SPECIAL ARTICLE

Cerebrovascular Disease and Late-Life Depression

Helen C. Kales, M.D. Daniel F. Maixner, M.D. Alan M. Mellow, M.D., Ph.D.

Depression may occur as a result of vascular disease in a signicant subpopulation of elderly persons. Indirect support for vascular disease as an underlying etiology of late-life depression includes the high rate of depression in patients with vascular disease, the frequency of silent stroke and white-matter hyperintensities in late-life depression, and the lower frequency of positive family histories of depression in such patients. The authors evaluate the associations of late-life depression with cerebrovascular disease by reviewing the existing pathophysiological, prognosis, and treatment-outcomes studies. Findings are based on review of the current literature systematically searched in electronic databases. Review of such studies indicates a high frequency of depression in older patients with cardiovascular and cerebrovascular diseases, and the possibility of a bidirectional relationship between depression and vascular disease. Studies examining patients with vascular depression have found that such patients have different symptom proles, greater disability, and higher risk for poorer outcomes than those with nonvascular depression. Since the vascular depression hypothesis was proposed as a conceptual framework, evidence has accumulated that patients with vascular depression may have poorer outcomes that may be related in part to executive dysfunction and consequent disability. However, the association of vascular risk factors with geriatric depression has not been consistent in the studies to-date. Although an association between a subset of late-life depression and vascular disease is clear, signicant gaps remain in our understanding. Further research is needed to establish the precise linkages and interactions between vascular disease and geriatric depression. (Am J Geriatr Psychiatry 2005; 13:8898)

eriatric depression is a heterogeneous syndrome. Patients with incident depression late in

life have less likelihood of a positive family history of depression, more neuropsychological impairment,

Received March 24, 2004; revised June 1, June 6, 2004; accepted June 10, 2004. From the Section on Geriatric Psychiatry, University of Michigan, Ann Arbor, MI (HCK,AMM), the VA Serious Mental Illness Treatment Research and Evaluation Center (SMITREC), Department of Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI (HCK), the Geriatric Research Education and Clinical Center, Department of Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI (HCK), the Electroconvulsive Therapy Program and Treatment-Resistant Depression Clinic, University of Michigan, Ann Arbor, MI (DFM), and the Mental Health Service Line, Veterans Healthcare Network 11, Department of Veterans Affairs (AMM). Please send correspondence and reprint requests to Dr. Helen Kales, Psychiatry Service (116A), VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, MI 48105. e-mail: kales@umich.edu 2005 American Association for Geriatric Psychiatry

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a stronger relationship with the development of subsequent dementia, and a higher association with brain changes on magnetic resonance imaging (MRI).1 Just as psychosocial factors likely interact with underlying genetic factors in early-onset depression, it has been proposed that vascular lesions may increase older patients vulnerabilities toward the development of subsequent depression, particularly in the face of life-event stressors or changes in social support.2 The proposed link between depression and vascular disease is not new. Indeed, in 1905, Gaupps treatise Depressive States in Old Age discussed arteriosclerotic depressive disease.3 Baldwin and OBrien4 thus noted that, with the more recently proposed vascular depression hypothesis, that history has come full circle. Although we know that there is a strong association between vascular disease and late-life depression, the exact relationship remains somewhat ambiguous. Depression may itself predispose to vascular disease. Mechanisms proposed for the linkage between depression and cardiovascular disease have included 1) the effects of hypercortisolemia;5 2) immune activation; 3) depression-related platelet aggregation leading to increased thrombosis;5 4) depression-induced impairment of arterial endothelial functioning;6 or 5) abnormal folate or homocysteine metabolism.7 Although these mechanisms have been proposed to relate depression to cardiovascular disease, several could pertain to depressioncerebrovascular disease linkages, as well. The depression and vascular disease association could also represent the consequences of a shared underlying etiology, such as atherosclerosis. Atherosclerosis could lead to events such as cerebral lesions, which could trigger depression either through 1) disruption of critical pathways implicated in moodregulation; or 2) accumulation of lesions exceeding a certain threshold.1 Vascular disease may also be linked to depression via shared genetic risk factors. Although the apolipoprotein 4 (APOE 4) allele is an established risk factor for coronary artery disease and Alzheimer disease (AD), the nding of an increased frequency in late-life depression is less clear.8,9 However, other genetic factors may be shared between depression and vascular disease. Finally, nonbiological factors may be involved in the depressionvascular disease linkage, including the effects of depression on decreasing adherence to treatment regimens for vascular diseases such as hypertension, heart disease, or diabetes. Depression could lead to a worsening of underlying vascular disease through depression-mediated amotivation and consequent treatment non-adherence. It is also likely that a combination of biological and nonbiological factors are involved in the depressionvascular disease connection. This article evaluates the associations of late-life depression with cerebrovascular disease, reviewing the existing pathophysiological, prognosis, and treatment-outcome studies.

POSTSTROKE DEPRESSION
Major depression is common after stroke10 and has been found to be signicantly more likely after stroke than in other illnesses with comparable disability.11 Whyte and Mulsant12 recently reviewed the poststroke depression (PSD) literature and, noting the signicant methodologic difculties associated with most extant prevalence studies, found the peak prevalence of major depression to be 3 to 6 months after the stroke, with a range of prevalence during this time-frame of 9%34%. Studies from outpatient clinics and inpatient or rehabilitation settings demonstrated higher prevalence rates, perhaps reecting greater patient disability than in the community, where subjects have a wider range of stroke severity. Two factors that appear to be important in the development of PSD are lesion location and time from stroke. Some investigators,13,14 but not all,15,16 have found that patients with left-hemispheric lesions have an increased frequency and severity of depression than those with right-hemispheric lesions. Others have noted that it may be intrahemispheric position, rather than leftright laterality, inuencing the development of PSD.17 In terms of time-from-stroke, although the peak prevalence of PSD has been reported to be greatest 3 to 6 months after a stroke, the risk appears to remain high even 1 to 3 years later, with the greatest risk in the rst 2 years.12 A recent study18 conrmed this persistently elevated risk for depression in stroke survivors even 2 or more years after index stroke, which was independent of functional disability, cerebrovascular risk factors, and previous depressive symptoms.

