|Year : 2015 | Volume
| Issue : 1 | Page : 4-11
Late onset depression: A recent update
Ananya Mahapatra, Pawan Sharma, Sudhir Kumar Khandelwal
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||8-Sep-2015|
Department of Psychiatry, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Late onset depression has recently emerged as a serious mental health issue in the geriatric population with significant public health implications. It is often challenging to diagnose and treat this entity. Various theories have been postulated to elucidate the etiology of late onset depression, but a unifying hypothesis is lacking. Although the vascular hypothesis is most researched; a complex interaction of multiple vulnerability factors is the current focus of attention. Numerous psychosocial variables have been implicated to play a significant role in predicting the onset and severity of late-life depression. Phenomenological differences have been delineated from depression occurring at a younger age, but the findings are equivocal. A better understanding of the natural trajectory of depression in the elderly is required for early diagnosis and effective treatment. This review attempts to summarize the current status of evidence regarding epidemiology, etiology, clinical features, and treatment options available for late-onset depression.
Keywords: Biopsychosocial model, epidemiology, late onset depression, treatment advances
|How to cite this article:|
Mahapatra A, Sharma P, Khandelwal SK. Late onset depression: A recent update. J Mental Health Hum Behav 2015;20:4-11
| Introduction|| |
Late-onset depression constitutes a complex terrain, both in terms of diagnosis, as well as management. Elderly patients are not only physically frail; they often suffer from multiple medical comorbidities, which makes the diagnosis of depression difficult and at the same time pose challenges in its management. Because of this, depression in them remains at risk of being under-recognized and undertreated. Patients in this age group often have limited access to health services and meager social support, further complicating the picture. Evidence accumulated from recent research seems to suggest that depression in the elderly follows a more adverse course than in younger patients. There is no consensus regarding the age that distinguishes between the late- and early-onset depressions. Late-onset depression generally refers to depressive syndromes defined in the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV) and in the International Classification of Diseases (ICD-10) that arise in adults older than age 65 years. 
| Epidemiology|| |
The point prevalence estimates for major depressive disorders (MDD) in elderly in the community have been reported to be 4.4% in women and 2.7% in men in the cache county study.  The prevalence of either a major depressive episode or dysthymia in the epidemiologic catchment area survey was 2.5% in the geriatric age group.  Although depression is common and clinically significant in late life, estimating its prevalence is usually challenging. The variability in the definition of late-life depression, as well as the measurement of depression, makes it difficult to estimate its prevalence.  A review of the prevalence of depression in adults aged 65 years or older found a range from 0.9% to 42.0%, with clinically relevant depressive symptom cases in similar settings varying between 7.2% and 49.0%.  An extensive body of literature is available regarding the prevalence of old age depression, in spite of the methodological issues. However, same cannot be said about its incidence. Incidence studies are more relevant in terms of service planning, and to identify, as well as quantify the causal relationship, between risk factors and disease onset. A systematic review of 20 studies found the incidence rate of major depression to be 0.2-14.1/100 person-years, and incidence of clinically relevant depressive symptoms as 6.8/100 person-years.  Female incidence was found to be mostly higher than male, and associations between age and incidence were found to be inconsistent. In recent times, the emphasis is more on incidence studies, as they can help in formulating preventive interventions in the future.
| Etiology|| |
The biopsychosocial model  of mental illness can be employed to elucidate the various factors contributing to depression in the elderly. Old age is associated with deteriorating health, vascular disease, changing sleep patterns, bereavement, and so forth, and many of these potential precipitants accumulate with an increasing age.  These interact with biological and psychosocial factors to predispose vulnerable individuals to various depressive disorders ranging from sub-threshold depressive symptoms to MDD.
The genesis of depression in old age is being considered to be from complex interactions of various biological factors such as genetic factors, vascular changes, preexisting medical, and neurological disorders.
