Diagnosis and management of late-life depression

INTRODUCTION — 

The term late-life depression includes both aging patients whose depressive disorder presented in earlier life, and patients whose disorder presents for the first time in later life. Depressive illness in the older population is a common and serious health concern that is associated with impaired functioning, medical comorbidity, excessive use of health care resources, and increased mortality (including suicide) [1].

Late-life depression remains underdiagnosed and inadequately treated [2-5]. In the United States, older men, especially older African Americans and Hispanic Americans, are at even greater risk of unrecognized depression [6-8]. The public health consequences of inadequately treated depression in late life will increase over time as the population continues to age.

Most mental health treatment for older adults with depression is delivered in the primary care setting. Depression often goes undiagnosed in primary care [9], and is often left untreated, even when diagnosed [10]. Recognition and management of late-life depression is an important responsibility for the primary care clinician. Either pharmacotherapy or psychotherapy can benefit patients [1].

This topic reviews the epidemiology, diagnosis, and treatment of late-life depression. The clinical features, assessment, diagnosis, and treatment of major depression in adults aged 18 to 65 years are discussed separately. (See "Depression in adults: Clinical features and diagnosis" and "Approach to the adult patient with suspected depression" and "Major depressive disorder in adults: Approach to initial management" and "Unipolar depression in adults: Choosing treatment for resistant depression".)

EPIDEMIOLOGY AND PATHOGENESIS — 

Depression is not a normal consequence of aging [11,12]. Sadness and grief are normal responses to life events that occur with aging such as bereavement; adjustment to changes in social status with retirement and loss of income; transition from independent living to assisted or residential care; and loss of physical, social, or cognitive function from illness (see "Bereavement and grief in adults: Clinical features"). Despite these losses, healthy independent community-dwelling older adults in the United States have a lower prevalence rate of clinical depression than the general adult population (figure 1) [13].

Prevalence in the general population

●Prevalence – The global estimated rates of major depression and minor depression for community-dwelling older adults are 4 and 10 percent [14,15].

Cultural factors [16] as well as variations in methods of assessment lead to significant variations in reported prevalence. Rates of depression are higher for older adults with comorbid medical illness and in general medical settings [17]. Hospitalized geriatric populations have prevalence rates of depression over 30 percent, and patients with stroke, myocardial infarction (MI), or cancer have rates over 40 percent (figure 1) [18-20].

●Incidence – Although the prevalence of depression in the older population is lower than in comparable younger groups, incidence rates may not differ. In a prospective study of older community-dwelling persons in the Netherlands who were followed for eight years, the incidence of depressive syndromes (major depression and persistent depressive disorder) was 7 per 1000 person-years [21].

The true incidence of depressive disorders in the oldest old (>80 years old) may be underestimated, although few epidemiologic studies have included participants of these ages [22,23]. In one study, the global incidence rates for major depressive disorder among participants 80 years and older were comparable to those for participants ages 60 to 80 years [15].

●Recurrence – Most depressive episodes occur in persons with a prior history of depression, with a recurrence rate of 25.5 per 1000 person-years [21]. Clinically significant but subthreshold depressive symptoms occurred at twice the rate of depressive syndromes.

Risk factors — Patients who experience their first episode of depression later in life are less likely to have a family history of depression or other major mental disorder than patients whose first episode occurred earlier in life. This difference suggests that genetic or familial factors are less likely to have a role in late-onset depression [3,24].

Risk factors for late-life depression include [25]:

●Female sex

●Social isolation

●Widowed, divorced, or separated marital status

●Lower socioeconomic status

●Comorbid general medical conditions

●Uncontrolled pain

●Insomnia

●Functional impairment

●Cognitive impairment

Depression occurring in the course of adverse life events was previously termed "reactive depression" and felt to be an expected consequence of stress or trauma. Clinical major depression should be addressed as a serious medical condition regardless of life precipitants because it causes significant functional impairment and can be effectively treated.