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Pathophysiological Relationships Biological and psychosocial pathways. Although DSM-IV lists stroke as one of the few conditions directly causing depression, and PSD has been theorized to be the result of disrupted neural circuits involved in mood-regulation,13 the literature does not support a completely neurobiological conceptualization.12 Other risk factors may also play a role, including family or personal depression history,19 living alone,20 previous stroke,21 female sex,19,21,22 high school education,22 and life stressors.23 Previous reports24 have also noted that severity of disability after stroke was also predictive of depression, although, in Whyte et al.s study,18 disability did not mediate the link between stroke and depressive symptoms; disability may primarily be a risk factor for depression in the acute and subacute poststroke period. Ultimately, the development of PSD may depend on complex interactions of biological factors,25 including lesion size, site, and laterality; cerebral-hemispheric assymmetry; and time post-stroke; as well as family and personal history and psychosocial factors such as social support and life stressors. Prognosis PSD has been associated with: excess disability,26 poor rehabilitation outcomes,27 suicidality,28 and mortality.29 Dementia is also a frequent outcome of stroke. A recent study30 found that stroke signicantly increases a subjects risk of dementia, as compared with age- and sex-matched control subjects. Depression was not examined as a risk factor, so it remains unclear whether PSD increases the risk of eventual development of dementia. Treatment outcomes: PSD. Two randomized controlled trials of selective serotonin-reuptake inhibitors (SSRIs) in PSD have used standardized criteria for the diagnosis of depression.31,32 Robinson et al.31 studied patients with either DSM-IV major or minor depression with stroke within 6 months of the study and found that nortriptyline was superior to both uoxetine and placebo, and uoxetine was not signicantly different from placebo. In the other study,32 uoxetine was found to be superior to placebo in patients with major depression and stroke within 3 months of treatment. Neither study matched subjects for previous histories of depression or lesion location/type, and, as above, time from stroke is likely an important factor. Other treatment modalities that may be effective for PSD include electroconvulsive therapy (ECT),33 psychostimulants,34 and cognitivebehavioral therapy;35 however, such studies are limited. Prevention. Studies have also examined the prophylactic use of antidepressants after stroke to prevent PSD,3638 physical impairment,39 and mortality.40 Two of the three studies investigating the use of antidepressants to prevent PSD were positive, nding signicantly lower rates of development of PSD with nortriptyline or uoxetine37 (8% and 8%, versus 33% with placebo) and sertraline38 (10%, versus 30% with placebo). In one study,37 the authors reported an increase in the frequency and severity of depressive symptoms after stopping antidepressants, suggesting the need for extending prophylactic treatment. Palomaki et al.s study36 did not show that early initiation of antidepressant therapy with a tetracyclic antidepressant (mianserin) prevented the development of PSD, probably because the prevalence of such depression was low in their study sample. In Rasmussen et al.s study,38 a signicantly lower percentage of sertraline-treated patients were subsequently hospitalized for cardiovascular disease, as compared with placebo-treated patients (7% versus 22%), suggesting that SSRIs might reduce cardiovascular complications. A recent study39 found that antidepressant treatment within 1 month of stroke was associated with improvement in activities-of-daily-living impairment that was maintained signicantly longer than in a group who received later treatment. This nding suggests a time-related therapeutic window for the treatment of physical impairment associated with PSD. Finally, treatment with uoxetine or nortriptyline during the rst 6 months poststroke has been found to increase signicantly the survival of both depressed and nondepressed patients (68% survival on antidepressant versus 36% survival on placebo).40 Thus, current evidence suggests that prophylactic administration of antidepressants to stroke patients may prevent depression and may also decrease vascular complications and mortality. The mechanisms through which antidepressants affect vascular complications and mortality are unclear, but might in-

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clude antidepressants effects on increasing compliance with vascular-diseasepreventing regimens or pathophysiological mechanisms, including effects on serotonin-mediated platelet activation.5 higher prevalence of depressive disorders is also clearly compatible with the vascular depression hypothesis.50 Pathophysiological Relationships Biological pathways. The MRI lesions found in association with depression in late life include subcortical (periventricular and deep) white-matter and gray-matter hyperintensities.5153 Recently, it has been proposed that the term subcortical ischemic depression may be a more accurate representation of the disease process.54 Subcortical hyperintensities found in late-onset depression correlate with: psychomotor slowing,51,52,55 negative family history of depression,52 poor outcomes of depression,5557 functional impairment,58 executive dysfunction,55,5961 and other cognitive impairment.55,62,63 The frequency of periventricular WMHs appears comparable in elderly depressed and age-matched control subjects, but deep WMHs are increased.64,65 Those with lateonset depression also have been found to have more severe hyperintensity ratings in the deep white matter than those with early-onset depression;25,66 later onset of depression has also been found to be associated with left-sided white-matter lesions.25 Persistent depressive symptoms have also been associated with small basal ganglia lesions and large cortical white-matter lesions.67 Deep WMH, but not periventricular WMH or subcortical gray-matter hyperintensities, have been found to be signicantly associated with mortality in depressed older patients, after controlling for other potential confounders (medical comorbidity, gender, race, and age).68 A recent study found that the APOE 4 genotype was linked with the volume of subcortical gray-matter vascular lesions in older depressed, but not control subjects.69 Do WMHs have an underlying vascular etiology? Taylor et al.,70 using diffusion tensor imaging of the brain tissue of geriatric depressed and control subjects, found that WMHs showed evidence of damage to brain tissue structure in both groups. They suggested that WMHs have a vascular etiology, but that it is the location, volume, or broader effects on whitematter tracts that contribute to depression. Thomas et al.71 found that all deep WMHs in depressed subjects showed evidence of ischemic damage, versus less than one-third of these lesions in control subjects, a highly signicant difference. Although larger le-