The genetic basis of MDD has been investigated extensively, but the results have been conflicting, and studies largely underpowered. A meta-analyses conducted in 2008 for 20 polymorphisms in 18 susceptibility genes based on previous studies found statistically significant associations for apolipoprotein E, DRD4, GNB3, MTHFR, SLC6A3, and SLC6A4.  However, the effect sizes were typically very small and no single gene, acting alone, appears to play a major role. The major limitation of genetic association studies is that they do not account for differences in exposure to the multitude of potential environmental influences. It is being hypothesized that particular genes interact with particular environments to influence MDD. Since environmental factors play a major role in old age depression, current research is more focused on gene-environment interaction studies.  In older adults, medical illness is one specific type of precipitating environmental stressor. Here, the results are fairly consistent. In a 2 years prospective study of elderly depressed patients, the S/S genotype was found to increase the risk for MDD in those with four or more chronic medical disorders.  The S/S genotype has also been associated with an increased risk for depression in those with Parkinson disease (PD),  with severe coronary disease  following a myocardial infarction,  and following a stroke. 
In 1997 Alexopoulos et al., proposed that small vascular lesions might critically affect frontal and subcortical regions leading to a progressive disruption of the monoaminergic pathways involved in the pathogenesis of depression.  Since then, several lines of evidence have indicated that the cerebrovascular injury is linked to late-life depression. The homocysteine depression hypothesis proposes that elevated levels of homocysteine lead to cerebral vascular disease and neurotransmitter deficiency, which then cause depressed mood. This linkage has been demonstrated in population and imaging studies. The levels of homocysteine may increase because of a number of factors including dietary deficiency of B 12 , folate, and B 6 ; and the genetic variation of enzymes such as methylenetetrahydrofolate reductase and cystathionine beta-synthetase, which are both essential for the metabolism of homocysteine.  Endothelial dysfunction is another mechanism being looked into as a mediator of old age depression. The impairment of endothelial function may also be a final consequence of a variety of inflammatory phenomena that are often present in elderly patients with depression.  Over the years, there has been a paradigm shift from a lesional view to complex vulnerability models of multiple factors such as endothelial dysfunction, immunological mechanisms, and homocysteine, etc., which interact in complex multidirectional ways to mediate depression, although advanced research is required to explore further possibilities. 
Other medical and neurological disorders
In the Institute of Medicine's Report, in community-living adults aged 60 years and older who had major depression or dysthymia, the most common coexisting physical health conditions were hypertension (58%), chronic pain (57%), arthritis (56%), loss of hearing or vision (55%), urinary tract and prostate disease (39%), heart disease (28%), and diabetes (23%).  Drugs that have been linked to old-age depression include methyldopa, benzodiazepines, propranolol, reserpine, steroids, antiparkinsonian agents, beta-blockers, cimetidine, clonidine, hydralazine, estrogen, progesterone, tamoxifen, vinblastine, vincristine, and dextropropoxyphene.  The rate of depression among those with PD is higher than in general population. The prevalence of MDD in patients with PD varies from 7.7% in population studies to more than 25% in outpatient samples.  There is accumulating evidence suggesting that depression in PD is secondary to underlying neuroanatomical degeneration, which results in changes in central serotonergic function and in neurodegeneration of certain cortical and subcortical circuits, rather than solely being a reaction to psychosocial stress and disability.  An increasing body of evidence suggests that alterations in the principal excitatory and inhibitory neurotransmitter systems in the central nervous system, glutamate, and gamma-aminobutyric acid, respectively, may contribute to the onset of depression and cognitive impairment in late-life. A review on the relationship between late-life depression and Alzheimer's disease found that the neurobiological bases linking late-life depression and Alzheimer's disease are largely unknown. 
A review of the research findings on psychosocial risk factors for late-life depressive disorders identified a number of significant psychosocial risk factors for late-life depressive disorders including life events and ongoing difficulties; death of a spouse or other loved one; medical illness and injuries; disability and functional decline; and lack of social contact.  Personality attributes, cognition, social support, and life stressors in elder depression are some the psychosocial variables that have been investigated extensively in late life depression. 
Neuroticism, in particular, was found to be a consistent and important predictor of the onset of depressive symptoms in late life. It was an even more important predictor of depression than health-related and situational factors.  Other personality factors that played an important role in predicting depression were mastery and self-efficacy.  A recent study assessing the relationship of multiple domains and facets of the five-factor model of personality with presence, onset, and severity of late-life depression found that depression was related to higher neuroticism and lower extraversion.  Linear regression found that personality was unrelated to depression severity at the beginning of treatment, but improvement after 3 months was related to lower neuroticism and higher warmth and competence. Improvement after 12 months was related to lower neuroticism. Other personality attributes that may contribute to late-life depression include the presence of a personality disorder, attachment style, and obsessional traits. 