Insomnia is not only a risk factor for developing dysthymia and depression in older adults, but persistence of insomnia has been associated with persistence of depression [26]. Additionally, a history of sleep disturbance was an independent risk factor for recurrence of depression in older adults in remission from depression [27]. Further studies are indicated to determine whether insomnia, rather than a symptom of depression, is a comorbid disorder in at least some older patients, and whether treatment for insomnia would improve depression response or prevent recurrent depression.

●Nursing home residence – As many as 50 percent of nursing home residents are depressed. A study of 634,060 nursing home residents 65 years and older found that during their first year, 54 percent had physician-diagnosed depression [28]. Severe cognitive impairment was associated with lower rates of depression; such impairment may interfere with detecting depression.

●Sex – The prevalence of depression is higher in females across all age groups. Several factors may account for the disproportionate prevalence of depression in older females: greater susceptibility to depression, greater persistence of depression after its onset, and lower mortality [29]. This may also be an artifact of how depression is defined and symptoms are elicited [30-32]. Males are more likely to present with anger, irritability, anhedonia, withdrawal or apathy, and excess alcohol use and are less likely to acknowledge sadness or psychologic symptoms [33]. With increasing age, the gender gap in depression prevalence narrows [31]. Males, with a higher prevalence of vascular risk factors, may also present with a depression subtype known as vascular depression.

●General medical illness – Medical conditions and their treatments can increase the risk of developing depression. The risk in physically ill older adults increases with:

•Recent onset of physical illness

•Greater severity of physical illness

•Functional disability and limited mobility

•Poorly treated pain

•Multiple illnesses

As an example, in a prospective cohort of adults without depressive symptoms at baseline, new diagnoses of cancer, chronic lung disease, and heart disease were associated with higher rates of developing depressive symptoms, compared with adults without these diagnoses [34]. Depressed mood may also be the first symptom of common medical conditions that affect older adults, including stroke, diabetes, cancer, hypothyroidism, and coronary disease.

The effect of medical comorbidities on the risk of depression in the general population is discussed separately. (See "Depression in adults: Clinical features and diagnosis", section on 'Medical illnesses'.)

●Vascular depression – Cerebrovascular disease may increase an older person's risk for depression through a variety of neurobiologic mechanisms [35,36]. Depression may develop after an acute cerebrovascular event (termed "poststroke depression") [37] or may develop in association with chronic ischemic changes in the brain (termed "vascular depression") [36,38]. Poststroke depression is discussed elsewhere. (See "Complications of stroke: An overview".)

Several studies illustrate the importance of chronic ischemic cerebral changes. A study of patients with depression with and without magnetic resonance imaging (MRI) abnormalities demonstrated that positive MRI findings correlated with older age at onset of depression, vascular comorbidity, greater psychomotor slowing or Parkinsonism, anhedonia, increased functional impairment, and lower incidence of psychosis [38,39]. In another study of participants with late-onset depression, those with cerebrovascular risk factors had more cognitive impairment and disability, more psychomotor retardation, less agitation, less guilt, and less insight into their illness, compared with participants without cerebrovascular risk factors [36]. Individuals with depression and vascular risk factors have also been found to be at higher risk of developing vascular dementia [40]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

Preliminary data suggest that these patients may preferentially respond to nonstandard antidepressant therapy, including older antidepressants, combination therapies, or electroconvulsive therapy [35,37,41].

The syndrome of depression with executive dysfunction may also be related to cerebrovascular disease or age-related neurodegeneration [42,43]. Patients present with frontal executive impairment manifested by difficulties with motivation, organization, planning, sequencing, and abstracting. They typically exhibit anhedonia and apathy rather than sadness and have cognitive impairment with psychomotor retardation [43,44].

Pathogenesis — The pathogenesis of late-life depression is multifactorial and likely involves a complex interplay of biochemical abnormalities, alteration of neural networks, neuroinflammation, neuroimmune dysregulation, deposition of beta-amyloid (and tau), and genetic factors [45-47]. Subclinical cerebrovascular disease may also influence the susceptibility to, and expression of, late-life depression. Cerebral atrophy, subcortical deep white matter and periventricular ischemic lesions, and decreased volumes in specific brain regions may be implicated [48-51].