VASCULAR DEPRESSION
Although depression associated with acute cerebrovascular events has been recognized for some time, more recent attention has been given to depression associated with chronic ischemic changes in the brain. Krishnan2 noted that early descriptions of depression secondary to arteriosclerosis, such as Gaupps,3 were based only on clinical evidence of cerebral-vascular damage, such as strokes. With the advent of MRI and other imaging techniques, demonstration of subtle invivo structural brain change became possible, and the linkage of late-onset depression with brain changes on MRI was noted beginning in the late 1980s. Several groups reported the frequent occurrence of whitematter hyperintensities (WMH) in late-onset depression.4143 Fujikawa et al.44 described the nding of silent stroke in 94% of patients with late-onset major depression, notably, in the absence of family history or psychosocial stressors.45 Krishnan and McDonald46 suggested that cerebrovascular disease contributed to the development of late-onset depression and demonstrated a return to the use of Gaupps term of arteriosclerotic depression. These lines of evidence led to the proposal of the vascular depression hypothesis by two groups of researchers1,47 in 1997. The vascular depression hypothesis (VDH), as proposed by Alexopoulos et al., describes depression with 1) a late age at onset (after age 65) or change in course after early onset; 2) persistent symptoms; and 3) the association of such depression with vascular disease or risk factors and diffuse or multifocal cerebrovascular lesions.1 Alexopoulos et al.48 noted the large amount of existing indirect support for the VDH, including: high rates of depression in patients with hypertension, diabetes, and coronary artery disease; the high rate of PSD; the frequency of silent stroke and WMHs in late-onset depression4245,49; and the infrequent family history of depression found in those with depression and silent stroke.45 A recent study nding that more severe atherosclerosis is signicantly associated with a

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sions were usually ischemic in both groups, they noted that the difference between depressed elderly and control subjects largely appeared in punctate lesions, which were predominantly ischemic in depressed elderly but not in control subjects. Other causes of deep WMHs in control subjects included demyelination and dilation of perivascular spaces. Ischemic deep WMHs were more frequently located in the dorsolateral prefrontal cortex of depressed subjects. How might such lesions cause depression? There are ve frontal subcortical systems connecting the frontal lobe to the basal ganglia; vascular disconnection of these frontal executive areas from input areas could result in changes in attention and cognition; vegetative and somatic symptoms; and mood, cognitive, and autonomic responses.72 Alexopoulos et al.1 have proposed two mechanisms for such disconnections: 1) small direct lesions might themselves disrupt critical brain pathways; or 2) an accumulation of lesions could eventually reach a threshold level, perhaps then conferring a predisposition to depression. In the latter case of the threshold hypothesis, nonbiological factors might be required to trigger depression in such vulnerable patients.1 Taylor et al.73 provided additional evidence for this vascular disconnection by use of MRI and statistical parametric mapping. They demonstrated that elderly depressed subjects exhibited WMHs in bilateral frontal and left parieto-temporal regions, whereas whitematter lesions in control subjects were more likely to occur only in parieto-temporal regions bilaterally. They further noted that frontal white-matter lesions occur in areas that may contain connecting whitematter tracts extending from inferior frontal regions toward the basal ganglia, and these lesions may represent a disruption of connectivity. Vascular Risk Factors Given the considerable evidence associating MRI changes with late-life depression, the association of WMHs and vascular risk factors,74 and the more limited evidence71 indicating that many such lesions are ischemic in nature, some investigators have suggested testing the relationship between vascular risk factors (VRFs) and late-life depression. VRFs include hypertension, atrial brillation, smoking, diabetes, and cardiovascular disease. Lyness et al.75 believe it is plausible that VRFs are associated with late-life depression, given that such VRFs increase with age and are associated with the development of small-vessel brain disease, which, in turn, is linked with late-life depression. However, studies testing this theory have been mixed in terms of clearly supporting such a link. In two studies examining patients with late-life major depression, VRFs that were dened by use of a stroke risk factor scale were not found to be signicantly associated with severity of depression,75 associated clinical features,76 or prognosis of late-life depression.76 A signicant association was found for VRF score and rst onset of depression after age 60.76 Two other studies examined VRFs in primary care patients, both cross-sectionally77 and longitudinally.78 In the rst study, VRFs were not signicantly linked to depression diagnosis or symptom severity. The second study found that baseline VRF severity was signicantly independently associated with depressive symptoms and diagnoses at 1-year follow-up, but this nding was no longer signicant after controlling for overall medical burden. In a study of geriatric rehabilitation patients,79 there was a signicant increase in depression frequency among patients without stroke as CVRF burden increased. A gender vascular condition interaction effect on mortality was also found in elderly women with depression.80 In a British cross-sectional study of Caribbean-born community elderly subjects, depression was found to be signicantly associated with stroke,81 but not individual vascular risk factors. A British prospective study of hypertensive patients82 found that incident depressive symptoms were signicantly associated with baseline smoker status, low serum cholesterol levels, poorer cognitive/executive functioning, female gender, and increasing age. However, depression was not signicantly associated with all other VRFs. Taking the use of VRFs as a proxy for vascular disease a step further, pooled data from two randomized double-blind studies were used to compare sertraline treatment for depression in patients with and without such vascular risk.83 The antidepressant effect of sertraline was not found to be signicantly affected by the presence of comorbid vascular illness (86% response in those with hypertension, 89% in those with cardiovascular illness, 77% in those with no vascular illness). These studies indicate that VRFs may not consis-

