Late-Life Depression: A Review
This article is no longer available for CME credit.
At the conclusion of this activity, participants should be able to:
1. Describe the prevalence and consequences of late-life depression.
2. Accurately diagnose late-life depression.
3. Explain the neurobiology and risk factors for late-life depression.
4. Recommend appropriate treatments for late-life depression.
Major depressive disorder (MDD) is undiagnosed in approximately half of all elderly persons with this disorder.1 Contributing to this fact is that elderly patients are more likely than their younger counterparts to see their primary care physician rather than a psychiatrist.2 Major depressive disorder is not uncommon, occurring in approximately 2% of all community-dwelling elderly.3,4 In primary care clinics, the prevalence increases to approximately 6-9%,5 while among the patients admitted to acute care hospitals, the prevalence is approximately 10-12%. Among all nursing home residents, 12-14% meet the criteria for MDD.6 However, the rates of depressive symptoms in general are much higher, with studies showing prevalence rates between 30% and 45%.3,7
Beyond its prevalence, geriatric depression has severe ramifications, carrying with it an increased risk of both morbidity and mortality. Elderly patients with depression have a 1.5-3 times increased morbidity and a lifetime suicide risk of approximately 15%, with almost 10% of these patients dying annually from suicide.3 Given this broad-reaching clinical significance, it is imperative for the primary care and the psychiatric community to appreciate the unique presentation, diagnosis, and treatment of MDD in geriatric patients as compared to the general population. In this article, we review late-life depression and highlight the issues that need to be considered in treating patients with this disorder.
Presentation and Diagnosis
The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM–IV-TR) defines MDD as a condition characterized by the presence of depressed mood or loss of interest or pleasure. Associated symptoms include changes in appetite or weight (5% of total body weight), sleep, energy, concentration, and psychomotor activity, as well as feelings of inappropriate guilt or worthlessness, and recurrent thoughts of death or suicide.
Although not part of any standardized classification system, late-life depression is generally described as depression arising in adults older than 65 years of age who have not had a previous history of mood disorder.6 Population studies reveal that the presentation profile of late-life depression is distinct from that of the younger population. In general, patients with late-life depression are less likely to have a family history of depression than their younger counterparts.8 Their symptoms are more likely to develop insidiously, and these patients are less likely than their younger counterparts to attribute their symptoms to depression as opposed to “the normal aging process.”3
Elderly patients with depression usually present with higher rates of psychotic symptoms as compared to their younger counterparts. Proposed explanations for this disparity include age-related deterioration of cortical areas, neurochemical changes common in aging, comorbid physical illnesses, social isolation, sensory deficits, cognitive changes, and polypharmacy.9 The Epidemiologic Catchment Area survey reported a range of psychosis from 16% to 23% in an older adult population.10 In addition, psychotic late-life depression accounts for nearly 25-50% of admissions to the inpatient geriatric psychiatry units.11 Patients may present with delusions that are nihilistic, somatic, or poverty-based,3 and these patients also appear to have higher rates of insomnia, somatic symptoms, diurnal variation of mood, and poor insight.11 Although delusions are common, hallucinations appear less likely in these patients. Psychotic symptoms generally occur in those elderly patients who are single, widowed, or living alone.11 The presence of psychotic symptoms in depression appears to be a poor prognostic sign, as patients with these symptoms present with frequent recurrences and repeated hospitalizations.3
Dementia and its relation to depression in the elderly deserves particular attention, especially with regard to the accuracy of diagnosis, as these two conditions can easily mimic each other. Dementia of depression (previously called pseudodementia) refers to reversible cognitive impairment seen in the setting of a depressive episode that improves with the treatment of that episode.3,6 Conversely, depression can be an early-presenting symptom of dementia. It is unclear whether such an episode of depression is a prodrome for the onset of dementia, a risk factor for dementia, or an independent event. It appears most likely that the relationship between affective abnormality and cognitive decline is patient-dependent. Care must also be taken when making the proper diagnosis, as both the treatment and prognosis differ greatly between an MDD and dementia.12
Acute onset of symptoms, presence of guilt or self-reproach, diurnal variation of mood, poor effort on testing, past affective episodes, gives up easily when a mistake is made, can be coached on practice effects, and impaired registration and recall help differentiate dementia of depression from a primary progressive dementia. Patients with dementia of depression usually do not have any other cognitive deficits, and their symptoms often tend to improve with sleep deprivation.13
Given the complex relationship between mood disturbances, cognitive function, and somatic complaints, it is recommended that any elderly patient with multiple unexplained medical complaints or cognitive decline be screened for depression. During the medical work-up, a full psychiatric interview should also be performed. If depression is suspected, prompt treatment should be initiated. Treatment of the depressive symptoms often alleviates the somatic symptoms and/or cognitive deficits.6 Given the high prevalence of depression and dementia in the elderly, it is recommended that routine screening for late-life depression (including an assessment of any changes in mood, activity, level of self-care, social interaction, and neurovegetative symptoms) and cognitive deficits be completed during their annual medical review to prevent missing the diagnosis of these two very important disorders. The two most widely used, efficient, and effective tools for this purpose are the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS). The PHQ-9 is a nine-item depression scale that consists of two components: an assessment of impairment to make a tentative diagnosis and the derivation of a severity score to help select and monitor treatment. The GDS is a 30-item self-report assessment developed in 1982 by Yesavage et al14 that has demonstrated reliability and validity when compared to other diagnostic criteria. However, these responses should be considered in the setting of a comprehensive diagnostic work-up, as is true of any individual scale.