Additional information about the pathogenesis of depression is discussed separately. (See "Unipolar depression: Pathogenesis".)

COMORBIDITY — 

Depression amplifies disability and lessens quality of life. Late-life depression is associated with increased office and emergency department visits, increased drug use and cost for both prescription and over-the-counter medications, higher risk for use of alcohol or illicit drugs, increased length of inpatient stay, and overall higher costs of care [52,53]. Depression in late life also tends to be a recurrent or persistent condition and adversely impacts both medical and psychiatric morbidity and mortality [30,54].

General medical comorbidity — Treatment of depression can improve health outcomes in patients with chronic medical conditions, such as chronic pain, diabetes, cardiovascular disease, and osteoarthritis [55-57]. The impact of depression on medical mortality is being recognized and quantified:

●Depression onset in post-MI patients was associated with a fourfold increase in death [58].

●Patients who developed depression after a stroke were 3.4 times more likely to have died over a 10-year follow-up period [59,60].

●Depression at the time of admission to a nursing home increased one year mortality [61].

●A modified diagnosis of major depressive disorder and a past history of depression independently predicted in-hospital death with an odds ratio of 7.8 after controlling for severity of illness [62].

Treatment of depression may also impact medical mortality. A decrease in overall risk of death at five years, attributed to fewer cancer deaths, was seen in patients age 60 and older with major depression who were randomly assigned to an intervention to improve depression treatment (involving a care manager), compared with patients assigned to a control group receiving usual care [63].

The impact of depression on health outcomes in the general population is discussed separately. (See "Depression in adults: Clinical features and diagnosis", section on 'Medical illnesses'.)

Dementia — Late-life depression is associated with an increased risk of subsequently developing dementia:

●A meta-analysis of 23 prospective, community-based, observational studies included more than 49,000 subjects who did not have dementia at baseline and were followed for a median of five years [64]. The risk of all-cause dementia was greater in subjects with late-life depression than the nondepressed controls (risk ratio 1.9, 95% CI 1.7-2.0). Specifically, late-life depression was associated with an increased risk of Alzheimer disease and vascular dementia, and the risk of vascular dementia was greater than the risk of Alzheimer disease. The elevated risk for all-cause dementia persisted in analyses that included only those studies (n = 17) that adjusted for potential confounders (risk ratio 1.6, 95% CI 1.4-1.8).

●A retrospective study of medical records (n>13,500 individuals who did not have dementia at baseline) over a six-year follow-up period found that after adjusting for potential confounds, the risk of all-cause dementia was increased by 70 percent in subjects who had late-life depressive symptoms (hazard ratio [HR] 1.7, 95% CI 1.5-1.9) [65]. Specifically, depression was associated with an increased risk of Alzheimer disease and vascular dementia.

Late-life depression may reflect a prodromal stage of dementia or may act as an independent risk factor for dementia.

Conversely, Alzheimer disease and other dementia are associated with an increased risk of incident depression. As an example, in a Swedish population-based cohort, rates of new-onset major depression were higher in those with Alzheimer dementia, compared with those without dementia, after adjustment for potential confounders (HR 2.2, 95% CI 2.1-3.2 in females; HR 2.7, 94% CI 2.5-2.9 in men) [66].

Presentation and treatment responsiveness may significantly differ from early onset and other types of depression [67,68]. A proposal from the American Association for Geriatric Psychiatry suggests revised diagnostic criteria for depression in Alzheimer disease (table 1) [69]. Additionally, depression is a common complication in many other dementia syndromes including Parkinson dementia, Lewy body dementia, frontotemporal dementia, and Huntington dementia. (See "Management of neuropsychiatric symptoms of dementia".)

Suicide — Depression is a major risk factor for suicide in older adults, who account for approximately 13 percent of the United States population, but for nearly 24 percent of all completed suicides [70]. Older patients attempt suicide less often than younger patients, but are more successful at completion [71]. Older adult males have the highest suicide rate; in the United States, males age 85 or older have the highest rate of completed suicide: 55.7 per 100,000 [72].