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tently serve as a proxy for actual vascular disease in a given patient. The lack of association of VRFs with depression found in some studies may be due to several factors. First, given the heterogeneity of geriatric depression, previous study of VRFs in older depressed subjects may have included large numbers of subjects without signicant vascular disease. Second, cross-sectional examination of psychiatric or primary care samples is limited because the model of vascular depression suggests that VRFs lead to depression via the development of small-vessel brain disease over time.75 Third, the only longitudinal primary care study78 included patients who were depressed at baseline, rather than solely detecting new cases over time. Fourth, older patients typically are being actively treated for vascular diseases such as hypertension; hence, their risk is being modied while under study.84 For example, although WMHs are associated with hypertension, pharmacological control of hypertension reduces WMH progression85 and so might also reduce the risk of depression. Also, VRFs examined have often been those used to assess stroke risk, and these might not be sensitive to more subtle cerebrovascular disease.86 Thus, depression may be more closely linked to underlying vascular disease actual vascular loadthan clinical risk factors would suggest.71 A recent study found that increases in WMH lesion volumes in those with late-life depression over a 2-year period were associated with diabetes mellitus, but not other vascular risk factors.87 The most recent longitudinal study found a positive association between baseline vascular burden and subsequent depressive symptoms in geriatric rehabilitation patients.88 Longitudinal study of populations with high levels of vascular disease/complications as well as depression, such as older patients with diabetes, may also improve our understanding of the relationship between vascular load and depression. Finally, the relationship between VRFs and development of neuropsychiatric symptoms likely depends not only on global effects on the brain but on whether or not certain brain regions are affected.54 Psychosocial Pathways There is limited research on psychosocial pathways as potential mechanisms of vascular depression. Oldehinkel et al.89 examined whether VRFs could be interpreted within the stress-vulnerability model of depression, comparing 83 patients with major or minor depression with 83 control subjects with respect to VRFs and the occurrence of stressful life events, longterm difculties, and neuroticism. VRFs were not associated with depression onset in this sample, and, unexpectedly, VRFs seemed to neutralize the depressogenic effect of stressful life events. The effect of vascular risk was signicantly stronger in depressive episodes not preceded by a life event. Additional studies are needed to examine the role of psychosocial stressors in the development of vascular depression. Such studies could draw on the cardiovascular disease literature, where evidence has been found for causal relationships between chronic stress, socioeconomic status, and social support and the development of coronary artery disease.90 Clinical Picture It has been proposed that the symptom picture seen in patients with vascular depression differs from that of non-vascular depression. In patients thought to have vascular depression, the following have been found: executive dysfunction, psychomotor retardation, limited depressive ideation, poor insight, and excess disability.1,48 Nebes et al.91 discovered that patients with depressive symptoms associated with deep WMHs had impaired motivation, concentration, and decision-making; notably, the relationship between deep WMHs and such symptoms was especially strong in those carrying the APOE 4 allele. A recent study of depressed elderly subjects54 (N139) found that 54% met criteria for subcortical ischemic depression; such depression was most strongly correlated with age, but also with symptoms of lassitude and history of hypertension. Executive dysfunction involving compromised integrity of frontal structures and subcortical connections (striatofrontal dysfunction92) manifests as impairments in planning, organization, and abstraction. Lockwood et al.93 showed that patients with late-life depression have signicant impairments in executive functioning. Although it is not the only cause of executive dysfunction, ischemic brain damage is thought to be a major potential contributor to such pathology.94 A recent study of older, community African Americans found that, after controlling for age and education, VRF score was signicantly associated with frontal-executive impairment.95 Study of

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patients with MRI-dened subcortical ischemic vascular disease (SIVD) found that this group was signicantly more likely to be depressed than patients with other types of stroke, and that the main cognitive domain that differentiated SIVD patients from those without SIVD was executive dysfunction (51% versus 39%).96 Other disorders causing executive dysfunction include those affecting subcortical structures, such as Parkinson disease, and other causes involving degeneration of the basal ganglia. over (N20). Notably, this study sample also included small numbers of patients with late-onset depression (N15). A recent placebo-controlled study did not nd a signicant difference in response to sertraline between groups of depressed older patients with either low or high levels of subcortical hyperintensities.110 The authors noted that the lack of ndings may have been related to a small sample, a lack of robust drug effect overall, a low number of patients with high subcortical hyperintensity severity, and use of a visual rating scale to measure hyperintensities. In Simpson et al.s study,55 total white-matter load was not associated with poor treatment outcomes; however, patients with lesions in the pontine reticular formation, basal ganglia, and deep white matter had an especially poor response to pharmacotherapy. The latter ndings suggest that the association between subcortical hyperintensities and treatment response may be related to lesion location. A subsequent study111 found that greater progression of WMH volume was associated with poor outcomes of geriatric depression. In this study, a 1% increase in WMH volume was associated with a 7% increased risk of poor outcome. Although this study appeared to validate the vascular depression hypothesis, notably, the measure of comorbidity used did not capture subtler distinctions (mean blood pressure over time, cigarette use) that may have affected WMH progression. There have been several studies examining outcomes of ECT in those with vascular depression. Two studies reported poorer response,56,57 whereas one noted good response.112 Steffens et al.57 reported that those with depression and severe subcortical graymatter hyperintensities had a poorer response to ECT as measured by Clinical Global Impression severity. ECT may also be more likely to precipitate delirium in those with extensive subcortical hyperintensities.113 The treatments needed for vascular depression and striatofrontal dysfunction may be different from current standard antidepressant treatments. Alexopoulos94 has noted that such treatments might include drugs that modify neurotransmitters involved in striatofrontal pathways (e.g., dopamine, acetylcholine, and opiates) such as dopamine D3-receptor agonists, cholinesterase inhibitors, and opiate-receptor