Beck et al. noted a distinctive pattern of thinking in depressed patients that was characterized by a global negative view of themselves, the outside world, and the future. This cognitive triad consists of the following: I am defective; the world is a hostile place, and things will never change.  Elderly people with more depressive symptoms were reported to use rumination and catastrophizing to a significantly higher extent and positive reappraisal to a significantly lower extent than those with lower depression scores. 
Negative life events
The social causation versus social selection debate is relevant to the relationship between negative life events (NLE) and depression.  The social causation perspective posits that stressors have a causal effect on depressive symptoms and MDD. The social selection hypothesis contends that being depressed leads to the experience of NLEs. Two studies examined the reciprocal effects of NLEs and depression. , Both studies found evidence of both social causation and social selection, but the effects of NLEs on depression were stronger than those of depression on NLEs. A study showed that in a large nationally representative sample of an adult about 30% of the later-onset disorders were associated with childhood abuse.  This was in line with a recent study which showed that 53% of the depressed older adults reported childhood abuse, compared to 16% of the nondepressed older adults. 
Social isolation and impaired social support have been associated with moderate and severe depressive symptoms in the elderly.  Chi and Chou, found that a significant relationship existed between social support, and depressive signs and symptoms, on all dimensions of social support including social network size, network composition, social contact frequency, satisfaction of social support, instrumental/emotional support, and helping others.  Four studies have shown that subjective social support has been the social factor most strongly related to recovery from MDD in later life. Although levels of social support that predate the MDD are not known. ,,, Loneliness and lack of contact with friends have also been suggested to increase the risk of depression in the elderly. The risk of depression caused by a lack of contact with friends has been estimated to be 2.5, and the risk of depression caused by loneliness has been calculated to be 3.6. 
Neurobiology of late-life depression
The advent of advanced neuroimaging techniques has further added to the understanding of late-life depression. Most studies have replicated the findings obtained in depression in younger adults. The major areas implicated in magnetic resonance imaging have been hippocampus, orbitofrontal cortex, and anterior cingulate cortex (ACC). In a meta-analysis of structures involved in depression, the ACC had the largest effect size.  Depressed individuals had smaller ACC volumes. The age of onset correlates negatively with hippocampal volume; patients with late-onset depression have smaller volumes compared with those who have early onset depression and with controls.  A recent systematic review found that white matter intensities are more common and severe in individuals with geriatric depression than in healthy controls, and specifically, in individuals with late-life depression.  A recent study investigating the relationship of orthostatic blood pressure changes to white matter hyperintensities and subcortical gray matter volumes in late-life depression found evidence for an association between the degree of orthostatic systolic blood pressure drop and white matter hyperintensities volume in the depression group.  Since blood pressure drops lead to white matter hyperintensities in animals, their findings implicated that systolic blood pressure drops may be a factor contributing to these lesions in late-life depression. 
| Clinical Features|| |
Phenomenological differences between early-onset and late-onset depression
Late-life depression may be associated with specific depressive syndromes including vascular depression and depression-executive dysfunction syndrome.  A systematic review of comparative studies concluded that late-life depression tends to have a worse prognosis, a more chronic course, and a higher relapse rate compared with patients who develop symptoms at a younger age.  A recent meta-analysis of 11 studies showed no difference in the Hamilton Depression Rating Scale (HAM-D) criteria of loss of insight, work and activity, and psychomotor retardation between early- and late-onset patients.  However, older patients were found to have more agitation, hypochondriasis, somatic preoccupation (including gastrointestinal [GI]), less guilt, and loss of sexual interest compared to younger patients. A recent study examining differences in symptom profiles of early- and late-onset depression of the melancholic subtype, found that the only symptoms that differed across the groups were feelings of anger and irritability, which scored lower in the late-onset group. 
The risk for suicide increases with age in individuals with the major affective illness.  A recent study to identify the factors associated with suicide ideation in the aged population found that depression severity was the most important predictor of suicide ideation among older people.  Another study examining intrapsychic and psychosocial issues in suicidal geriatric inpatients obtained mean HAM-D score of 17.1 in the patient group compared to 6.1 in the control group.  Older age has been significantly associated with more determined and planned self-destructive acts and with fewer warnings of suicidal intent. 
