Research Highlights
DEMENTIA AND DEPRESSION IN OLDER PEOPLE

JOANNE EDWARDS

Introduction

The incidence of dementia rapidly increases over the age of 65 and there is evidence to suggest that although major depression decreases in prevalence within older populations, subclinical depressive syndromes are increasingly common. The two disorders occurring together have received recent attention, as possible mechanisms for their co-morbidity are sought to assist treatment strategies. No clear evidence has been found to explain this relationship, but many theories have been proposed.

Aging and Psychiatric Illness

With increasing age, structural changes occur in the brain - the total weight decreases, ventricles enlarge, the meninges thicken, the quantity of synaptic clefts decreases and there is a minor loss of some cell types. Aging is also associated with the development of brain lesions, including neurofibrillary tangles and amyloid plaques. Increased expression of these normal findings plays an important role in the pathogenesis of the major cause of dementing illness, Alzheimer’s disease (AD) (Mesulam, 2000). Over time, gradual decline occurs in cognition particularly memory, information processing, concentration and problem solving ability. Cognitive decline is less manifest in those who are better educated, those who continue to undertake strenuous activity, those with peak pulmonary flow rate and those with heightened self-efficacy (US Dept. of Health and Human Services, 1999).

Older people are subject to psychiatric illnesses similar to those affecting the general population: neurosis, anxiety, personality disorders, depressive disorders, mania, delirium, dementia and substance abuse disorders. The expression of disorders and syndromes in the elderly is often different from those of younger people and this difference may lead to under-diagnosis or non-recognition. Many older people present with somatic symptoms of psychiatric illness and do not meet the criteria for diagnosis, although these subclinical disorders can cause treatable morbidity. There is a particularly well recognized under-diagnosis of depression in the elderly (US Dept. of Health and Human Services, 1999).

Dementia in Aged Populations

One of the most common causes of morbidity in older people is dementia, defined as progressive brain disease causing disturbance of higher cortical functions and changes to emotional and social behaviors. Dementia is caused by AD in about 65% of cases and other causes include vascular dementia, a mixed syndrome of vascular dementia and AD, dementia with Lewy bodies and fronto-temporal dementias.

Dementia can also be found on the spectrum of normal degenerative brain changes associated with aging. Because the brain is a post-mitotic organ, the cells are subject to the cumulative effects of a lifetime of biological wear and tear. Cerebral degenerative change associated with aging includes decline of cerebral matter density and perfusion, both accelerated in the presence of cerebrovascular disease. The rate of tissue degeneration varies markedly and accelerates linearly following age 60 and correlates with cortical and subcortical atrophy and ventricular enlargement (Meyer et al., 1999). Approximately 10% of neurones are lost between the ages of 20 and 90. Despite this loss and the consequent loss of synapses, the surviving synapses are thought to increase in efficacy with age with more potential for structural plasticity (Mesulam, 2000).

The clinical expression of dementia is usually heralded by memory impairment. Early memory impairment normally involves declining recall of recent events and as the dementia becomes more severe also encompasses long-term memory. Other clinical features of dementia include lack of orientation, dysphasia, personality changes, paranoia and psychosis.

Dementia affects approximately 6% of people at 65 years and approximately 24% of those over 85 years, although these figures are not consistently found (Henderson & Jorm 1998). A 1987 meta-analysis showed that despite the variability in data, the prevalence rate for dementia doubles with every additional 5.1 years of age, (4.5 years for AD and 5.3 years for vascular dementia) (Jorm et al., 1987). Subsequent meta-analyses have shown these figures to be remarkably consistent (Chiu et al., 1999). With an aging population and increasing survival of those over 80, the prevalence of dementia is expected to increase markedly.

Depression in Later Life

Depression in later life is distinguished by more somatic symptoms. The prevalence of major depression decreases with age, but symptoms of depressive disorders are much more common. Rating scales used for depressive disorders in the general population may fail to adequately assess the symptoms of elderly patients, particularly those who have not presented depressive disorders earlier in life (Dunner, 1999). The more common minor depression is diagnosed with fewer symptoms and less impairment as a result of those symptoms. Minor depression is used to describe depressive syndromes due to a variety of causes including a manifestation of early or residual major depression, a chronic but mild form of depression known as dysthymia or as a response to identifiable stressors (US Dept. of Health and Human Services, 1999).