PROGNOSIS
Development of Dementia Although WMH disease is associated with cognitive impairment,55 longitudinal studies have not always reported consistent relationships between progression of WMHs and cognitive decline.97 Patients with executive dysfunction and depression as a result of cerebrovascular pathology may develop dementia over time.98 A 25-year follow-up of British elderly patients with depression, versus control subjects, found that 14% of depressed patients and no control subjects had dementia at follow-up; vascular dementia was the most common dementia type.99 The French Personnes Age es (PAQUID) study found that in a subgroup of men in whom vascular disease led to depressive symptoms, depression later progressed into dementia.100 The pathway from vascular disease to depression and onto dementia may not be direct and sequential, but, instead, bidirectional, in that depression may itself increase the risk of vascular diseases.101 Treatment Outcomes Studies of patients with executive dysfunction102105 or vascular depression52,55,56,106108 indicate that these patients have a poorer and delayed response to antidepressants, decreased long-term recovery, increased relapse risk, and more adverse events and disability. The single study109 that found no difference in treatment response for subjects with depression with (N16) or without (N41) MRIconrmed vascular changes was notably a mixed-age sample, where a minority of patients were age 60 or

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agonists and antagonists, as well as medications that may improve executive dysfunction (modanil). Considering the evidence that vascular disease is one of the strongest potential contributors to striatofrontal dysfunction, the future treatment of vascular depression may also involve primary prevention of vascular disease.94 The latter would entail the continued emphasis on advising the discontinuation of smoking and excessive drinking, given their effects on the vascular system, as well as modication of treatable vascular risk factors (e.g., blood pressure, cholesterol level, etc.). The prevention of future vascular damage through the use of antiplatelet agents and cytoprotective agents (e.g., calcium-channel blockers, antioxidants, etc.) may also be important in the treatment of vascular depression. To date, there is one study114 examining the use of the calcium-channel blocker, nimodipine, as an augmenting agent in the treatment of vascular depression. The investigators noted that vascular injury can be caused by calcium inux into neurons deprived of their blood ow or increased glutamatergic excitotoxicity mediated by such calcium inux. They theorized that, in addition to standard antidepressant treatment, the prevention of such neuronal injury could lead to improved outcomes of depression. Patients with vascular depression were treated with antidepressants at standard doses; patients were also randomized to nimodipine or an inactive comparator (Vitamin C). Patients whose treatment was augmented by nimodipine experienced greater and more rapid improvements in depressive symptoms, a higher rate of full remission, and a fourfold lower risk of recurrence among treatment responders. The authors noted that their results supported the vascular depression hypothesis and suggested that nimodipine may have prevented additional/ongoing neuronal injury from cerebrovascular disease through calcium blockade, which, in turn, may have affected the course of vascular-mediated depression. It is also theoretically possible that drugs such as memantine could be of benet in vascular depression through blockade of glutamatergic excitotoxicity, but this idea remains unstudied. Other strategies for the treatment of vascular depression may include nonpharmacological approaches for executive dysfunction. Problem-solving therapy (PST) may be particularly useful for those with late-life depression with executive dysfunction.115 Specically, it was proposed that PST with components of behavioral activation, increased exposure to positive events, and remediation of communication decits might potentially target symptoms, including lack of interest in activities, diminished insight, and substantial disability.104,105 These investigators then compared PST to supportive therapy in elderly patients with major depression and executive dysfunction. PST was more effective than supportive therapy in leading to remission of depression and decreasing disability.115

RESEARCH DIRECTIONS
Since the vascular depression hypothesis was proposed, evidence has accumulated that patients with vascular depression may have poorer outcomes, in part, related to executive dysfunction and consequent disability. Although an association between late-life depression and vascular disease is clear, signicant gaps remain in our understanding. Important areas for future study include examination of the association of VRFs and depression in populations with high vascular risk (e.g., patients with diabetes mellitus); clarication of the neurobiological changes involved; assessment of the relationship between vascular depression and the development of vascular dementia; study of pharmacological interventions aimed at targeting implicated critical brain pathways; evaluation of the treatment of vascular risk factors on the course of vascular depression; and further research on psychosocial interventions targeting executive dysfunction in patients with vascular depression. Clearly, additional studies are also needed to examine the role of psychosocial stressors in the development of vascular depression. Such studies could draw on the literature on psychosocial risk factors in the development of cardiovascular disease. This research was supported by a V A Health Services Research and Development Career Development Award from the Department of Veterans Affairs.

