., 1995; Schwartz et al., 1993). Thetwo most widely studied risk factors in relation topost-stroke depression have been physical disabilityand location of stroke lesion. The relationshipbetween physical disability and depression is com-plex, as there appears to be a reciprocal relationshipbetween the two factors. There is comparativelygreater evidence for depression being a risk factorfor prolonged neurological disability rather thanvice versa (Ebrahim et al., 1987; Colantonio et al.,1992; Diamond et al., 1995). Other studies have notfound a signi®cant relationship between depressionand physical disability (Robinson and Price, 1982;Lammi et al., 1989).

Interest in the relationship between location ofstroke lesion and depression began during the1980s, largely owing to a large number of studies byRobinson and colleagues. These and other relevantstudies are outlined in Table 2. Only two studiesinvolved community residents on a stroke register

Copyright # 2000 John Wiley & Sons, Ltd. Int. J. Geriat. Psychiatry 15, 419±433 (2000)

420 R. RAO

(Sharpe et al., 1990; House et al., 1990b), butinvolved the same study cohort. Although themajority of studies examined patients with bothright and left hemisphere strokes, some werecon®ned to particular sub-groups, such as right/left handed subjects or those with subcorticallesions (Robinson and Szetela, 1981; Robinsonet al., 1984a, 1985a; Starkstein et al., 1987, 1989;Hermann et al., 1993). Furthermore, arbitrary cut-o� points for the anterior and posterior borders oflesions as a percentage of maximum anterior±posterior distance have been de®ned in all studiesinvolving Robinson and colleagues.

This de®nition fails to include lesions that extendbeyond these cut-o� points, thus creating anarti®cially de®ned criterion for classifying `proxi-mity to the frontal pole'. The majority of studies inTable 2 indicate that there is evidence for an

association between depression and proximity tothe left frontal pole, but the two community-basedstudies (Sharpe et al., 1990; House et al., 1990b) didnot ®nd an association. In fact, if all studies byRobinson and co-researchers are excluded, 13 ofthe 17 remaining studies did not ®nd an associationbetween depression and proximity to the frontalpole, with some of these studies ®nding either noassociation, a weak association or additionalassociations with other brain areas.

It is possible that the previously noted higherprevalence of depression after stroke comparedwith other physical disorders may be related toaltered brain pharmacodynamics, yet there havebeen no prospective studies in stroke population inwhich the relationship between depression and post-mortem neurotransmitter levels has been examined.Theories put forward have been extrapolated from

Table 1. Studies of post-stroke depression using diagnostic instruments

Author (year) Study population

(assessment period

following stroke)

Total number

of subjects

Control group Prevalence of major

depression in stroke

(controls)

Robinson et al. (1983b)

Robinson et al. (1984a)

Robinson et al. (1987)

In-patients (52 weeks);

community follow-up

every 3 months until

1 year

103 at5 2 weeks

{86 at follow-up

None 52 weeks: 27%

3 months: 22%

6 months: 34%

1 year: 14%

2 years: 21%

Sharpe et al. (1993) Community sample

(Between 3 and 5 years)

60 None 8%

House et al. (1991) (238) Community sample

(Monthly over 1 year)

}128 Age/sex-matched

community residents

1 month: 11%

6 months: 9%

1 year: 5%

(7.5%)

Astrom et al. (1993) (239) In-patients (52 weeks);

community follow-up

at 3 months, 1, 2 and

3 years

76 (52 weeks)

45 (3 years)

None 52 weeks: 25%

3 months: 31%

1 year: 16%

3 years: 29%

Shima et al. (1994) (240) In-patients (51month) 68 None 50%

Burvill et al. (1995) (241) Community sample

(4 months)

248 Age/sex-matched

community residents

15% (5%)

Pohjasvaara et al. (1998) Mixed in-patient/

community sample

(Between 3 and

4 months)

277 None 26%

McHale et al. (1998) Mixed in-patient/

community sample

(6 months)

55 None 20%

{Total number interviewed over 2 years.}Total number interviewed over 12 months.