Clinical features that may increase the acute risk of suicide in older individuals include hopelessness, insomnia, agitation or restlessness, impaired concentration, active psychosis, active alcohol use or intoxication, and untreated, unremitting pain. (See "Suicidal ideation and behavior in adults".)

Other risk factors for suicide include [71,73,74]:

●Comorbid physical illness

●Chronic and inadequately treated pain

●Terminal illness or worsening of physical illness

●Widowhood and social isolation

●Personality disorders

●Prior suicide attempt

●Family history of suicide

Compared with usual care, collaborative care interventions for older adults with depression can lower rates of suicidal ideation [75,76]. (See 'Collaborative care' below.)

Other psychiatric comorbidity — Comorbidity of depressive illness with other psychiatric syndromes, such as anxiety, somatization, and substance use disorders, may affect depression's clinical presentation and treatment response and increase the risk of relapse and recurrence [3,25,77]. Comorbid substance misuse with alcohol, prescription pain, or hypnotic medications is underrecognized and increases the risk of falls, accidents, and cognitive impairment [4,25,77].

Comorbidity with anxiety may be a particular problem in the older population. The presence of anxiety with depression, especially if somatic complaints are overemphasized or primarily addressed, can lead to a missed diagnosis or inappropriate treatment with anxiolytic, hypnotic, or pain medications [4,77,78].

The types and impact of psychiatric comorbidities in the general population are discussed separately. (See "Depression in adults: Clinical features and diagnosis", section on 'Psychiatric'.)

CLASSIFICATION — 

The effects of age of onset, changes in the aging brain, and the presence of medical comorbidity influence the type and expression of depression as well as treatment responsiveness. Some patients may have clinically significant depressive symptoms but do not totally fulfill the criteria for syndromal major depression as defined by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (table 2) [79]. (See "Approach to the adult patient with suspected depression".)

Major depression — The DSM-5-TR criteria for major depression (table 2) are identical for both older and younger patients [79]. Of note, major depression in later life is more likely to become chronic and recovery may be more transient, leading to frequent relapses. The risk of relapse and chronicity appears heightened by extensive comorbidity.

●With cognitive impairment – Older individuals with major depression may have cognitive impairment that develops coincident with or after the onset of mood symptoms, a condition referred to as dementia syndrome of depression (previously known as pseudodementia). Effective treatment with antidepressants or psychosocial interventions, such as behavioral activation, may improve the cognitive and mood symptoms of these patients. By contrast, mild to moderate depression in patients with Alzheimer disease may not respond to antidepressant therapy [80], or if depressive symptoms do improve [81-83], the primary cognitive deficits of Alzheimer disease persist or become worse. Older individuals with cognitive impairment secondary to major depression may be at higher risk of developing an irreversible dementia syndrome, such as Alzheimer disease [81-85]. (See "Management of neuropsychiatric symptoms of dementia", section on 'Depression'.)

●With psychotic features – Major depressive disorder with psychotic features (delusions or hallucinations) is a severe subtype of major depression (major depressive disorder), which occurs at least as often in older patients as in younger patients [86-89]. The epidemiology, clinical features, assessment, diagnosis, treatment, and prognosis of depression with psychotic features are discussed separately. (See "Unipolar major depression with psychotic features: Epidemiology, clinical features, assessment, and diagnosis" and "Unipolar major depression with psychotic features: Acute treatment" and "Unipolar major depression with psychotic features: Maintenance treatment and course of illness".)

Other depressive disorders

●Persistent depressive disorder – Older patients should fulfill the same DSM-5-TR criteria for persistent depressive disorder (table 3) as younger patients [79,90]. Persistent depressive disorder manifests with depressive symptoms that occur on the majority of days for at least two years. Older patients with late-onset persistent depressive disorder have a higher prevalence of cardiovascular disease but are otherwise similar to older patients with late-onset major depression [91]. Patients with persistent depressive disorder are at greater risk of developing major depression, so-called "double-depression," and may be particularly treatment resistant.