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References
1. Alexopoulos GS, Meyers BS, Young RC, et al: Vascular depression hypothesis. Arch Gen Psychiatry 1997; 54:915922 2. Krishnan KRR: Biological risk factors in late life depression. Biol Psychiatry 2002; 52:185192 3. Gaupp R: Depressive states in old age. (Classic Text 42, orig. published 1905). Historical Psychiatry 2000; 11:213225 4. Baldwin RC, OBrien J: Vascular basis of late-onset depressive disorder. Br J Psychiatry 2002; 180:157160 5. Musselman DL, Evans DL, Nemeroff CB: The relationship of depression to cardiovascular disease. Arch Gen Psychiatry 1998; 55:580592 6. Broadley AJM, Korszun A, Jones CJH, et al: Arterial endothelial function is impaired in treated depression. Heart 2002; 88:521 523 7. Godfrey PSA, Toone BK, Carney MW, et al: Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990; 336:392395 8. Krishnan KRR, Tupler LA, Ritchie JC, et al: Apolipoprotein E-4 frequency in geriatric depression. Biol Psychiatry 1996; 40:69 71 9. Steffens DC, Norton MC, Hart AD, et al: Apolipoprotein E genotype and major depression in a community of older adults. Psychol Med 2003; 33:541547 10. Burvill PW, Johnson GA, Jamrozik K, et al: Prevalence of depression after stroke: The Perth Community Stroke Study. Br J Psychiatry 1995; 166:320327 11. Folstein MF, Maiberger R, McHugh PR: Mood disorder as a specic complication of stroke. J Neurol Neurosurg Psychiatry 1977; 40:10181020 12. Whyte EM, Mulsant BH: Poststroke depression: epidemiology, pathophysiology, and biological treatment. Biol Psychiatry 2002; 52:253264 13. Robinson RG, Kubos KL, Starr LK, et al: Mood disorders in stroke patients: importance of location of lesion. Brain 1984; 107:81 93 14. Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 1987; 110:10451059 15. Schwartz JA, Speed NM, Brunberg JA, et al: Depression in stroke rehabilitation. Biol Psychiatry 1993; 33:694699 16. Agrell B, Dehlin O: Depression in stroke patients with left and right hemisphere lesions: a study in geriatric rehabilitation inpatients. Aging 1994; 6:4956 17. Gordon WA, Hibbard MR: Poststroke depression: an examination of the literature. Arch Phys Med Rehabil 1997; 78:658663 18. Whyte EM, Mulsant BH, Vanderbilt J, et al: Depression after stroke: a prospective epidemiological study. J Am Geriatr Soc 2004; 52:774778 19. Morris PL, Robinson RG, Raphael B: Prevalence and course of depressive disorders in hospitalized stroke patients. International Journal of Psychiatric Medicine 1990; 20:349364 20. Provinciali L, Coccia M: Poststroke and vascular depression: a critical review. Neurol Sci 2002; 22:417428 21. Andersen G, Vestergaard K, Ingermann-Nielsen M, et al: Risk factors for poststroke depression. Acta Psychiatr Scand 1995; 92:193198 22. Paolucci S, Antonucci G, Pratesi L, et al: Poststroke depression and its role in rehabilitation of inpatients. Arch Phys Med Rehabil 1999; 80:985990 23. Bush BA: Major life events as risk factors for poststroke depression. Brain Inj 1999; 13:131137 24. Burvill P, Johnson G, Jamrozik K, et al: Risk factors for poststroke depression. Int J Geriatr Psychiatry 1997; 12:219226 25. Tupler LA, Krishnan KRR, McDonald WM, et al: Anatomic location and laterality of MRI signal hyperintensities in late-life depression. J Psychosom Res 2002; 53:665676 26. Singh A, Black SE, Herrmann N, et al: Functional and neuroanatomic correlations in poststroke depression: The Sunnybrook Stroke Study. Stroke 2000; 31:637644 27. Gillen R, Tennen H, McKee TE, et al: Depressive symptoms and history of depression predict rehabilitation efciency in stroke patients. Arch Phys Med Rehabil 2001; 82:16451649 28. Kishi Y, Kosier JT, Robinson RG: Suicidal plans in patients with acute stroke. J Nerv Ment Dis 1996; 184:274280 29. House A, Knapp P, Bamford J, et al: Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001; 32:696701 30. Ivan CS, Seshadri S, Beiser A, et al: Dementia after stroke: The Framingham study. Stroke 2004; 35:15 31. Robinson RG, Schultz SK, Castillo C, et al: Nortriptyline versus uoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry 2000; 157:351359 32. Wiart L, Petit H, Joseph PA, et al: Fluoxetine in early poststroke depression: a double-blind, placebo-controlled study. Stroke 2000; 31:18291832 33. Murray GB, Shea V, Conn DK: Electroconvulsive therapy for poststroke depression. J Clin Psychiatry 1986; 47:258260 34. Grade C, Redford B, Chrostowski J, et al: Methylphenidate in early poststroke recovery: a double-blind, placebo-controlled study. Arch Phys Med Rehabil 1998; 79:10471050 35. Hibbard MR, Grober SE, Gordon WA, et al: Modication of cognitive psychotherapy for the treatment of poststroke depression. Behavior Therapist 1990; 13:1517 36. Palomaki H, Kaste M, Berg A, et al: Prevention of poststroke depression: 1-year randomized, placebo-controlled, double-blind trial of mianserin, with 6-month follow-up after therapy. J Neurol Neurosurg Psychiatry 1999; 66:490494 37. Narushima K, Kosier JT, Robinson RG: Preventing poststroke depression: a 12-week, double-blind, randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 2002; 190:296303 38. Rasmussen A, Lunde M, Loldrup-Poulsen D, et al: A double-blind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics 2003; 44:216221 39. Narushima K, Robinson RG: The effect of early versus late antidepressant treatment on physical impairment associated with poststroke depression: is there a time-related therapeutic window? J Nerv Ment Dis 2003; 191:645652 40. Jorge RE, Robinson RG, Arndt S, et al: Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry 2003; 160:18231829 41. Coffey CE, Figiel GS, Djang WT, et al: Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects. Am J Psychiatry 1990; 147:187189 42. Krishnan KRR, Goli V, Ellinwood EH, et al: Leukoencephalopathy in patients diagnosed as major depressive. Biol Psychiatry 1988; 23:519522 43. Figiel GS, Krishnan KRR, Doraiswamy PM, et al: Subcortical hyperintensities on brain magnetic resonance imaging: a comparison between late-age onset and early-onset elderly depressed subjects. Neurobiol Aging 1991; 12:245247