Late onset depression is a descriptive term for depression first diagnosed after the age of 65 years. It shares many characteristics with earlier onset depression, but some distinctions include greater apathy, less personality dysfunction and more prominent cognitive deficits including more impaired memory and executive functioning. Insomnia and sleep disturbance are major features of the clinical presentation of depression in old age although this may reflect increasing sleep disturbance in older people generally (US Dept. of Health and Human Services, 1999).

Studies vary in their estimates of the prevalence of depression or depressive disorders in later life and these differences may be explained by sampling and methodological differences. There is strong evidence that under-reporting of depressive symptoms occurs and that non-recognition also occurs. Age has not consistently been found to be a risk factor for depression (Blazer et al., 1991). Prevalence rates of major depression in older age groups have been estimated by an Australian study at 0.4% using DSM-IIIR criteria (Henderson et al., 1993), and in other international studies rates range from 2.02% (Beekman et al., 1995) to 10.4% (Kay et al., 1995). A major limitation of these community based cohort studies was that those with depressive disorders were less likely to agree to take part (Henderson et al., 1993). A recent review of 34 community based prevalence studies suggests major depression is rare among elderly people, with an average prevalence of about 1.8%, but that depressive disorders are more common with an average prevalence of 13.9% (Beekman et al., 1999).

The prevalence of major depression falls in later life (Christensen et al., 1999). However, proportionally more of the depressive disorders in old age are those other than major depression. As the prevalence of major depression falls, minor depression and depressive symptoms become increasingly common.

Developing depression results from an imbalance between predisposing, precipitating and protective factors (Forlenza, 1999). The major predisposing factors for depressive disorders in old age are associated with increasing levels of disability and chronic disease (Blazer et al., 1991; Prince et al., 1998). The types of disorders found to induce depressive symptoms at a significant level are arthritis, asthma, fractures and digestive diseases (Henderson et al., 1993). Other factors, including genetic pre-disposition, early adversity and serious life events have been found to be less significant (Prince et al., 1998). The increasing prevalence of minor depression in older age-groups is related to risk factors associated with the stress of growing old including being single, living in large cities, poor health, functional limitations as well as waning social networks (Beekman et al., 1995). Precipitating factors more immediate to the onset of an episode of depression, include adverse life events such as bereavement or ill health episodes. Protective factors include early development of good coping skills, achievement, socioeconomic status, marital status and social support (Forlenza, 1999).

Organic causes of late life depression are becoming increasingly significant as the understanding of brain function increases and visualizing techniques become more sophisticated. Much work has been done on pathological changes associated with late onset depressive disorders. Many studies have indicated neurodegenerative changes in the periventricular areas and subcortical white matter as associated with increased levels of depressive disorders, possibly associated with cerebrovascular disease.

Cerebrovascular disease, as determined by various vascular risk factors including atherosclerosis, hypertension, cardiac dysrhythmias, angina and transient ischemic attacks has been determined as a major risk factor in late onset depression (Baldwin et al., 1995). With age there is an absolute reduction in monoamine oxidase in the brain that leads to decreased levels of some neurotransmitters—depression has been found to be associated with this loss (Austin & Mitchell, 1995).

Dementia and Depression Occurring Together

The relationship between depression and dementia has received increasing attention over recent years, with a wide range of theories postulated to explain the prevalence of co-morbidity. Co-morbid depression in dementia patients is associated with increased disability, more functional and behavioral problems and greater stress to carers (Teri et al., 1992).