Etiologic Factors and Neurobiology
Several biological, sociological, and psychological factors are important to consider when dealing with late-life depression. The most striking in this population is the interaction between depression and medical disorders. Among patients who are status post-cerebral vascular accident, the incidence of MDD is approximately 25%, with the rates being close to 40% in patients with Parkinson’s disease.15 Approximately one-quarter of patients with symptoms of myocardial ischemia also meet the criteria for MDD.16,17
Additionally, patients with late-life depression are more likely than their age- and education-matched counterparts without depression to have cognitive deficits that are correlative to the presence of depressive symptoms.18-20 Studies have found that between 20% and 50% of patients with late-life depression have cognitive deficits, with executive dysfunction being the most prominent.18-21 Changes are also seen in information processing and visuospatial ability.22
The association of depression with cerebrovascular lesions and cerebrovascular risk factors has led to the concept of vascular depression. Computed tomography scan, magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography studies have revealed co-localization of atrophy and ischemic lesions, especially in the frontostriatal, limbic, and subcortical structures,3,6 which causes changes to the neuronal circuits and neurotransmitters that regulate mood. These result in psychomotor retardation, reduced interest in activities, and poor insight.6
The elderly patient is also more likely to take multiple medications that can cause or contribute to the development of depression. Methyldopa, reserpine, clonidine, hydralazine, levodopa, benzodiazepines, tamoxifen, vinblastine, vincristine, estrogen and progesterone, corticosteroids, and cimetidine are some of the common medications that can cause or exacerbate symptoms of depression in the elderly.6 Although beta blockers were initially thought to cause depression, emerging data indicate that they are not necessarily precipitants of mood abnormality.23
Social considerations for the development of MDD in the elderly include unique stage-of-life issues including isolation, bereavement, and disability.3 Some specific risk factors for late-life depressive disorders include death of a spouse or other loved one, medical illness and injuries, disability and functional decline, and lack of social contact.24 The effect of these stressors persists even while controlling for biological and physical health status variables. Preliminary evidence also suggests that the impact of these psychosocial risk factors on depression can be affected by personal or environmental factors. Lastly, caregiving is also a risk factor for the development of depressive symptoms in the caretaker. Depression develops more commonly when caregiving is long-term and the person receiving the care has behavioral problems. It is also more common when care is performed without other social supports in place.25
Some psychological traits have also been found to predict the development of late-life depression. Elderly patients with neuroticism, pessimistic thinking, and those with less open attitudes to new experiences have been found to have higher rates of depression and suicide than in the younger population and controls.26-28
Consequences of Depression
Depression has far-reaching health consequences. Those suffering with depression are more likely to have a coexisting anxiety disorder, substance abuse or dependence, or chronic diseases such as arthritis.29 Depression has also been found to increase the risk of inflammatory activity and bone resorption.30 A retrospective analysis of patients enrolled in the National Health and Nutrition Examination Survey suggests that patients with depression are also at greater risk of developing heart disease than healthy individuals, and that men with depression and heart disease have a higher death rate than women with the two conditions.31
Depression is extremely costly in terms of disability.29 Decreased or lost workplace productivity, healthcare utilization, and costs of associated illnesses lead to tremendous financial burden to the individual and to society in general. A study of the estimated economic burden of depression found that in addition to the $26.1 billon spent on the direct medical costs of depression, $51.5 billion was lost in workplace costs that include absenteeism.32 Depression resulting in suicides generated an additional $5.4 billion in mortality costs. In a large epidemiologic survey, depressive symptoms and, to a lesser extent, major depression were associated with increased utilization of emergency department or medical consultations for emotional problems.33 A retrospective analysis showed that comorbid psychiatric and chronic physical illnesses incurred over 70% of total healthcare costs in patients with depression.34