96

Am J Geriatr Psychiatry 13:2, February 2005

Kales et al.
44. Fujikawa T, Yamawaki S, Touhouda Y. Incidence of silent cerebral infarction in patients with major depression. Stroke 1993; 24:16311634 45. Fujikawa T, Yamawaki S, Touhouda Y: Background factors and clinical symptoms of major depression with silent cerebral infarction. Stroke 1994; 25:798801 46. Krishnan KRR, McDonald WM: Arteriosclerotic depression. Med Hypotheses 1995; 44:111115 47. Krishnan KRR, Hays JC, Blazer DG: MRI-dened vascular depression. Am J Psychiatry 1997; 154:497501 48. Alexopoulos GS, Meyers BS, Young RC, et al: Clinically dened vascular depression. Am J Psychiatry 1997; 154:562565 49. Coffey CE, Figiel GS, Djang WT, et al: White-matter hyperintensity on magnetic resonance imaging: clinical and neuroanatomic correlates in the depressed elderly. J Neuropsychiatry Clin Neurosci 1989; 1:135144 50. Tiemeier H, van Dijck W, Hofman A, et al: Relationship between atherosclerosis and late-life depression. Arch Gen Psychiatry 2004; 61:369376 51. Simpson S, Baldwin RC, Jackson A, et al: Is the clinical expression of late-life depression inuenced by brain changes? MRI subcortical neuroanatomical correlates of depressive symptoms. Int Psychogeriatr 2000; 12:425434 52. Hickie I, Scott E, Mitchell P, et al: Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic signicance in patients with severe depression. Biol Psychiatry 1995; 37:151160 53. Hickie I, Scott E, Wilhelm K, et al: Subcortical hyperintensities on magnetic resonance imaging in patients with severe depression: a longitudinal evaluation. Biol Psychiatry 1997; 42:367374 54. Krishnan KRR, Taylor WD, McQuoid DR, et al: Clinical characteristics of magnetic resonance imaging-dened subcortical ischemic depression. Biol Psychiatry 2004; 55:390397 55. Simpson SW, Jackson A, Baldwin RC, et al: Subcortical hyperintensities in late-life depression: acute response to treatment and neuropsychological impairment. Int Psychogeriatr 1997; 9:257 275 56. Simpson S, Baldwin RC, Jackson A, et al: Is subcortical disease associated with a poor response to antidepressants? neurological, neuropsychological, and neuroradiological ndings in late-life depression. Psychol Med 1998; 28:10151026 57. Steffens DC, Conway CR, Dombeck CB, et al: Severity of subcortical gray-matter hyperintensity predicts ECT response in geriatric depression. J ECT 2001; 17:4549 58. Steffens DC, Bosworth HB, Provenzale JM, et al: Subcortical white-matter lesions and functional impairment in geriatric depression. Depress Anxiety 2002; 15:2328 59. Salloway S, Malloy P, Kohn R, et al: MRI and neuropsychological differences in early- and late-life-onset geriatric depression. Neurology 1996; 46:15671574 60. Lesser IM, Boone KB, Mehringer CM, et al: Cognition and whitematter hyperintensities in older depressed patients. Am J Psychiatry 1996; 153:12801287 61. Kramer-Ginsberg E, Greenwald BS, Krishnan KRR, et al: Neuropsychological functioning and MRI signal hyperintensities in geriatric depression. Am J Psychiatry 1999; 156:438444 62. Steffens DC, MacFall JR, Payne ME, et al: Grey-matter lesions and dementia. Lancet 2000; 356:16861687 63. Harrell LE, Duvall E, Folks DG, et al: The relationship of highintensity signals on magnetic resonance images to cognitive and psychiatric state in Alzheimers disease. Arch Neurol 1991; 48:11361140 64. Rabins PV, Pearlson GD, Aylward E, et al: Cortical magnetic resonance imaging changes in elderly inpatients with major depression. Am J Psychiatry 1991; 148:617620 65. OBrien J, Desmond P, Ames D, et al: A magnetic resonance imaging study of white-matter lesions in depression and Alzheimers disease. Br J Psychiatry 1996; 168:477485 66. deGroot JC, de Leeuw FE, Oudkerk M, et al: Cerebral white-matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000; 57:10711076 67. Steffens DC, Krishnan KRR, Crump C, et al: Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. Stroke 2002; 33:16361644 68. Levy RM, Steffens DC, McQuoid DR, et al: MRI lesion severity and mortality in geriatric depression. Am J Geriatr Psychiatry 2003; 11:678682 69. Steffens DC, Trost WT, Payne ME, et al: Apolipoprotein-E genotype and subcortical lesions in older depressed patients and control subjects. Biol Psychiatry 2003; 54:674681 70. Taylor WD, Payne ME, Krishnan KRR, et al: Evidence of whitematter tract disruption in MRI hyperintensities. Biol Psychiatry 2001; 50:179183 71. Thomas AJ, OBrien JT, Davis S, et al: Ischemic basis for deep white-matter hyperintensities in major depression: a neuropathological study. Arch Gen Psychiatry 2002; 59:785792 72. Tekin S, Cummings JL: Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res 2002; 53:647654 73. Taylor WD, MacFall JR, Steffens DC, et al: Localization of ageassociated white-matter hyperintensities in late-life depression. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:539544 74. Fazekas F, Niederkorn K, Schmidt R, et al: White-matter signal abnormalities in normal individuals: correlation with carotid ultrasonography, cerebral blood ow measurements, and cerebrovascular risk factors. Stroke 1988; 19:12851288 75. Lyness JM, Caine ED, Cox C, et al: Cerebrovascular risk factors and later-life major depression. Am J Geriatr Psychiatry 1998; 6:513 76. Miller MD, Lenze EJ, Dew MA, et al: Effect of cerebrovascular risk factors on depression treatment outcome in later life. Am J Geriatr Psychiatry 2002; 10:592598 77. Lyness JM, Caine ED, King DA, et al: Cerebrovascular risk factors and depression in older primary care patients. Am J Geriatr Psychiatry 1999; 7:252258 78. Lyness JM, King DA, Conwell Y, et al: Cerebrovascular risk factors and 1-year depression outcome in older primary care patients. Am J Psychiatry 2000; 157:14991501 79. Mast BT, MacNeill SE, Lichtenberg PA: Poststroke and clinicallydened vascular depression in geriatric rehabilitation patients. Am J Geriatr Psychiatry 2004; 12:8492 80. Steffens DC, Levy RM, Wagner R, et al: Sociodemographic and clinical predictors of mortality in geriatric depression. Am J Geriatr Psychiatry 2002; 10:531540 81. Stewart R, Prince M, Richards M, et al: Stroke, vascular risk factors, and depression. Br J Psychiatry 2001; 178:2328 82. Cervilla J, Prince M, Rabe-Hesketh S: Vascular disease risk factors as determinants of incident depressive symptoms: a prospective, community-based study. Psychol Med 2004; 34:635641 83. Krishnan KRR, Doraiswamy PM, Clary CM: Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline. Prog Neuropsychopharmacol Biol Psychiatry 2001; 25:247361 84. Hickie I, Simons L, Naismith S, et al: Vascular risk to late-life depression: evidence from a longitudinal community study. Aust N Z J Psychiatry 2003; 37:6265