CEREBROVASCULAR DISEASE AND LATE LIFE DEPRESSION 421

studies in rats, but it is noteworthy that the greatestchanges in brain catecholamines in these studieshave been observed after right rather than lefthemisphere infarction (Robinson, 1979).Moreover,one study showed that changes in rat braincatecholamines after right hemisphere infarctionwere normalized following antidepressant adminis-tration (Robinson and Bloom, 1977). The other®nding from these studies is that, after unilateralmiddle cerebral artery ligation, changes in braincatecholamines have been observed both in injuredand uninjured tissue (Robinson et al., 1977),suggesting the possible in¯uence on mood ofneurotransmitter changes at sites distant to infarc-tion. The application of both animal modelsof stroke to post-stroke depression in humansawaits further clari®cation from clinicopathologicalstudies.

The only study of post-stroke depression to dateassessing levels of CSF 5-hydroxy-indoleacetic acid

(a metabolite of serotonin) found lower levels ofthis metabolite in depressed stroke patients than innon-depressed matched control subjects withoutstroke (Bryer et al., 1992).

Depression in asymptomatic cerebrovascular disease

In populations exposed to vascular risk factors,the role of clinically `silent' cerebrovascular diseasein depression is a growing area of research, particu-larly that of silent cerebral infarction (SCI). Thisterm refers to cerebrovascular pathology associatedwith asymptomatic neurological/neuropsychologi-cal de®cit. A recent study examining soft neuro-logical signs in older people with mild stroke andcarotid stenosis found depression to be anindependent predictor of primitive re¯exes (Raoet al., 1999), with these re¯exes showing a higherprevalence in the carotid stenosis group than incontrols. Preliminary ®ndings from the same study

Table 2. Studies examining association between lesion location and depression

Author (year) Time at which depression assessed Association with increased severity of depression

Robinson and Szetela (1981) 53 months Proximity to L frontal pole

Robinson and Price (1982) Between 6 months and 2 years L hemisphere lesions

Robinson et al. (1983a) 53 months L anterior lesions

Lipsey et al. (1983) 53 months L anterior lesions

Robinson et al. (1984a) 53 months L anterior and R posterior lesions

Robinson et al. (1984b) 3 to 6 months L anterior lesions

Robinson et al. (1985a) 53 months L anterior lesions

Robinson et al. (1985b) 3 months, 6 months, 1 year Proximity to L frontal pole

Sinyor et al. (1986) 2 months Proximity to L frontal pole (Weak association only)

Ebrahim et al. (1987) 6 months No relationship

Starkstein et al. (1987) 52 months Proximity to L and R frontal poles

Parikh et al. (1988) 1 year Proximity to L frontal pole

Eastwood et al. (1989) 3 months Proximity to L frontal pole

Starkstein et al. (1989) 53 months R parietal lesions

Dam et al. (1989) 51 month R hemisphere lesions

House et al. (1990b) Between 6 months and 1 year Proximity to L and R frontal poles

Arboix et al. (1990) 53 months L hemisphere lesions

Sharpe et al. (1990) Between 3 and 5 years No association

Morris et al. (1996a) 53 months Proximity to L frontal pole (Weak association only)

Yamaguchi et al. (1992) 14 months L frontal and R parieto-occipital lesions

(Weak association only)

Astrom et al. (1993) 51 month, 3 months, 3 years L anterior lesions

Hermann et al. (1993) 56 months, 46 months Proximity to L frontal pole

Iacobani et al. (1995) 51 month, 1 year R posterior and L anterior lesions

Ng et al. (1995) 1 year No relationship

Burvill et al. (1995) 4 months No relationship

Pohjasvaara et al. (1998) Between 3 and 4 months No relationship

McHale et al. (1998) 6 months R anterior lesions

Shimoda and Robinson (1999) 53 months

Between 3 and 6 months

Between 1 and 2 years

Proximity to L frontal pole

Proximity to R and L frontal poles

Proximity to R and L occipital poles


422 R. RAO

also suggest that depression is more likely to bepresent in people with carotid stenosis than inhealthy controls (Rao, 1998a). The observationsthat stress (Everson et al., 1997a) is a correlate andhopelessness (Everson et al., 1997b) an independentpredictor of carotid atherosclerosis, providesimportant pointers to a possible causal ratherthan an e�ectual relationship between mood andcerebrovascular disease.

