#### Summary points

Depression is a major contributor to healthcare costs and is projected to be the leading cause of disease burden in middle and higher income countries by the year 2030.w1 Depression in later life, traditionally defined as age older than 65, is associated with disability, increased mortality, and poorer outcomes from physical illness. Most clinicians will encounter older patients with depression in their day to day practice, but although treatment is as effective for older patients as for younger adults, the condition is often under-recognised and under-treated. According to WHO data, proportionately more people aged over 65 commit suicide than any other age group, and most have major depression. Older people who attempt suicide are more likely to die than younger people, while in those who survive, prognosis is worse for older adults.1

With a progressively ageing population worldwide, identification and treatment of depression in older adults becomes increasingly important, especially as older patients may have different presentations and needs than younger ones. We consider recent systematic reviews, meta-analyses, and randomised controlled trials to …

Depression in older adults

Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric symptoms, represent a heterogeneous group of non-cognitive symptoms and behaviors occurring in subjects with dementia. BPSD constitute a major component of the dementia syndrome irrespective of its subtype. They are as clinically relevant as cognitive symptoms as they strongly correlate with the degree of functional and cognitive impairment. BPSD include agitation, aberrant motor behavior, anxiety, elation, irritability, depression, apathy, disinhibition, delusions, hallucinations, and sleep or appetite changes. It is estimated that BPSD affect up to 90% of all dementia subjects over the course of their illness, and is independently associated with poor outcomes, including distress among patients and caregivers, long-term hospitalization, misuse of medication, and increased health care costs. Although these symptoms can be present individually it is more common that various psychopathological features co-occur simultaneously in the same patient. Thus, categorization of BPSD in clusters taking into account their natural course, prognosis, and treatment response may be useful in the clinical practice. The pathogenesis of BPSD has not been clearly delineated but it is probably the result of a complex interplay of psychological, social, and biological factors. Recent studies have emphasized the role of neurochemical, neuropathological, and genetic factors underlying the clinical manifestations of BPSD. A high degree of clinical expertise is crucial to appropriately recognize and manage the neuropsychiatric symptoms in a patient with dementia. Combination of non-pharmacological and careful use of pharmacological interventions is the recommended therapeutic for managing BPSD. Given the modest efficacy of current strategies, there is an urgent need to identify novel pharmacological targets and develop new non-pharmacological approaches to improve the adverse outcomes associated with BPSD.

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Behavioral and Psychological Symptoms of Dementia

The 'Vascular Depression' hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes.

The vascular depression hypothesis: mechanisms linking vascular disease with depression.

Depression occurs in around 35% of patients with Parkinson disease (PD) and is often persistent. Symptoms of depression can be evident in individuals at the time of diagnosis and might develop in the premotor stage of the disease. The underlying mechanisms of depression in PD are not known in detail, but changes in brain structure, signaling by neurotransmitters, and levels of inflammatory and neurotrophic factors are all suggested to contribute to its development. Psychosocial factors and pain could also have roles in depression. Changes in dopaminergic, noradrenergic and serotonergic systems in patients with PD might help to explain the incidence of depression in these individuals. Antidepressants that have dual serotonergic and noradrenergic effects are the drugs of choice for treating depression in PD. However, antiparkinsonian drugs might have beneficial effects not only on the motor symptoms of disease, but also on a patient's mood. Deep brain stimulation can worsen depression in some patients, but a preliminary study has suggested that transcranial magnetic stimulation could improve symptoms of depression. This Review describes the frequency and course of depression in patients with PD. The mechanisms that underlie depression in this disease are also discussed, and the management strategies for these patients are highlighted.

Depression in Parkinson disease—epidemiology, mechanisms and management

Purpose of reviewDepression in people with dementia has important implications, such as reduced quality of life of patients and carers, and is associated with increased costs and reduced cognition. Here, we review recent studies of the epidemiology, course, mechanisms and treatment of depression in

Depression in dementia: epidemiology, mechanisms, and treatment.

Background 

Depression is common in old age and is associated with risk of dementia, but its neuropathological correlates in the community are unknown.

Aims 

To investigate for the first time in a population-representative sample of people with no dementia the association between depression observed during life and neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, brain atrophy and cerebrovascular disease found in the brain at post-mortem.

Method 

Out of 456 donations to a population-based study, 153 brains were selected where donors had no dementia measured in life. Alzheimer and vascular pathology measures, Lewy bodies and neuronal loss were compared between those with ( n = 36) and without ( n = 117) depression ascertained using a fully structured diagnostic interview during life. Brain areas examined included frontal, parietal, temporal and occipital cortical areas as well as the entorhinal cortex, hippocampus and brain-stem monoaminergic nuclei.

Results 

Depression was significantly associated with the presence of subcortical Lewy bodies. No association was found between depression and cerebrovascular or Alzheimer pathology in cortical or subcortical areas, although depression was associated with neuronal loss in the hippocampus as well as in some of the subcortical structures investigated (nucleus basalis, substantia nigra, raphe nucleus).

Conclusions 

Late-life depression was associated with subcortical and hippocampal neuronal loss but not with cerebrovascular or Alzheimer pathology.

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Neuropathological correlates of late-life depression in older people

Objective

Vascular disorders are important potential causes of cognitive impairment and common mental disorders but their specificity as risk factors has yet to be clarified. The objectives of this analysis were to compare vascular and non-vascular health problems with respect to their associations with cognitive function and common mental disorder.



Method

An analysis was carried out of cross-sectional data from the 2000 UK National Survey of Psychiatric Morbidity. The two dependent variables analysed were common mental disorder (revised Clinical Interview Schedule) and cognitive function (TICSm and animal naming) in survey participants who were aged 60–74 years (n = 2007). Associations with self-reported vascular and common non-vascular (musculoskeletal, respiratory or gastrointestinal) disorders were compared. Disability (SF-12 physical scale) was considered as a potential confounding/mediating factor).



Results

Vascular disorders were associated with impaired global cognitive function and lower memory but not verbal fluency scores after adjustment for age, gender, education and social class. No such associations were found for non-vascular disorders. Vascular and non-vascular disorders were associated with common mental disorder to a similar extent, and associations were substantially explained by disability.



Conclusions

Lower cognitive function was specifically associated with vascular disorders. Findings for common mental disorder were more consistent with an effect of disability rather than the actual consequences of specific health complaints. Copyright © 2009 John Wiley & Sons, Ltd.

Christos Tsopelas

Papers

Neuropathological correlates of late-life depression in older people

Cognitive function and common mental disorders in older people with vascular and non-vascular disorders: a national survey.