Elderly patients with depression remain at very high risk of committing suicide. The elderly are two times more likely to commit suicide than their younger counterparts.8 Of these, approximately 80% suffered from a depressive syndrome.6 Among suicide completers, almost three-quarters had visited their primary care physicians within the preceding month. Most of these subjects were suffering from their first episode of depression, which was often undiagnosed and untreated.8 The most concerning group are elderly white males with MDD. These individuals are five times more likely to commit suicide than the general population.16 Additional risk factors for suicide include coexistence of somatic illness, bereavement, social isolation, disability, sedative use, substance abuse, and the availability of a firearm.3,6,15
Risk factors for late-life depression leading to suicide include all of the following: anxious agitation, increasing insomnia, worsening self-esteem, and comments made regarding suicide. Other risk factors include substance abuse, associated psychotic symptoms, personality disorders with aggressive and narcissistic features, previous suicidal attempts, the development of cancers (particularly pancreatic cancer), poorly controlled pain, and treatment with chemotherapeutic agents (most notably corticosteroids, procarbazine, L-asparginase, interferon alpha, and interleukin-2).3,6,15,35
Given the above risk factors, it is important to not only identify patients reporting overt suicidal thought or plans, but also to be able to conduct a formalized assessment that evaluates a patient’s level of risk for harm to self and suicidal ideation. Once a patient is identified as having an inclination toward suicide, simply completing a contract for safety is not sufficient—a systematic suicide risk assessment must be performed. Such an evaluation is an inductive process that weighs the patient’s risk and protective factors, and stratifies the patient into low, moderate, or high levels of risk. Clinical guidelines for the management of patients deemed to be at risk of committing suicide are given below.36
• Patients deemed to be at high risk should be hospitalized, especially if they have current psychological stressors and/or access to lethal means.
• Patients at moderate risk may be treated as outpatients, provided that they have adequate social support and no access to lethal means. These patients may require hospitalization if they do not have social support or adequate supervision.
• Patients at low risk should have a full psychiatric evaluation and be followed up carefully for any ongoing psychosocial stressors. Usually, they can be safely treated with antidepressant medication and followed as outpatients.
The treatment modalities used in the treatment of elderly patients with depression are similar to those in younger patients and include psychotherapy, pharmacotherapy, and/or electroconvulsive therapy (ECT).6,8,15 There are also good data to support the utility of exercise as a nonmedical intervention to target depressive symptoms in the elderly. Particularly effective are aerobic and supervised group exercise regimens.37
Supportive psychotherapy in the elderly population is often useful in dealing with situational depression and loss; however, controlled studies of formal psychotherapy are limited. Cognitive-behavioral therapy (CBT) has been found to be more effective than placebo,38 and interpersonal therapy (IPT) has been shown to augment treatment with nortriptyline as compared to nortriptyline with placebo.39 There is broad agreement that psychotherapy of some sort is a useful component in successful treatment of MDD in the elderly.15
When using pharmacotherapy, unique considerations must be made for the treatment of depression in the elderly. Changes in absorption, excretion, and metabolism lead to higher serum levels and longer half-lives of medications at equivalent doses, when compared to the young adults. In addition, as age increases, the fat-to-muscle ratio usually increases, and this increases the volume of distribution for most psychotropic medications.3 For these reasons, adverse reactions are more common. It is suggested that medications be started at low dosages, and upward titration be done slowly.
Noncompliance is also a more prominent problem among the elderly. It is most likely to be due to worsening memory and higher rates of unpleasant side effects. An estimated 70% of the elderly outpatients only receive even half of the recommended doses of medication.3 A summary of commonly used antidepressant medications in the elderly is provided in the Table.