The nature of the association between depression and dementia is poorly understood, with some purporting a bidirectional relationship. Recent studies have tried to look into whether depression is an independent risk factor, or a prodrome of dementia, with conflicting results. A meta-analysis of longitudinal studies indicated that subjects with depression had a higher incidence of than those without depression, suggesting depression to be a risk factor for dementia.  A previous quantitative meta-analysis of 13 cross-sectional and four prospective longitudinal studies showed that in old age, individuals with nondementia, cognitive impairment had neither significant higher prevalence, nor incidence rates of depression than those without. In old age, individuals with dementia had both significant higher prevalence and incidence rates of depression than those without suggesting depression to be a risk factor for dementia.  In view of largely mixed results, further research is required in this area.
Course and outcome
The Longitudinal Ageing Amsterdam Study, at 6 years follow-up, identified four trajectories of outcome-short-lived symptoms, remissions, a fluctuating course, and a severe chronic course.  Similar longitudinal studies have been conducted which followed up patients of 65 years or older for 10-12 years, showing similar trajectories. , Persistently mild or low depressive symptoms were most commonly found at long-term follow-up in these studies. A 20 years longitudinal study identified the risk factors for increasing depressive burden to be baseline smoking, physical inactivity, small social network, physical impairment, myocardial infarction, diabetes, and obesity.  However, the sample in this study consisted only of elderly women, limiting the generalizability of the findings.
The most widely used scale for assessment is the Geriatric Depression Scale (GDS). The GDS was originally developed as a 30 items questionnaire (GDS30), in a simple yes/no response format.  The GDS takes 5-7 min to complete, can be self-administered, has 84% sensitivity and 95% specificity, and correlates well with the HDS.  A 15 items version, and recently a 5- and 10-item shorter versions have also been devised to improve acceptability. Depression in the elderly is often missed, because of various factors. A growing body of evidence indicates widespread under-treatment of depressive disorders in older persons.  Several studies have shown that the majority of care for older people with depression occurs in primary care.  Primary care settings are generally less well equipped to manage chronic problems such as late-life depression. A qualitative study using semi-structured interviews highlighted that primary care practitioners conceptualized late-life depression as a problem of their everyday work, rather than as an objective, diagnostic category.  A recent meta-analysis is analyzing the diagnostic accuracy, clinical utility, and added value of the GDS in primary care found that the clinical utility of both the GDS30 and GDS15 was "poor" for case-finding. However, the GDS15 was rated as "good" for screening purpose. When identification using the GDS was compared with general practitioners' ability to diagnose late-life depressions, the GDS30 had no added benefit; whereas, the GDS15 helped identify an additional four cases per 100 primary care attendees, and also helped rule out an additional four noncases per 100 attendees. The potential gain of the GDS15 in primary care was found to be 8% over unassisted clinical detection. 
Management of late-life depression
Treatment of depression in the elderly involves a judicious use of pharmacological agents, keeping in view of their physical frailty, reduced hepatic and renal clearance with age, and presence of possible medical comorbidities. Psychosocial interventions should be opted for, wherever feasible. The role of neuromodulation therapies in old age depression is relatively less researched, and their potential benefit yet remains to be seen in this particular group of patients.