Chronic changes in cerebral vasculature second-ary to hypertension may also result in frontal/subcortical brain dysfunction (Rao and Howard,1998). It is possible that this may be responsible forthe association between raised blood pressure anddepression observed in other studies (Rabkin et al.,1983; Fujikawa et al., 1994a; Krishnan et al.,1994a).

Although diabetes mellitus has shown a higherprevalence of depression with longer exposure tothis vascular risk factor (Holroyd and Duryee,1997), it is equally likely to be present in depressionwith and without SCI (Krishnan et al., 1994a).Little is known about the role of other vascular riskfactors such as atrial ®brillation in the pathogenesisof depression accompanying SCI.

CEREBROVASCULAR DISEASEACCOMPANYING DEPRESSION

The contribution of cerebrovascular disease hasalso been explored in studies of patients with anestablished diagnosis of depressive disorder, whereSCI may be present. In a study of patients meetingDSM III-R criteria for depression, SCI wasobserved in over 65% of participants (Fujikawaet al., 1993). In one of the largest magneticresonance imaging (MRI) studies, 244 patients(average age 34), with a wide variety of psychiatricdisorders were compared with 154 control subjects(Brown et al., 1992). The only group in whom asigni®cant di�erence was observed in the preva-lence of white matter hyperintensities (WMHI) inrelation to the control group was patients withmajor depression. However, age was noted to bethe largest contributing factor in that this di�erencewas not observed in a sub-group younger than 45.

Interest in the contribution of cerebrovasculardisease to late life depression developed as struc-tural brain imaging became more widely used, withthe relatively higher prevalence of cerebrovasculardisease noted in depression compared with non-depressed controls (Jacoby and Levy, 1980). As

most of these studies involved the use of MRI,white matter hyperintensities (WMHI) becameincreasingly relevant as correlates of depression(Zubenko et al., 1990; Sultzer et al., 1995).

One aspect of this became the subject of anumber of studies during the 1980s: namely, thecontribution of cerebrovascular disease to resistantdepression in patients referred for electroconvulsivetherapy (ECT) (Co�ey et al., 1987). In a study ofbrain imaging carried out in patients referred forECT, Co�ey et al. (1988) found that subcorticalwhite matter lesions seen onMRI were signi®cantlyassociated with lacunar infarcts of the basal gangliaand thalamus. In two other MRI studies, the samegroup found that over 50% of depressed patientsreferred for ECT had white matter lesions rated asmoderate or severe (Co�ey et al., 1989) and thatsubcortical white matter hyperintensities weremore common compared with an age/sex-matchedcontrol group (Co�ey et al., 1990). Subcorticalwhite matter disease in depression continues tocommand great interest, particularly in relation topathology in frontal/subcortical brain circuitry. Astudy comparing 67 elderly subjects with majordepression and 44 matched controls found thatdepressed patients were two and a half times aslikely to show subcortical white matter disease thancontrols (Zubenko et al., 1990).

Treatment resistant depression has also been thefocus of more recent studies. Following anobservation that treatment resistance may beassociated with subcortical cerebrovascular disease(Simpson et al., 1997a), Simpson et al. (1997b)studied 58 treatment resistant older people withDSM III-R depression. Lesions of the basalganglia, diabetes, lower mean arterial pressure,and hyperintensity of the pontine reticular for-mation correctly predicted 96% of patients withpoor outcome. A study of 39 elderly people withsevere depression by Hickie et al. (1995) also foundsubcortical hyperintensities on MRI to be associ-ated with a poorer response to treatment.