A systematic review of placebo-controlled trials in geriatric depression revealed that no significant difference in efficacy exists between active agents (ie, tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors [SSRIs], bupropion, and mirtazapine), although many of these studies were underpowered to detect such differences.5 Number-needed-to-treat analysis for all antidepressants has revealed that eight patients must be treated to have one additional patient achieve a 50% reduction in depressive symptoms, as measured by the Hamilton Rating Scale for Depression (HAM-D) score.5
As most available agents are roughly equal in terms of efficacy, safety and tolerability often dictate choice of medication. The relatively benign side-effect profile of the SSRIs makes these agents the first-line treatment for MDD in the geriatric population.15 The most common side effects, including nausea, diarrhea, anxiety, and sleep disturbance, are not life-threatening.40
Tricyclic antidepressants are no longer considered first-line treatment for MDD in the elderly.8,15 Although efficacious, they are associated with multiple side effects due to their broad receptor profile. Histamine receptor effects can cause sedation and weight gain. Alpha-adrenergic receptor effects can cause hypo/hypertension. Muscarinic receptor effects can cause tachycardia, dry mouth, visual problems, and dizziness. When used, the secondary amine TCAs (nortriptyline and desipramine) are safer in the elderly as compared to the tertiary amine TCAs (imipramine and amitriptyline).8,15 Tricyclic antidepressants are lethal in overdose, which is particularly pertinent given the increased risk of suicide in the elderly population.15
Other antidepressant medications that have been used in elderly patients include venlafaxine, which was shown to be as effective as citalopram in a randomized placebo-controlled trial of 151 patients over age 65 years. As venlafaxine has no monoamine oxidase inhibitory activity and does not interact with either muscarinic or histaminergic receptors, it is thought to have a good tolerability profile.41 Duloxetine, similar in its receptor activity to venlafaxine, was recently shown to be superior to placebo in a randomized, double-blinded trial in older patients. Duloxetine may prove to be particularly useful in the elderly population, as it has also been shown to improve pain symptoms; however, this observation requires further inquiry.42
Mirtazapine was found to have quicker onset of action, better tolerability, and equal efficacy when compared to paroxetine in a trial of 255 elderly patients.43 The side-effect profile of mirtazapine, which includes increased appetite and sedation, are also often beneficial to elderly patients with poor appetite and decreased sleep duration.
Available data on the treatment of depression in younger patients indicate that augmentation and/or switching strategies are effective for those who do not respond to first-line antidepressants treatment.44 However, similar data for the treatment of depression in the elderly are limited.45 A 2004 published study reporting on this issue indicates that there were similar rates and speed of response with an augmentation strategy as compared to a strategy of switching to venlafaxine extended release.46
Electroconvulsive therapy has been shown to be an effective treatment for depression resistant to medications.47 Unilateral ECT is preferable in the short term (after five treatments), but after 3 weeks of treatment, bilateral and unilateral ECT have similar efficacy.47 Fixed, high-dose right unilateral treatment yielded faster results and required fewer treatments as compared to titrated moderate-dose right unilateral ECT; however, final outcome measurements were similar between these two modalities.47 No randomized trials have been conducted comparing ECT with antidepressant medications. The evidence available shows that ECT is generally safe in this population. The data regarding cognitive decline and ECT are not conclusive, with some studies even showing an improvement and stabilization of cognitive functioning. The prevalence of interictal confusion and delirium appear to be short-lived. Evidence also indicates that cardiovascular side effects such as hypertension and tachycardia may occur more regularly, but they are mild and temporary.47
Consensus guidelines published in 2001 supported medication plus psychotherapy as the most widely accepted first-line treatment for severe depression in the elderly population, with medication alone as an alternative first-line treatment approach.15 Medications designated as first-line agents included SSRIs (specifically citalopram and sertraline) and venlafaxine extended release, with TCAs, bupropion, and mirtazapine being designated as second-line agents. Electroconvulsive therapy was considered an appropriate alternate treatment for severe depression when treatment with two medications had failed, an acute suicide risk was present, or medical comorbidity made medical treatment impossible. These experts did not recommend psychotherapy alone for more severe forms of depression. Psychotherapies that were rated as being first line by these experts included CBT, supportive psychotherapy, IPT, and problem-solving therapy.15
For psychotic MDD, the recommendation is to use an antidepressant medication with an antipsychotic medication in combination as first-line agents, with an ECT trial if the patient did not respond to medical treatment.15 Atypical antipsychotics (except clozapine) are clearly preferred in these patients. The choice of antidepressants includes SSRIs and venlafaxine as first-line treatment, with TCAs being the alternative. For more minor depressive episodes, medication combined with psychotherapy was regarded as the first-line treatment strategy, with either modality of treatment alone being an acceptable alternative. It is recommended that a 4-7–week trial on the maximally tolerated dose of one medication be achieved before switching to another medication.15
Suggested duration of treatment for a first major depressive episode is 6 months, assuming the patient tolerates the medication with no adverse effects. However, recent data indicate that longer treatment (2 years) may prevent a relapse.48 Usually some symptomatic improvement is seen within 4-6 weeks of initiating treatment. Longer-term therapy should be considered after a second episode. Evaluating effectiveness of treatment should consist of regular assessment of mood, function, and quality of life.49 It is useful to follow objective end points, including hours spent out of the house, enjoyable activities, and hours able to read/watch television.