Epidemiology

Estimates of the prevalence of syndromes of dementia and depression occurring together range from 0-86%; and estimates of major depressive disorder in dementia range from 11-25% (Alexopoulos et al., 1992; Zubenko & Moossy; 1998; Ritchie et al., 1999; Hargrave et al., 2000). Variability in the reporting of frequencies is associated with differences in diagnostic criteria, methodology and patient populations. The assessment and diagnosis of depressive symptoms has been conducted using a variety of diagnostic instruments and the inclusion of caregiver assessment has also been variable. Many studies have found that depression is more common in dementia caused by cerebrovascular disease rather than AD (Ballard et al., 1996; Greenwald et al., 1989; Newman, 1999; Hargrave et al., 2000). Many studies agree that depression is most common in dementia that is mild (Skoog, 1993).

A significant aspect of depression in older cognitively impaired persons is the high mortality rate. Found across a number of studies and reported in a 1996 review, there is a reduced survival rate in patients with both dementia and depression compared with those with either syndrome separately (Ballard et al., 1996). Associated with the increased morbidity and mortality is the increased likelihood that depressed patients with dementia will be withdrawn from social and vocational activities and have more problems with concentration (Reding et al., 1985). A recent study has postulated that the increased morbidity reflects the greater degree of neuropathology of those suffering from both dementia and depression (Geerlings et al., 1999). A 1992 study found that by year three, of those diagnosed with dementia and mild depression, 60% had died or developed a chronic mental illness (Copeland et al., 1992).

Correlations Between Dementia and Depression

There is a wide range of reasons postulated for the co-morbidity of depression and dementia. There appear to be two major classes of theories—those that suggest a common genetic, neuropathological or neurochemical basis which favors the development of both disorders and others that suggest neuropathological changes resulting from depression cause an increased vulnerability or sensitivity to other risk factors for dementia (Buntinx et al., 1990).

The depressive symptoms most likely to occur in those with dementia are dysphoria and loss of interest. Other common symptoms include psychomotor changes (50-60%), appetite disturbance (12-70%) and guilt (6-50%) (Forsell et al., 1993). The depressive syndrome of severe dementia is associated with a paucity of symptoms, possibly due to an inability of dementia sufferers to experience complex integrated emotions in advanced brain pathology (Burns et al., 1990).

Depressive pseudodementia is used to describe reversible cognitive impairment occurring with major depression. The term is applied to two categories of patients – those who demonstrate such reduced motivation in questioning that cognitive assessment is impaired and others who participate in the assessment and demonstrate cognitive deficits. The unifying feature of these patients is that on treatment or resolution of depression the cognitive impairment is reversed (Ballard et al., 1996). The patient with pseudodementia has varying cognitive capacity whereas the cognitive capacity of demented patients progressively declines (Raskind, 1998).

Explaining Depression in Dementia

Considerable research has been conducted looking at whether depression is a true risk factor for the onset of later dementia. A recent extensive review on this topic by Jorm (2000) suggests that there is now sufficient evidence, despite small cohorts limiting studies, “to take seriously the possibility that depression is a risk factor for dementia and cognitive decline” although the association may be small. In support of this thesis, many studies have found that depression in early life does convey a risk for the subsequent development of dementia. Two studies assessing the relation between depression and dementia found an odds ratio of 1.82 for developing dementia with depression, with a statistically significant confidence interval when related to late onset dementia (Buntinx et al., 1996; Cooper & Holmes, 1998). There is a consistent finding that depression more than ten years prior to onset of dementia is late onset dementia cases, and Jorm and colleagues (1991) suggest that this implies that depression is not a mere prodromal symptom of dementia. Other studies have found an association between depression and subsequent dementia (Cooper & Holmes, 1998; Devanand et al., 1996; Rovner et al., 1989), but one recent study suggests that the depressive symptoms are actually an early manifestation, rather than predictor of dementia (Chen et al., 1999).

The results of these studies suggest that depression may occur in the early stages of dementia as a symptom and also that depression occurring 10 years prior to dementia is a risk factor.