However, both these studies de®ned treatmentresistance according to global clinical impressionrather than clearly de®ned treatment regimens,prompting a further study of treatment resistancein 75 elderly people with DSM III-R majordepression. In this study, Simpson et al. (1998)found that neuropsychological impairment sugges-tive of frontal/subcortical dysfunction was morecommon in the treatment resistant group than incontrols. Resistance to antidepressant mono-therapy over 12 weeks was associated with a higher



prevalence of deep white matter and basal ganglialesions as well as frontal, extrapyramidal andpyramidal neurological signs. Severe deep WMHIare also known to in¯uence long-term survival. In atwo year longitudinal study of 60 older people withDSM III-R depression and no history of stroke, thepresence of severe WMHI predicted persistence ofdepression and relapse, with the median survivaltime in people with severe lesions being less thanhalf of that of those without such lesions (O'Brienet al., 1998).

Other studies have replicated the associationbetween WMHI and late life depression, assessingthese in elderly depressed patients matched with acontrol group. Greenwald et al. (1996) found moresevere subcortical hyperintensities in depressedpatients; Iadaka et al. (1996) found that depressedpatients showed more extensive periventricularhyperintensities in the frontal region/greaterseverity of hyperintensities in the putamen andglobus pallidus. As ischaemic cerebrovascularpathology is known to be closely linked withwhite matter pathology, the claim that depressionin later life is associated with WMHI even aftercontrolling for vascular risk factors (O'Brien et al.,1996a) may be ¯awed in that such lesions may berelated to SCI (Rao, 1996). There is, however, somelimited evidence for an association betweenWMHIand depression even after controlling for vascularrisk factors (O'Brien et al., 1996b).

Another approach to the study of cerebro-vascular disease in depression is the comparisonof cerebrovascular pathology seen on structuralimaging between early- and late-onset depression.A similar ®nding of an increased prevalence ofWMHI (Iadaka et al., 1996) and subcorticalperiventricular hyperintensities (Figiel et al., 1991;Salloway et al., 1996) in late-onset cases hasemerged.

Functional imaging represents a breakthroughin the assessment of cerebrovascular circulationand studies employing this tool have enabled therelationship between mood and regional blood¯ow to be examined. The most widely usedmethod of studying regional cerebral blood ¯ow(rCBF) is by means of single photon emissioncomputerized tomography (SPECT) using radio-labelled HMPAO. There has been some consist-ency in the association between regional blood¯ow abnormalities and depression (Mathew et al.,1980). The vast majority of studies using controlgroups have found that depression is stronglyassociated with decreased rCBF in either the

frontal or prefrontal cortex. This has beenobserved both bilaterally (Schlegel et al., 1989;Austin et al., 1992; Mayberg et al., 1994; Ito et al.,1996) or con®ned to the left hemisphere (Benchet al., 1993; Sackeim et al., 1993). One study foundleft frontal hyperperfusion (Uytdenhoef et al.,1983), but this ®nding has not been consistentlyreplicated.

DEPRESSION IN VASCULAR DEMENTIA

Depression accompanying vascular dementia wasthe subject of a number of studies during the mid1980s to mid 1990s, but has not drawn a great dealof interest since that time. These studies aredescribed in Table 3. The majority of studies todate have found a signi®cantly higher prevalenceof depression in vascular dementia than inAlzheimer's disease.

As seen from the table, the prevalence of majordepression as de®ned by DSM III, DSM III-R orResearch Diagnostic Criteria (RDC) ranges from6% to 45%. However, in only two of these studieswere groups equivalent in age, sex ratio andseverity of cognitive impairment (Sultzer et al.,1992; Cohen et al., 1993). The relationship betweenbrain imaging abnormalities and depression invascular dementia has been examined in a recentstudy by Barber et al. (1999), in which an associa-tion between frontal deep white matter (but notperiventricular) lesions and depression was noted.The same study also found that basal gangliahyperintensities were more frequent in vasculardementia than in Alzheimer's disease or controls. Itis possible that both of these pathologies areimplicated in the pathogenesis of mood disorderin vascular dementia.