Am J Geriatr Psychiatry 13:2, February 2005

97

Cerebrovascular Disease and Depression

85. Dufouil C, de Kersaint-Gilly A, Besancon V, et al: Longitudinal study of blood pressure and white-matter hyperintensities. Neurology 2001; 56:921926 86. Thomas AJ, Kalaria RN, OBrien JT: Depression and vascular disease: what is the relationship? J Affect Disord 2004; 79: 8195 87. Taylor WD, MacFall JR, Provenzale JM, et al: Serial MR imaging of volumes of hyperintense white-matter lesions in elderly patients: correlation with vascular risk factors. Am J Roentgenol 2003; 181:571576 88. Mast BT, Neufeld S, MacNeill SE, et al: Longitudinal support for the relationship between vascular risk factors and late-life depressive symptoms. Am J Geriatr Psychiatry 2004; 12:93101 89. Oldehinkel AJ, Ormel J, Brilman EI, et al: Psychosocial and vascular risk factors of depression in later life. J Affect Disord 2003; 74:237246 90. Strike PC, Steptoe A: Psychosocial factors in the development of coronary artery disease. Prog Cardiovasc Dis 2004; 46:337347 91. Nebes RD, Vora IJ, Meltzer CC, et al: Relationship of deep whitematter hyperintensities and apolipoprotein-E genotype to depressive symptoms in older adults without clinical depression. Am J Psychiatry 2001; 158:878884 92. Tranel D, Anderson SW, Benton A: Development of the concept of executive function and its relationship to frontal lobes, in Handbook of Neuropsychology, Vol. 9. Edited by Boller F, Spinnler H, Hendler JA. Amsterdam, Netherlands, Elsevier, 1994, pp 125148 93. Lockwood KA, Alexopoulos GS, van Gorp WG: Executive dysfunction in geriatric depression. Am J Psychiatry 2002; 159: 11191126 94. Alexopoulos GS: New concepts for prevention and treatment of late-life depression. Am J Psychiatry 2001; 158:835838 95. Pugh KG, Kiely DK, Milberg WP, et al: Selective impairment of frontal-executive cognitive function in African Americans with cardiovascular risk factors. J Am Geriatr Soc 2003; 51:1439 1444 96. Pohjasvaarra T, Mantyla R, Ylikoski R, et al: Clinical features of MRI-dened subcortical vascular disease. Alzheimer Dis Assoc Disord 2003; 17:236242 97. Schmidt R, Fazekas F, Kapeller P, et al: MRI white-matter hyperintensities: three-year follow-up of the Austrian Stroke Prevention Study. Neurology 1999; 53:132139 98. Steffens DC, Taylor WD, Krishnan KR: Progression of subcortical ischemic disease from vascular depression to vascular dementia. Am J Psychiatry 2003; 160:17511756 99. Brodaty H, Luscombe G, Anstey KJ, et al: Neuropsychological performance and dementia in depressed patients after 25-year follow-up: a controlled study. Psychol Med 2003; 33:12631275 100. Fuhrer R, Dufouil C, Dartigues JF, et al: Exploring sex differences in the relationship between depressive symptoms and dementia incidence: prospective results from The PAQUID Study. J Am Geriatr Soc 2003; 51:10551063 101. Alexopoulos GS: Vascular disease, depression, and dementia. J Am Geriatr Soc 2003; 51:11781180 102. Kalayam B, Alexopoulos GS: Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry 1999; 56:713718 103. Alexopoulos GS, Meyers BS, Young RC, et al: Executive dysfunction and long-term outcomes of geriatric depression. Arch Gen Psychiatry 2000; 57:285290 104. Kiosses DN, Alexopoulos GS, Murphy C: Symptoms of striatofrontal dysfunction contribute to disability in geriatric depression. Int J Geriatr Psychiatry 2000; 15:992999 105. Kiosses DN, Klimstra S, Murphy C, et al: Executive dysfunction and disability in elderly patients with major depression. Am J Geriatr Psychiatry 2001; 9:269274 106. Fujikawa T, Yokota N, Muraoka M, et al: Response of patients with major depression and silent cerebral infarction to antidepressant drug therapy, with emphasis on central nervous system adverse reactions. Stroke 1996; 27:20402042 107. OBrien J, Ames D, Chiu E, et al: Severe deep white-matter lesions and outcome in elderly patients with major depressive disorder: a follow-up study. BMJ 1998; 317:982984 108. Yanai I, Fujikawa T, Horiguchi J, et al: The three-year course and outcome of patients with major depression and silent cerebral infarction. J Affect Disord 1998; 47:2530 109. Krishnan KRR, Hays JC, George LK, et al: Six-month outcomes for MRI-related vascular depression. Depress Anxiety 1998; 8:142146 110. Salloway S, Boyle PA, Correia S, et al: The relationship of MRI subcortical hyperintensities to treatment response in a trial of sertraline in geriatric depressed outpatients. Am J Geriatr Psychiatry 2002; 10:107111 111. Taylor WD, Steffens DC, MacFall JR, et al: White-matter hyperintensity progression and late-life depression outcomes. Arch Gen Psychiatry 2003; 60:10901096 112. Coffey CE, Figiel GS, Djang WT, et al: Leukoencephalopathy in elderly depressed patients referred for ECT. Biol Psychiatry 1988; 24:143161 113. Figiel GS, Coffey CE, Djang WT, et al: Brain magnetic resonance imaging ndings in ECT-induced delirium. J Neuropsychiatry Clin Neurosci 1990; 2:5358 114. Taragano FE, Allegri R, Vicario A, et al: A double-blind, randomized clinical trial assessing the efcacy and safety of augmenting standard antidepressant therapy with nimodipine in the treatment of vascular depression. Int J Geriatr Psychiatry 2001; 16:254260 115. Alexopoulos GS, Raue P, Area n P: Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry 2003; 11:4652

98

Am J Geriatr Psychiatry 13:2, February 2005