Evidence-Based Reviews

Late-life depression: Managing mood in patients with vascular disease

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Newly diagnosed major depressive disorder (MDD) in patients age ≥65 often has a vascular component. Concomitant cerebrovascular disease (CVD) does not substantially alter the management of late-life depression, but it may affect presenting symptoms, complicate the diagnosis, and influence treatment outcomes.

The relationship between depression and CVD progression remains to be fully explained, and no disease-specific interventions exist to address vascular depression’s pathophysiology. When planning treatment, however, one can draw inferences from existing studies. This article reviews the evidence on late-life depression accompanied by CVD and vascular risk factors, the “vascular depression” concept, and approaches to primary and secondary prevention and treatment.

CVD etiology of depression

Vascular depression constitutes a subgroup of late-life depression, usually associated with neuroimaging abnormalities in the basal ganglia and white matter on MRI.1 The cause of the structural brain changes is thought to be sclerosis in the small arterioles.2 These end-artery vessels may be particularly susceptible to pulse-wave changes caused by arterial rigidity or hypertension.

Alexopoulos et al1 and Krishnan et al3 proposed the concept of vascular depression on the premise that CVD may be etiologically related to geriatric depressive syndromes. Krishnan et al3 examined clinical and demographic characteristics of depressed elderly patients with vascular lesions on brain MRI. Those with clinically defined vascular depression experienced greater cognitive dysfunction, disability, and psychomotor retardation but less agitation and guilt feelings than patients with nonvascular depression.

Clinically, vascular depression resembles a medial frontal lobe syndrome, with prominent psychomotor retardation, apathy, and pronounced disability.4 Depression with vascular stigmata or cerebrovascular lesions on neuroimaging is characterized by poor outcomes, including persistent depressive symptoms, unstable remission, and increased risk for dementia.5,6 Patients with depression and subcortical vascular lesions have been shown to respond poorly to antidepressants.6

Impaired brain function also may predispose to geriatric depression, described by Alexopoulos as “depression-executive dysfunction syndrome of late life.”7 This common syndrome’s presentation—psychomotor retardation, lack of interest, limited depressive ideation and insight, and prominent disability—is consistent with its underlying abnormalities.5 Executive dysfunction also predicts limited response to antidepressants.8 Thus, the presentation and course of depression-executive dysfunction syndrome are consistent with those of subcortical ischemic depression.

Neuroimaging support

The vascular depression hypothesis is supported by observations related to MRI hyperintensities (HI):

  • CT and MRI studies identify HI in persons with late-life depression.
  • HI are associated with age and cerebrovascular risk factors.
  • Pathophysiologic evidence indicates that HI are associated with widespread diminution in cerebral perfusion.9

Neuropathologic correlates of HI are diverse and represent ischemic changes, together with demyelination, edema, and gliosis.9-11 The putative link between HI and vascular disease is central to the vascular theory of depression.

In a study of 56 patients age ≥50 meeting DSM-III-R criteria for MDD, Fujikawa et al12 reported “silent cerebral infarctions” on MRI in 60% of patients. High rates of abnormalities consistently have been observed on MRIs of older adults with MDD,10,11 and these can be classified into 3 types (Figure):

  • Periventricular HI are halos or rims adjacent to ventricles that in severe forms may invade surrounding deep white matter.
  • Deep white matter HI are single, patchy, or confluent foci observed in subcortical white matter.
  • Deep gray matter HI may be found, particularly in the basal ganglia, thalamus, and pons.9

These leukoaraiosis (or encephalomalacia) occur more frequently in patients with geriatric depression than in normal controls13 or patients with Alzheimer’s disease14 and may be comparable to the rate associated with vascular dementia.15 Observations in older adults11 suggest that diminished brain volume (especially in frontal regions) and HI may provide additive, albeit autonomous, pathways to late-life MDD. Vascular and nonvascular medical comorbidity contribute to HI, which in turn facilitate MDD.

Figure: Subcortical cerebrovascular disease in late-life depression

Structural MRIs of elderly adults with major depressive disorder consistently show high rates of brain abnormalities. Subcortical white matter abnormalities manifest as (1) periventricular hyperintensities [halos or rims adjacent to ventricles] and (2) deep white matter hyperintensities [single, patchy, or confluent foci]. Strategic subcortical gray matter infarctions (3) are observed, particularly in the basal ganglia, thalamus, and pons.

Bidirectional relationship

The relationship between depression and cardiovascular disease appears to be bidirectional:

  • Depression may be the first clinical expression of an underlying cardiovascular disease, which is expressed as an increased risk for ischemic events.
  • Depression itself, whether or not contributed by a silent cardiovascular disease, increases the risk of vascular damage, which in turn further promotes depression.
  • Vascular pathogenesis affecting heart and brain is likely to increase the risk for depression through a variety of mechanisms.


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