The other important factor in¯uencing theinterpretation of these studies is the in¯uence ofcognitive impairment on mood. The term `pseudo-dementia' as applied to depression mimickingchronic organic brain disease came into popularuse in the 1970s (Wells, 1979), and refers to thein¯uence of mood disorder on cognitive state.Conversely, cognitive impairment is known toin¯uence mood state, and the term `depression ofdementia' has been applied to depressed mood (notresponsive to somatic treatment for depression) inthe setting of intellectual decline, whose severity isassociated with the severity of cognitive de®cit.This latter phenomenon has been noted in post-stroke depression (Andersen et al., 1996), but


424 R. RAO

Table 3. Studies of depression in vascular dementia

Author (year) Number in study (study population) Assessment of depression Prevalence of depression in vascular

dementia (Alzheimer's disease)

Bucht et al. (1984) 20 vascular dementia

19 Alzheimer's disease

20 controls

(Memory clinic)

DSM III

Major depression

30% (5%)

Reding et al. (1984) 16 vascular dementia


10 mixed dementia

(Memory clinic)

DSM III

Major depression

6% (19%)

Mixed dementia: 10%

Cummings et al. (1987) 15 vascular dementia


(Memory, neurology and old age

psychiatry clinics)

DSM III

Major depression

HRSD*

27% (0%)

Mean score 15.9 (10.7)

Fischer et al. (1990) 37 vascular dementia


(in-patients)

30 controls

HRSD* Mean score 10.3 (12.4)

Sultzer et al. (1992) 28 matched pairs with vascular

dementia/Alzheimer's disease

(Memory and neurology clinics)

NBRS{HRSD*

Increased guilt/somatic concern in

vascular dementia on NBRS


Cooper and Mungas

(1993)

502 vascular dementia


(Memory clinic attenders)

Clinical impression Early 27% (14%)

Middle 13% (7%)

Late 23% (7%)

Cohen et al. (1993) 135 vascular dementia


86 mixed dementia


Clinical impression Increased prevalence of depressed

mood in mixed dementia

Ballard et al. (1993) 9 vascular dementia


5 mixed dementia

(Consecutive day hospital referrals)

DSM III

Major depression

22% (20%)

Mixed dementia: 20%

Reichman and Coyne

(1995)

38 vascular dementia



DSM III-R

Major depression

29% (10%)

Ballard et al. (1996) 20 vascular dementia


(Memory clinic attenders, old age

psychiatry referrals)

RDC

Major depression

CSDD}

45% (17%)


Barber et al. (1999) 25 vascular dementia


26 controls

(Community referrals to old age

psychiatry/geriatric medicine and

dementia research clinic)

MADRS} No di�erence in mean MADRS

score between groups

*Hamilton Rating Scale for Depression.{Neurobehavioural Rating Scale.{National Institute of Neurological and Communicative Disorders and Stroke±Alzheimer's Disease and Related Disorders.}Montgomery and AÊ sberg Depression Rating Scale.}Cornell Scale for Depression in Dementia.



studies examining the relationship between intel-lectual function and mood listed in Table 3 foundno signi®cant association between score on themini mental state examination and major depres-sion or depression rating scale scores.

Although one study found depression afterstroke to be associated with lower mini mentalstate examination scores for up to one year(Downhill and Robinson, 1994), a communitystudy of stroke patients found a negative associa-tion between severity of cognitive impairment anddepressive symptoms on the Beck Depression Scaleand Present State Examination, revealing noassociation with major depression (House et al.,1990a).

In the context of cerebrovascular disease, therelationship between cognitive impairment anddepression is complex for several reasons. It islikely that (as discussed above) cognitive impair-ment and depression co-exist in the same personwith cerebrovascular disease. However, there isalso a longitudinal relationship known to existbetween the two factors. This is exempli®ed by theconcept of `pre-stroke depression', in which silentcerebrovascular pathology manifests as depressionprior to the onset of cognitive dysfunction inboth lacunar and cortical stroke (Colantonio et al.,1993).