●Minor depression – Minor depression (subsyndromal depression) is diagnosed in patients with depressive syndromes that do not meet DSM-5-TR criteria for major depression (table 2) or persistent depressive disorder (dysthymia) (table 3) because of too few symptoms or the duration of symptoms is too short. In DSM-5-TR, minor depression is classified as "other specified depressive disorder," followed by the reason that the depressive syndrome does not meet the criteria for a specific disorder such as major depression or persistent depressive disorder [79,90]. Reasons include "depressive episode with insufficient number of symptoms" or "short duration depressive episode."

Minor depression in late life is more prevalent than major depression, and minor depression is important in the older population because these patients suffer disease burdens comparable to patients with major depression, including poorer health and social outcomes, functional impairment, and higher health care utilization and treatment costs [92-95].

In addition, patients with minor depression are at high risk for subsequently developing major depression and may develop suicidal ideation. In one study, patients with minor depression, age 60 years and older, had a sixfold risk of developing major depression at one year compared with patients without depression [95].

The clinical features, diagnosis, and treatment of minor depression in mixed-age populations are discussed separately. (See "Minor depression in adults: Epidemiology, clinical presentation, and diagnosis" and "Minor depression in adults: Management".)

SCREENING — 

We routinely screen older individuals for depression. Several screening tools are available (table 4). Patients who screen positive should undergo additional evaluation to establish the diagnosis of major depression or another depressive disorder and to identify factors contributing to depression that can be addressed through treatment. Depression screening for older adults is discussed separately. (See "Screening for depression in adults", section on 'Older patients (ages 65 and older)'.)

DIAGNOSIS — 

Assessing patients to make the diagnosis of depression in late life is challenging, especially in physically frail older adults. Multiple factors complicate the diagnosis of depression in older adults:

●Concurrent medical illness with overlapping symptoms of depression (fatigue, psychomotor slowing, loss of appetite, sleep disturbance, lack of sexual interest, memory complaints)

●Medication effects that may cause or exacerbate symptoms of depression

●Impaired communication skills in older adults

●Patient presentation with multiple somatic complaints

●Lack of time in the clinical examination to evaluate psychologic problems in patients with complex medical issues

●Therapeutic nihilism regarding depression on the part of the patient, family, or provider

●Patient's reluctance to acknowledge psychologic distress due to perceived stigma of mental illness [96]

Depression diagnosis with medical comorbidity — A few clues are helpful in diagnosing late-life depression in the setting of medical comorbidity. Depression should be considered when the following are present:

●Mood or somatic symptoms out of proportion to what is expected

●Poor response to standard medical treatment

●Poor motivation to participate in treatment

●Lack of engagement with care providers

Depression diagnosis in frail older adults — Dysphoric mood may be less reliable as an indicator of depression in the oldest old (>85 years of age) [33]. Depression criteria in frail older adults should emphasize a change in mood or interest with at least two weeks duration, nonphysical symptoms, and social regression or incapacity. Physical symptoms used to support the diagnosis of depression should occur with or worsen after mood symptoms and should be out of proportion to what is expected of the illness or usual treatments. Depression is less likely to be present if the patient responds to affection from family and caregivers, retains humor, looks forward to visits, and accepts assistance and care.

MANAGEMENT

Approach to treatment — Successful treatment of depression in late life includes several components: addressing comorbid conditions, tailoring pharmacologic or other interventions to the individual patient, monitoring therapy for side effects and effectiveness, and assuring close follow-up. Consultation with a mental health specialist should be considered for patients who have failed multiple trials of antidepressants or who have a preference for nonpharmacologic treatment [97].

●Assessment – A complete history guides treatment decisions (see "Approach to the adult patient with suspected depression", section on 'Initial evaluation'). Aspects of the history that are particularly important in managing late-life depression include:

•Suicidality, including ideation, plan (lethality, intent, and means), and behavior. Acute suicidal ideation requires urgent psychiatric referral [75].

•Psychotic symptoms of hopelessness, insomnia, and malnutrition.