Another theory to explain the relationship between dementia and depression is that mild sub-clinical forms of both syndromes will increase the likelihood that both will be clinically manifest (Geerlings et al., 2000). Related to this are theories that depressed people may already have a mild cognitive impairment and will reach threshold for dementia earlier (Jorm et al., 1991) and also that depression may be an early reaction to recognized cognitive impairment (Bassuk et al., 1998; Geerlings et al., 2000). These theories fail to account for the anatomical and chemical changes consistently seen in those suffering from both disorders.

Recent research has shown that anatomical and chemical changes occurring in the brain with age may cause the two disorders. The degeneration of the cereleus locus and substantia nigra have been shown to be consistent anatomical changes common to those suffering both dementia and depression and demonstrable over other hallmarks of dementia alone including senile plaques and neurofibrillary tangles (Forsell et al., 1993; Zubenko & Moossy, 1988). This may indicate that depression associated with dementia is related to the catecholaminergic deficit caused by the degeneration of areas of the brain known to be involved with catecholamine production (Jorm et al., 1991; Devanand et al., 1996). Importantly, dementia sufferers with degeneration of both nuclei were more likely to suffer from depression than those with degeneration of only one nucleus (Zubenko & Moossy, 1988). Conversely, there is an increased serotonin theory suggesting that with ventricular enlargement found in dementia and depression (Pearlson et al., 1989) there is a loss of serotonin producing neurones that leads to an increased production of serotonin elsewhere by reduced negative feedback (Alexopoulos et al., 1992). A recent hospital based study of people aged over 85 found no association between ventricular enlargement and depression, although no comparison was made between demented and non-demented patients (Palsson et al., 1999).

A convincing and long held theory involves depression causing changes to the hypothalamic-pituitary-adrenal axis, which in turn causes alterations to neurotransmitter levels predisposing those with depression to develop dementia. Depression increases cortisol levels thus causing damage to the hypothalamus, further impairing the endocrine axis and causing degeneration to the hippocampus and medial temporal lobe which may be associated with the cognitive symptoms of dementia (Palsson et al., 1999; Raskind, 1998).

Other theories to explain this complex relationship relate to treatment of side effects, social support networks and depressive perception. The effects of antidepressant treatment have been examined as possible causes of dementia because of the anticholinergic effects of some antidepressants. Case control studies have found no association between the treatment of depression and subsequent dementia (Devanand et al., 1996). Other theories have used social factors to explain the relationship between dementia and depression. One suggests that cognitive impairment will lead to reduced social support that in turn may precipitate depression (Cervilla & Prince, 1997). As suggested above, these theories may contribute to the relationship but fail to account for the structural changes found in patients suffering from both disorders.

Dementia and depression are common in older populations and occur more frequently than can be explained by coincidence alone. Numerous theories have been reported to explain the complex relationship with their basis in a variety of disciplines from epidemiology to neurochemistry and neuroanatomy. There is no definitive theory to explain the relationship. Convincing and widely regarded theories include the role of the disturbance of the hypothalamicpituitary- adrenal axis in depression leading to eventual dementia and the destruction of neurotransmitter producing areas of the brain predisposing to both conditions. More recent theories have been postulated with the aid of new imaging techniques and within the context of increasing understanding of brain function. The clinical significance of this work will allow treatments to be developed for depressive syndromes of dementia; syndromes that markedly increase the morbidity associated with dementia.

 

Joanne Edwards is enrolled in the 2nd year of the MBBS graduate medical program at the University of Queensland, Brisbane, Australia. Prior to entering medicine she was employed for 6 years by the Queensland Department of Environment and Heritage as an architectural historian, following completion of a Masters in Heritage Conservation at the University of Sydney. Joanne’s career change was prompted by a growing interest in medical science, particularly psychiatry.
Editor’s Note: This essay, was recently awarded equal first prize in the 2001 Psychiatry of Old Age Essay Competition run annually by the Faculty of Psychiatry of Old Age of the Royal Australian and New Zealand College of Psychiatrists. The prize is awarded for ‘the most outstanding essay submitted by a Medical Student or Student in another health-care discipline in the area of Psychiatry of Old Age’.
Reprinted from IPA Bulletin, Volume 19, Number 2