FRONTAL/SUBCORTICAL DYSFUNCTION:A FINAL COMMON PATHWAY INDEPRESSION ACCOMPANYINGCEREBROVASCULAR DISEASE?

There is some suggestion from the evidence abovethat damage to anterior brain regions, theirprojections to subcortical structures and sub-cortical structures themselves, is associated with ahigher prevalence and severity of depression thanpathology in other brain areas. The suggestion ofcerebrovascular disease as a putative underlyingmechanism, however, may ignore the contributionof non-vascular processes.

This is borne out by studies in younger peoplewith depressive disorder. Baxter et al. (1989) foundthat younger depressed patients showed bilateralprefrontal glucose hypometabolism and thatdepression severity correlated with a decrease inmetabolic rate. Likewise, depression in schizo-phrenia is known to share a similar picture ofprefrontal hypometabolism (Cohen et al., 1989).Frontal lobe dysfunction is also a feature of

depression accompanying other neurological dis-orders. Depression has been associated with pre-frontal hypometabolism in both Parkinson'sdisease (Ring et al., 1994) and Huntington's chorea(Mayberg, 1993). Additionally, frontal hypo-perfusion has been noted in depression associatedwith epilepsy (Schmitz et al., 1997) and Alzheimer'sdisease (Hirono et al., 1998).

The neuroanatomical circuit most commonlyimplicated in depression is a loop comprising thedorsolateral prefrontal cortex, caudate nucleus,globus pallidus and thalamus (Fig. 1). Damage toone or more of these pathways may result indisruption to a number of neurochemical path-ways. Depression is thought to result from overallexcessive inhibitory input to the prefrontal cortex(Alexopoulos et al., 1997a). This is a rathersimplistic model, as other frontal/subcortical path-ways arising from orbitomedial and anteriorcingulate cortices have also been implicated indepression associated with cerebrovascular disease(Alexopoulos et al., 1997b). These, together withthe prefrontal dorsolateral cortex, have additionalconnections with the limbic system, subthalamicnuclei and substantia nigra. In addition to theneurochemical pathways already de®ned, this mayalso in¯uence noradrenergic, serotonergic anddopaminergic function (Cummings, 1993).

The key issue is whether, given that frontal/subcortical dysfunction has a consistent associationwith depression and that such dysfunction alsoexists in younger people/other neurological dis-orders without vascular risk factors, depressionassociated with cerebrovascular disease is a noso-logically distinct entity. Hickie and Scott (1998)have suggested that so-called `vascular depression'is characterized by observable psychomotorchange, subcortical neuropsychological signs, late-onset, reduced familial rates of depression, treat-ment-resistance, vascular risk factors and subcor-tical MRI changes. There is also evidence for theinvolvement of genetically determined vascular riskfactors such as Apolipoprotein E-4 (Krishnan et al.,1994b), but two more recent studies have notreplicated this ®nding when examining the associ-ation between ApoE-4 and late-onset depression(Forsell et al., 1997; Schmand et al., 1998).

CONCLUSIONS

Studies of post-stroke depression have shown aprevalence of up to 50% within the ®rst month of


426 R. RAO

stroke using standardized diagnostic instruments inhospitalized patients, remaining high for the ®rsttwo years after stroke. Although a lower prevalencehas been demonstrated in community studies, theprevalence still appears to be higher than in age/sex-matched community samples. Similarly, thecomparatively higher prevalence of both silentand symptomatic cerebrovascular disease inelderly depressed than in matched non-depressedpatients points to a strong contributory role forcerebrovascular pathology in the pathogenesisof depression in later life. The involvement offrontal lobe pathology in vascular dementia andAlzheimer's disease may explain di�erences in the

prevalence of depression in these dementias. Thiswould require further exploration. It would appearthat the in¯uence of generalized cognitive dysfunc-tion on depression in cerebrovascular disease is lessconvincing.