According to the expert consensus guidelines for the treatment of late-life depression published in 2001, first-line treatment strategy, for both mild and severe geriatric major depression, was an antidepressant plus psychotherapy, and for psychotic major depression, an antidepressant plus an atypical antipsychotic.  The experts also recommended the serotonin-norepinephrine reuptake inhibitor venlafaxine as first-line pharmacotherapy. Eleven meta-analyses have been conducted from 1992 to 2002, of both uncontrolled and controlled trials of the efficacy of different classes of antidepressants in the elderly population.  selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants have been found to have comparable efficacy. SSRIs may have a favorable side effect profile. A recent meta-analysis and meta-regression of placebo-controlled randomized trials in late-life depression suggests that antidepressants are efficacious in late-life MDD, but significant heterogeneity in the studies included suggests that other factors may contribute to these findings. A secondary analysis raised the possibility that the efficacy of these agents may be reduced in trials involving patients aged 65 years or older.  Another recent meta-regression of double-blind, randomized clinical trials in depressed adults older than 60 years, showed that a lower rate of response to antidepressants of all classes was found in patients of male gender, of older age, and with a longer mean duration of the current episode.  A higher rate of response was found in patients with a higher baseline severity, and at their 1 st episode of illness. Methodological differences have often been implicated in influencing the response rates in these trials. A meta-analysis of seven placebo-controlled, and nine comparator trials in late-life depression, found that antidepressant response rates in comparator trials were significantly higher (60%) than antidepressant response rates in placebo-controlled trials (46%).  Recent neurobiological research is focused not only in determining the specific circuits implicated in late-life depression, but also to determine quantifiable measures to gauge treatment response. Indices of functional connectivity in the default mode network (DMN) are promising neural markers of treatment response in late-life depression. Andreescu et al., examined the differences in DMN functional connectivity between treatment-responsive and treatment-resistant depressed older adults, using the posterior cingulate cortex as the seed region-of-interest. Comparison of pre- and post-treatment scans of depressed participants revealed greater posttreatment functional connectivity in the frontal precentral gyrus. 
Nearly all antidepressants have the common side effects of GI side effects, headaches, and increased anxiety, most of which subside within few days. Certain side effects of antidepressants can be even more serious in the elderly. Elderly inpatients on SSRIs or venlafaxine are at definite risk for developing hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone. They need sodium level monitoring before and after starting antidepressant medications. Other serious side effects reported with SSRIs include the risk of falls and hip fractures, serotonin syndrome (lethargy, restlessness, hypertonicity, rhabdomyolysis, renal failure, and possible death), GI bleeding, and insomnia. Apart from this, SSRIs can worsen restless legs and periodic limb movements which further contribute to difficulties in sleep. Due to this starting dose in each case should be half of the lower dose of these suggested dose ranges and as a rule titration should be gradual. The norm "start low and go slow" should be followed. 
A meta-analysis of 25 randomized trials found that psychological treatments have moderate to large effects on depression in older adults.  The various psychological interventions generally used are cognitive and behavioral therapy, problem-solving therapy, reminiscence and life review therapy, brief psychodynamic therapy, and interpersonal therapy. Data obtained from a study involving 1602 depressed older primary care patients, found more patients preferred counseling (57%) than medication (43%).  Previous experience with a treatment type was the strongest predictor of preference. A systematic review of the common psychological interventions used in elderly depression found that problem-solving therapy, cognitive and behavior therapy and treatment initiation and participation program have supportive evidence in reducing depression in this population.  However, results need to be replicated, and methodological differences were a major limitation. Interventions for which evidence is still inconclusive are supportive therapy and interpersonal psychotherapy.
Two psychological interventions, which have specifically been used in elderly depressed patients are reminiscence therapy and life story review. Reminiscence has been defined as "the vocal or silent recall of events in a person's life, either alone or with another person," or a group of people.  Life review is more structured, systematically addresses the whole life-span, and focuses on both positive and negative events (conflicts). In life review interventions, reframing of negative events and the integration of important life-events in a coherent, meaningful life story (synthesis), is actively looked for by both participant and counselor. A meta-analysis of 15 controlled outcome studies found that life-review had significantly greater effect on psychological well-being than simple reminiscence. 
Role of alternative treatments
Nyer et al.,  reviewed the various complementary and alternative medicine treatments available for elderly depressed patients, and concluded that interventions such as exercise, yoga, tai chi, and massage therapy have demonstrated benefit in the elderly. Less physically oriented interventions such as music therapy and spiritual-religious based therapy also have encouraging outcomes, but there exists only preliminary evidence in their support. Research in this area is still scarce, and clinician should weigh the risks and benefits in individual patients before recommending these treatment options [Table 1] and [Table 2]. ,
| Conclusion|| |
Late-life depression presents with a host of challenges in both assessment and management. A significant proportion of patients with late-life depression remain under-recognized, and hence, untreated. The increased risk of serious side-effects with pharmacological agents warrants judiciousness while prescribing them. consequently (or therefore), a holistic approach should be adopted while treating these patients, with greater emphasis on psychosocial management, improving utilization of health services, and increased emphasis on social re-integration.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]