•Medications that can cause depression (eg, benzodiazepines, central nervous system depressants, opiates, and other pain medications) or using alcohol, cannabis, or illicit drugs such as stimulants, which can cause mood symptoms.

•General medical conditions that are commonly associated with depressive symptoms, particularly unrecognized thyroid disease or diabetes. Additionally, pain syndromes can be a barrier to treatment response in depression and should be treated along with the depression [98].

•History of prior depressive episodes, age of depression onset, prior drug therapy and outcome, and length of prior remission if achieved.

•Family history of depression and family response to medication.

●Treatment selection – Treatment selection for late-life depression depends on the severity, type, and chronicity of the depressive episode; contraindications to medication; treatment access; prior response to treatments; and patient preference. First-line treatment options include psychotherapy, medications, and electroconvulsive therapy (ECT).

Psychotherapy and pharmacotherapy may be used singly or in combination [99]. For moderate to severe forms of depression, we typically use pharmacotherapy. For chronic forms of depression, the combination of pharmacotherapy and psychotherapy may be most effective [100]. In primary care settings, treatment programs that offer a choice of medication and/or psychotherapy, often combined with patient outreach by a care manager in a collaborative care model, may have significantly better outcomes than usual care [75,101-103]. (See 'Collaborative care' below.)

In a meta-analysis of 89 controlled studies involving older adults with depression of varied severity (major depression, minor depression, and dysthymia), psychotherapy and medication demonstrated similar efficacy in reducing depressive symptoms, with a moderate to large effect size [104]. Variability in trial quality limited the certainty of these findings. Randomized trials in the general population of adults with major depressive disorder have shown similar results. (See "Major depressive disorder in adults: Approach to initial management", section on 'Choosing a treatment regimen for patients with major depression'.)

Physical activity and exercise programs may be effective for minor or major depression in older adults [105]. However, patients with major depression may have difficulties engaging in an exercise program and, thus, may benefit from concomitant pharmacotherapy or psychotherapy. Exercise is discussed elsewhere in this topic. (See 'Exercise' below.)

Psychotherapy — Psychotherapy is a useful but frequently underutilized treatment for older adults with depression [99,106]. The availability of adequately trained therapists is a limiting factor, and health insurance coverage for psychotherapy may be incomplete. Available formats include individual, couples, family, or group therapy (table 5). Settings include private offices, community senior centers, partial hospital day programs or intensive outpatient group programs. The discussion below focuses upon the efficacy of psychotherapy in older adults; a general discussion of psychotherapy is presented separately. (See "Overview of psychotherapies".)

Multiple randomized trials have found that psychotherapy is beneficial for late-life depression. As an example, a meta-analysis of 27 trials (n>2000 patients) compared various psychotherapies with different controls and found a significant, clinically moderate to large effect favoring psychotherapy [107]. However, heterogeneity across studies was substantial and publication bias was significant.

Psychotherapy and community-based programs for older adults may be particularly helpful for patients with minor depression for whom pharmacologic intervention has not demonstrated consistent effectiveness [95,108].

Short-term treatments with demonstrated efficacy in older adults include cognitive-behavioral therapy (CBT), interpersonal psychotherapy, problem-solving therapy, and behavioral activation (table 5) [109-113]. These treatments are usually delivered over a period of two to four months.

●Cognitive-behavioral therapy – CBT is the most widely studied psychotherapy. A meta-analysis of 10 randomized trials (380 older adults with depression) found a clinically large effect favoring CBT over treatment as usual or waiting list controls; heterogeneity across studies was small to moderate [108]. A prior meta-analysis of three trials found that improvement of depression was comparable for CBT and interpersonal psychotherapy [113]. Additional information about the efficacy of interpersonal psychotherapy for older adults with depression is discussed separately. (See "Interpersonal Psychotherapy (IPT) for depressed adults: Indications, theoretical foundation, general concepts, and efficacy", section on 'Older patients'.)