In considering the role of aetiological factorsin the pathogenesis of post-stroke depression, thereis better evidence for a relationship with factorssuch as time since stroke and lesion location thanwith those such as physical disability. MRI andfunctional imaging studies have largely supportedthe hypothesis that depression is associated withfrontal and subcortical lesions rather than a�ectingother regions. CT studies have only found a

Fig. 1. MRI axial section at level of corpus striatum showing frontal/subcortical structures and neurotransmitter pathwaysimplicated in depression associated with cerebrovascular disease. Scan also showed multiple lacunar infarcts and deep white/greymatter hyperintensities



consistent association with depression less thanthree months after stroke, mostly in hospitalizedpatients. It is likely that some of the di�erencesbetween studies exploring the relationship betweenproximity to the frontal pole and severity ofdepression are attributable to the fact that di�erentstudies represent the same cohort. This is clearlyshown by studies that have (Robinson and col-leagues) and have not (House, Sharpe and col-leagues) found a strong association. There are twopossible explanations for these ®ndings. Firstly, onegroup involved hospital in-patients and the otherassessed people on a community stroke register.Secondly, di�erent methods were employed inde®ning the location of lesions.

It is clear that a standardized quanti®cation ofparameters such as `distance from the frontal pole'is urgently needed before a more de®nitive state-ment can be made from structural brain imaging.

Taken as a whole, the available evidence suggeststhat depression accompanying cerebrovasculardisease is more likely to be associated withfrontal/subcortical dysfunction than with damageto other regional brain areas. Thus, clinical ®ndingsof psychomotor slowing, frontal-type cognitivede®cit, brain imaging evidence of subcorticalinfarction/white matter lesions and treatmentresistancemay not be surprising. The comparativelyhigh prevalence of depression associated withcerebrovascular disease may be explained by thefact that lacunar infarction accounts for up to 40%of anterior circulation ischaemic stroke (Lodderet al., 1994).

These are selectively subcortical in their distri-bution, sparing the cortex and subcortical arcuate`U' ®bres supplying the deeper gyri, and frequentlyinvolve the lenticulostriate end-arteries from thecarotid circulation (Ghika et al., 1990). Hyperten-sion is known to be associated with a similaroutcome in the absence of demonstrable infarction,by ischaemic demyelination of subcortical projec-tions from the frontal cortex (Cummings, 1994).Both processes may be clinically silent, as shown bya recent study that found a similar prevalence ofdepression in patients with carotid stenosis andthose with stroke (Rao, 1998b).

There is still considerable scope for examiningrisk factors, clinical and brain imaging features,treatment and outcome of depression associatedwith cerebrovascular disease in unbiased samples(such as the use of a community stroke register).Studies would also need to distinguish ®rst-everfrom recurrent stroke, as well as examining

di�erences between stroke sub-types. To be morevalid, imaging and mood assessment should ideallytake place within close temporal proximity.

The development of combined imaging tech-niques such as di�usion- and perfusion-weightedMRI (Philips, 1999) would allow both anatomicaland physiological correlates of depression to beassessed. Clinicopathological studies such as theuse of postmortem radio-ligand binding would giveclues regarding brain pharmacodynamics afterstroke, particularly in the case of the treatment ofpost-stroke depression. Lastly, the role of otherpathological mechanisms such as hypertension andtransient ischaemia requires exploration.

Depression accompanying stroke represents asizeable public health problem, particularly giventhat the presence of depression is also associatedwith higher mortality (Morris et al., 1993a, 1993b),even after controlling for sociodemographic andother vascular risk factors such as hypertension(Everson et al., 1998). Improved detection ofdepression, and referral from the settings ofprimary care, health care of the elderly andneurology is critical. Psychiatrists should have acentral role in this process, so that appropriatepharmacological and psychological treatment canbe implemented for a neurological disorder thataccounts for 3±4% of the National Health Servicebudget and is still conceived by physicians as an`understandable' (and therefore undertreated)cause of depression (Feibel and Springer, 1982).

ACKNOWLEDGEMENTS

I would like to thank Dr Robert Howard for hisadvice on earlier drafts of the manuscript andProfessor Alistair Macdonald for his supportduring its preparation.

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Cerebrovascular disease and late life depression: an age old association revisited