The increase in life expectancy in the 20th century has resulted in a major increase in the prevalence of age-dependent diseases and conditions, such as depression, Alzheimer's disease (AD) and other dementias, Parkinson's and cerebrovascular disease, vision and hearing loss, type II diabetes, osteoporosis, hip fractures, osteoarthritis, infections.
Therefore, prolonged life and postponed mortality have a great impact on quality of life, since elderly patients are more frequently exposed to the vulnerability of extreme ages.
Depression in the elderly is now a predominant health care problem and is the most common psychiatric disease in the elderly.
In fact, major depression may affect from 10 to 35% of hospitalized elderly, while from 10 to 34.5% of older persons in the community may have depressive symptoms if mild forms are included.
In the consensus statement on the diagnosis and treatment of depression in late life, it was emphasized that depression in the elderly is a persistent or recurrent disorder resulting from psychosocial stress or physiologic effects of disease and can lead to disability, cognitive impairments, increased symptoms from medical illness, increased utilization of health care services and increased rates of suicide and non-suicide mortality.
In contrast to younger depressed patients, elderly patients often avoid reporting or showing that their mood level is lowered because they tend to hide their state of disease or, worse, they think that enjoying life less than before is an inevitable consequence of aging.
Anxiety, worry, apprehension or panic that is out of proportion to an actual threat, tachycardia, tremor, hypoventilation and light-headedness are common symptoms in the elderly, due to the activation of the autonomic nervous system.
Patients with anxiety may also complain of inner tremulousness and unsteadiness.
Depression is difficult to diagnose in elderly people; in fact, depressive symptoms are often masked by somatic complaints or by cognitive symptoms, conditions once called 'masqued depression' or 'pseudodemence'.
Therefore, depression in the elderly is often under-recognized and under-treated; this may be due to the mistake, both from the physician and from the patient, of considering depression as a physiologic response to aging.
Other factors may be the lack of consciousness of disease from the patient, the presence of concomitant diseases, especially dementia and the usually atypical onset of depression in elderly people.
The increased incidence and prevalence of depression with aging can be also explained considering some stressors which elderly people frequently have to face, such as physical disability, bereavement, cognitive abilities and social isolation.
Moreover, elderly subjects sometimes attribute their depressive symptoms to somatic disorders and these methods do not take into account, or even exclude, depressive disorders due to general medical conditions.
Chronic somatic diseases increase the risk of depression, the severity and length of the mood disorder and induce poorer outcomes (Table 1).
Depression may be caused by a variety of drugs; this is remarkable especially in elderly people, where polypathology is often associated with polypharmacotherapy.
In the last 15 years there has been an increasing interest in the contribution of the immune system to psychiatric diseases; the impact of cytokines on neuroendocrine function and behavior has also been determined and the relevance of cytokines to the pathophysiology of depression has become an exciting new research frontier.
Hypotheses of depression
The pathogenesis of geriatric depression is not well understood; major depression may arise from dysfunction of the limbic-hypothalamic-pituitary-adrenal axis.
Some clinical observations also suggest that striato-frontal dysfunction is associated with late life depression.
In fact, stroke of the basal ganglia or the left frontal region often leads to depression.
Moreover, it is well known that depression is the complication of some diseases affecting basal ganglia and their prefrontal projections, such as Parkinson's disease, vascular dementia, Lewy body dementia and Huntington's disease.
Executive dysfunction, that is the clinical expression of striatofrontal impairment, is often observed in depressed patients, especially those with late-onset depression; it may also predict poor or slow response to treatment, as well as early relapse and recurrence in geriatric depression.
On the other hand, neuro-imaging studies suggest that in geriatric depression white matter hyperintensities are prevalent, especially in subcortical structures and their frontal projections; reduced basal ganglia volumes, hypo activity of the caudate nucleus and of the frontal regions are also observed in depressed patients.
Furthermore, heredity is the most important known cause of depression, even if it seems to be less important in the elderly.
A number of hypotheses have been made, suggesting that mood disturbances are probably linked to a disturbed central metabolism of neurotransmitters - monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA); however most of this knowledge is derived from animal models.
Many factors both in the young and in the elderly can influence the onset of a depressed mood.
Alzheimer's and Parkinson's diseases are the prototypes of age-related models of secondary depression in old age.
In fact, studies examining glucose metabolic rates or blood flow changes in regional brain areas showed that Parkinson's disease and AD, together with stroke and Huntington's disease, as well as primary depression, are all associated with decreased activity or brain lesions in the orbital frontal cortex and basal ganglia.
Abnormalities may be also noted in the basal temporal lobes, cingulated cortex and thalamus.
These observations lead to the hypothesis that the dysfunctions of one or more of the cortical basal ganglia-thalamic neuronal loops are involved in the pathophysiology of primary and secondary depression.
This dysfunction may be mediated by decreased serotonin release and in stroke, depletions of serotonin receptors in left temporal cortex have also been noted in association with depression.
Most patients affected with Parkinson's disease are depressed; in fact, it is caused by the degeneration of nigrostriatal dopaminergic neurons. Depression in Parkinson's disease often becomes overt when physical symptoms are too modest to justify a depressant reaction.
As regards Alzheimer's disease (AD), a number of studies have shown that depression is common in pre-clinical AD and may be an early manifestation of this disease even before cognitive symptoms become apparent.
In particular, patients with depression and pre-clinical AD usually have at baseline a poorer performance on the cognitive tasks and are older than the patients with depression-related cognitive impairment.
Several studies show that depression is a risk factor for AD; this may be especially important if the depressive episode occurs within 2 years of the diagnosis of dementia and might be therefore considered as a prodrome of dementia.
The reasons for the development of depressive symptoms in AD are primarily biological ones, such as the depletions of neurons in the locus coeruleus or in the central superior raphe nucleus.
Moreover, pathologic over secretion of glucocorticoids during episodes of severe depression might have some effects on the hippocampus, leading to an increase in the dementia prevalence later.
AD is defined to be an age-related condition, since even in individuals with genetic predisposition; it rarely develops before 55 years old.
Aging is associated with an increase in the production of oxygen radicals and also with a decreased ability to defend against the accumulation of free radicals.
Oxidative stress is thought to be of primary importance in driving the aging process.
The free radical theory of aging, first proposed several decades ago, envisions that the molecular basis of aging derives from accumulation, over a lifetime, of oxidative damage to cells resulting from excess reactive oxygen species, which are produced as a consequence of aerobic metabolism.
Furthermore, an increase in advanced glycosylation end products (AGEs) is observed in particular in human skin; other effects of aging are the decrease in protein turnover and the subsequent accumulation of damaged proteins that would normally be removed rapidly.
Indeed, aggregates of abnormal proteins, such as neurofibrillary tangles and senile plaques, are the only definitive criteria for the post-mortem diagnosis of AD.
The increase of oxidative stress and protein glycation are to be added to several independent parameters suggested to be responsible for the pathogenesis of AD, including apolipoprotein E genotype, hyperphosphorylation of cytoskeletal proteins or metabolism of β amyloid.
Changes in cell-membrane composition might constitute a major molecular mechanism of AD too; in fact, these membrane alterations result in impaired signal transduction in a manner similar to that of normal aging.
The impaired signal transduction seems to be related to dysfunction in the coupling of G-proteins to their receptors and effectors; changes in coupling and affinity properties of G-protein-coupled receptors might also contribute to aging and to the onset of some psychiatric disorders such as depression in the aged.
These studies might offer a complementary alternative to the amyloid hypothesis and may also be the opportunity for considering new therapeutic approaches.