●Problem-solving therapy – Several randomized trials have demonstrated the efficacy of problem-solving therapy [101]:

•A 12-week trial compared problem-solving therapy with supportive therapy in 221 nondemented patients with major depression and executive dysfunction (difficulty with goal setting and planning, and with initiating and sequencing behavior) [114,115]. Executive dysfunction is associated with poor response to antidepressants. Remission of depression occurred in more patients who received problem-solving therapy compared with controls (46 versus 28 percent). In addition, improvement of disability (self-care, communicating, and psychosocial functioning) was greater with problem-solving therapy, and the advantage was retained at the 24-week follow-up after the end of treatment.

•Another 12-week trial compared problem-solving therapy with supportive therapy in 74 patients with major depression and cognitive impairment ranging from mild deficits to moderate dementia [116]. Both interventions were administered weekly in the home. Remission of depression was greater with problem-solving therapy than supportive therapy (38 versus 14 percent). In addition, reduction of disability was greater with problem-solving therapy.

●Life review therapy – Life review therapy can help some older patients with depression [117]. In a meta-analysis of randomized trials of 3361 older adults with depression, life review therapy and reminiscence more effectively reduced depressive symptoms, compared with control interventions [118].

Pharmacotherapy

Optimizing patient acceptance of medications — Some older patients are reluctant to take medication for their depression. In interviews with patients 60 years and older with depression (n = 68), participants expressed the following concerns about antidepressant treatment: fear of medication dependence, rejection of the concept of depression as a medical illness, belief that medications inhibit normal emotional reactions, and prior negative experience with medications for depression [119]. Understanding a patient's reluctance to initiate medication can promote clinician-patient dialogue, help clinicians address the patient's specific concerns and initiate effective treatment, and enhance ongoing medication adherence (table 6).

Medication selection and management

●Medication selection – We typically select a single agent based on patient comorbidities, side effect profiles, and patient preferences [120,121]. A systematic review of 26 randomized trials of patients with depression ages 55 years and older found little difference in efficacy between different antidepressant classes [122]. However, withdrawals due to side effects were higher among patients randomized to tricyclic antidepressants, compared with selective serotonin reuptake inhibitors (SSRIs). Tailoring antidepressant selection to individual patients is discussed separately. (See "Major depressive disorder in adults: Initial treatment with antidepressants", section on 'Tailoring antidepressant selection'.)

Monotherapy is preferred in older adults to minimize drug side effects and drug-drug interactions. Although one nonrandomized open label study demonstrated good response to augmentation for treatment-resistant older patients with no medical contraindication to augmentation medications (lithium, bupropion, or nortriptyline) [123], combination strategies for augmented or accelerated responses in older adults are preferably avoided in the primary care setting.

●Initial dosing – The initial medication dose should be adjusted for the older adult, typically cutting the usual starting dose for younger patients in half. Lower starting doses will compensate for decreased drug clearance in older adults, minimize initial side effects, and promote medication compliance and maintenance. However, the undertreatment of older adults with depression is well documented; it is important to reach the same therapeutic dose range as in younger adults to maximize the chances of achieving complete remission.

●Monitoring and dose adjustment – We contact or see patients within one or two weeks of initiating medication to ensure adherence, address concerns, explore side effects, discuss tolerance, and adjust the dose as indicated. Patients should have an office visit within two to four weeks of starting medication to assess for response, complications, or deterioration. Depression-specific care management (involving specially trained nurses or social workers collaborating with primary care clinicians to assist with depression identification, guideline-based treatment, and follow-up) was effective, compared with usual care, in reducing mortality and depressive symptoms in older patients with major depression in a randomized trial involving 20 primary care practices in three United States cities [124]. (See 'Collaborative care' below.)

●Time to treatment effect – Medications typically take up to four to six weeks to show efficacy. In older patients, a full antidepressant response may not occur until 8 to 12 or even 16 weeks of therapy [120,125,126]. However, one study of 472 older patients with major depression found that patients who had no improvement at all by four weeks of treatment were unlikely to respond even after eight additional weeks and would be candidates for an early change in their treatment plan [127].

Duration of treatment

●Acute treatment – The usual course of treatment for the first lifetime episode of major depression in adults is 6 to 12 months beyond the time of achieving full remission.