Bartels et al50 showed that older patients are most likely to engage in depression treatment when it is offered in a primary care setting. Although involving a mixed population group (19-90 yr), Hunkeler et al51 also indicated that the presence of a skilled and empathic care manager was vital to the success of treatment of depression in primary care. Two studies also indicated that collaborative care can reduce depression over a 2-5–year period.50,52
Keeping these lessons in mind, two specific studies for the treatment of depression in elderly patients were designed. In the first, patients were randomly assigned to the Improving Mood Promoting Access to Collaborative care Treatment (IMPACT) program or usual care for depression. The findings from this study indicate that tailored collaborative care can actively engage older adults in treatment for depression and delivers substantial and persistent long-term benefits such as less depression, better physical functioning, and an enhanced quality of life.53
In another collaborative study, the PRevention Of Suicide in Primary care Elderly: Collaborative Trial (PROSPECT), researchers tested whether a trained clinician (the “health specialist”) can work in close collaboration with a primary care physician to implement a comprehensive depression management program and improve outcomes in older patients with depression.54
In the first published result from the PROSPECT study, the rates of suicidal ideation declined faster in intervention patients compared with usual care patients at 4 months in the intervention group. Raw rates of suicidal ideation also declined in the intervention group. Among patients who reported suicidal ideation, the resolution of ideation was faster among the intervention patients, who also had a more favorable course of depression in both the degree and speed of symptom reduction, with the group difference peaking at 4 months.55
In the second published result from the PROSPECT study, patients with major depression and a 24-item HAM-D score of 18 or greater were randomly assigned to the PROSPECT intervention with trained care managers or to usual care. First remission occurred earlier and was more common among patients receiving the intervention than among those receiving usual care. Patients experiencing hopelessness and those who had low baseline anxiety were more likely to achieve remission if treated in intervention practices.56
These studies indicate that elderly patients with depression respond very well to treatment, especially if it is structured and provided within the rubric of their primary care.
While there is no clear consensus as to when a patient should be referred for a psychiatric evaluation, primary care physicians should consider referral when the elderly patient does not respond to first-line medications, is reticent to trial of medications, would prefer therapy, or presents with a difficult diagnostic picture (ie, rule out depression-associated dementia). Severe depression with psychotic symptoms, suicidal ideations, and/or inability to care for self requires immediate psychiatric evaluation and possible hospitalization.
A recent systematic review indicated that older patients with an index episode of depression appear to have a higher risk of repeat episodes. In these patients, the presence of medical comorbidity represented a risk factor for inferior treatment response and poor antidepressant tolerability.57 It is estimated that among elderly persons with depression, 25% will achieve full remission with or without treatment. Twenty-five percent of these subjects never achieve any response to treatment, with the remaining 50% having a waxing-and-waning course.3 Poor prognostic indicators that have been identified in the elderly include physical handicap, psychotic features, comorbid medical illness, and lack of social support.3,11
There are sufficient data that early treatment with medications and psychotherapy improve symptoms of depression and prevent serious consequences such as suicide.56,58,59 The data on primary prevention of depression are extremely limited.60 The few references that are available focus on blood pressure control to prevent cerebrovascular disease as a means of preventing vascular depression.7 However, a study by Rybarczyk et al61 randomly assigned elderly people who experienced chronic illness to a classroom intervention, a home study program, or a wait list, which was considered the control condition. Compared to the control condition, both interventions led to a significant decrease in self-report of pain, sleep difficulties, and symptoms of depression and anxiety. A more recent study confirmed the effectiveness of minimal interventions such as self-help books reviewed with home care nurses in preventing patients with subthreshold depression from developing into late-life depression.62
Late-life depression is a common condition seen in the elderly. The onset of depression in late life is associated with multiple complications that impair the health and well-being of elderly patients. The diagnosis of late-life depression is often missed in the primary care setting, and the adverse consequences of untreated depression remain high. Both medications and psychotherapy have been found to be helpful in the treatment of depression in late life. Prognosis of this condition depends on the presence or absence of medical comorbidity, physical handicap, psychotic features, and social support. Recent studies indicate that the development of depression can be prevented in the elderly, but this topic requires further research to confirm these findings and to clarify the effectiveness of such interventions.
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The authors report no relevant financial relationships.
Dr. Tampi wishes to acknowledge the support of Geriatric Academic Career Award (1 K01 HP 00071-03) for this academic activity.
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