Vascular Depression

Vascular depression is defined by Miller et al. (1992) [49] as: ``the presence of a vascular score in the range 1-4 ^3.1 on the Cumulative Illness Rating Scale in patients aged 60 years or older with a first onset of depression.'' It is hypothesised that elderly subjects presenting with late-onset depression and vascular risk factors have co-morbidity of depression with vascular disease. This form of depression is by definition late-onset, although in order to avoid recruitment problems, the age threshold chosen is often lower than the recommended 60 years [50]. Various factors suggest that this form of depression has a different cause (namely age-related pathology) than earlier-onset depression. The older the subject at first onset, the smaller the likelihood of a familial history of the disease. Secondly, subjects presenting with vascular depression typically show greater cognitive dysfunction, disability, retardation and anhedonia, and less agitation, guilt and psychosis than non-vascular depressives [51,52].

It is currently unknown whether the vascular disease causes the depression or vice versa, or whether both have a common aetiology. As a consequence, the misdiagnosis of depression as dementia where there are confounding vascular problems is common. Several groups have attempted to resolve this problem, with the evidence pointing to vascular disease resulting in the depression. Taragano et al. (2001) [53] treated vascular depression subjects undergoing anti-depressant therapy with calcium channel blockers (a putative treatment for cerebrovascular disease), which resulted in a greater reduction in both the severity and rate of recurrence of depression than in the group only treated with anti-depressants and a placebo. Thomas et al. (2001) [54] performed a post mortem investigation into atheromatous change in the cerebral vasculature of vascular depressives and non-depressed controls. They found that the depressed subjects had atherosclerotic disease in large and medium vessels, but microvascular disease was absent. In addition, there was no Alzheimer's Disease-like pathology (amyloid plaques and neurofibrillary tangles; see section 3.3) or Lewi Bodies. Tiemeier et al. (2002) [55] showed using Doppler ultrasonography in subjects from the Rotterdam elderly population study that those subjects with depressive symptoms had reduced middle cerebral arterial blood velocity and lower CO$_2$ vasomotor reactivity. They claim that this reduced reactivity is a possible cause of depressive symptoms, whereas the reduced flow seen might be a consequence of reduced demand. Naish et al. (2002) [56] showed that compared with controls, depressed patients had decreased arterial vascular compliance, indicative of vascular disease, which correlated with the severity of the depression.

Another indicator of vascular problems are the hyperintense lesions seen on FLAIR (Fluid Attenuated Inversion Recovery) MR images. White and grey matter lesions are associated with old age [57,58]. Such small age-related lesions are non-pathogenic and are generally caused by vascular aneurism and expansion of perivascular spaces. The larger punctate, more diffuse lesions are a result of axonal demyelination and degeneration, proliferation of oligodendricytes, occlusional macrophages and occasionally microinfarction. The small arterioles in the deep white matter are sensitive to diabetes and hypertension, rendering the deep white matter at particular risk. White matter lesions are associated with the occurrence of a first depressive episode after 50 years of age [57], and also with impaired psychomotor speed although Dahabra et al. (1998) [59] also show that compared to controls both early- and late-onset depressives have increased slow-wave activity on EEG (electroencephalography), slowed reaction times and global impairment in cognitive function. This is consistent with cerebrovascular disease causing some of the symptoms of vascular depression. If the cerebrovascular disease resulted in axonal demyelination/death then this would result in both the observed hyperintensities and the reduced psychomotor speed, due to loss or decreased efficiency of connectivity. Late-onset depressives typically have a greater whole brain lesion volume [59,60] and more severe subcortical white matter lesions than early onset [59]. Longitudinally [61], the persistence of depression is associated with small basal ganglia lesions and large cortical white matter lesions. The worsening of depression over time correlates with the presence of subcortical white matter lesions. Typically, severity of depression is associated with pre-frontal cortical volume (the smaller the volume, the more severe) [60,62]). Dahabra et al. (1998) [59] showed that late-onset depressives have larger third and lateral ventricles in comparison to early-onset, indicating greater brain tissue loss.

There is increasing evidence for a genetic risk factor for Alzheimer's Disease, the APO$\epsilon$-4 allele, but this allele of the APO gene does not seem to be associated with cerebrovascular disease [63]. However, the APO $\epsilon$-2 allele is linked to vascular dementia and raised levels of triglycerides [58]. Elevated homocysteine and low levels of vitamins B$_{12}$, B$_{6}$ and serum folate are all associated with vascular disease. By analogy, these factors may also be risk factors for vascular depression.

A method for quantifying cerebral flow for use in subjects with depression would be useful for determining the extent of the vascular component to this form of depression.