●Continuation and maintenance treatment – The goal of continuation and maintenance treatment is to prevent relapse. Relapse rates in older adults are higher than in younger populations, which may indicate a need for longer periods of maintenance therapy [128]. Prior to discontinuing maintenance treatment, clinicians should educate patients about monitoring themselves for symptoms of recurrent episodes, and restarting treatment if symptoms recur.

Evidence for the efficacy of maintenance treatment includes a meta-analysis of six randomized trials that compared antidepressants (citalopram, dothiepin, escitalopram, nortriptyline, or sertraline) with placebo for up to three years in 708 older patients who remitted from major depressive episodes [129]. Recurrent episodes occurred in fewer patients who received antidepressants than placebo (37 versus 59 percent). In addition, discontinuation of treatment due to side effects was comparable.

Maintenance treatment with monthly psychotherapy, either alone or as add-on treatment with pharmacotherapy, does not appear to be effective for preventing recurrent late life depressive episodes. As an example, a two year randomized maintenance trial found that interpersonal psychotherapy did not prevent recurrence [130]. Among patients 70 years of age and older who had responded to treatment for major depression (n = 116) and were then assigned to one of four maintenance treatments, the rate of recurrence was as follows:

•Paroxetine (10 to 40 mg per day) plus monthly interpersonal psychotherapy – 35 percent

•Paroxetine plus monthly "sham" psychotherapy (clinical management sessions) – 37 percent

•Pill placebo plus psychotherapy – 68 percent

•Placebo plus clinical management – 58 percent

For older patients who experience frequent relapses or recurrences or who have persistent depressive disorder, long-term treatment may be needed; for patients requiring continuous treatment beyond two to three years, consultation with a psychiatrist may be helpful. Studies in adult populations younger than age 65 suggest that chronic antidepressant therapy should be considered for patients with three or more serious episodes of depression before age 50. However, similar data are lacking for the treatment of recurrent depression in older populations, and consultation with a psychiatrist may be helpful in such cases.

Discontinuing antidepressants may be prompted by tachyphylaxis or side effects, or by the need to initiate another medication that may cause a drug-drug interaction with the existing antidepressant. Development of an intercurrent illness, especially of major organ, cerebral, or systemic disease, may also make continuation of antidepressants problematic. Long-term safety data on chronic antidepressant use in older adults with chronic comorbid medical conditions are lacking.

Additional information about continuation and maintenance treatment is discussed separately. (See "Major depressive disorder in adults: Continuation and maintenance treatment".)

Benefits of antidepressant treatment — Antidepressants are efficacious for late-life depression, based upon meta-analyses of randomized trials [131,132]. As an example, a patient-level data meta-analysis of seven randomized trials (n = 2283 patients) compared antidepressants (bupropion, citalopram, duloxetine, escitalopram, fluoxetine, or paroxetine) with placebo and found that response (reduction of baseline symptoms ≥50 percent) occurred in more patients who received active treatment than placebo (49 versus 40 percent) [133]. Duration of illness (current age minus age at onset of depression) was associated with response, such that response was greater in patients with a duration of illness >10 years, compared with patients with a duration of illness <2 years.

The efficacy of antidepressants may be less robust in older individuals with depression, compared with younger patients:

●A meta-analysis of 15 randomized trials compared antidepressants with placebo in 4756 patients aged 55 years and older (mean age 70 years). Response was greater with antidepressants than placebo (risk ratio 1.3, 95% CI 1.2-1.5) [131]. However, in the subgroup of participants with a minimum age of 65 or 75 years (mean age 74 years; six trials, 1840 patients), response was comparable for antidepressants and placebo. Both analyses were limited by heterogeneity across pooled trials, the lack of trials that focused on patients older than 80 years, and the exclusion of patients with more severe depression.

●A meta-analysis of patient-level data from four randomized trials compared fluoxetine (10 to 30 mg per day) with placebo in 960 geriatric patients (older than 60 years) who were treated for six weeks [134]. Although rating scale scores improved more with fluoxetine than placebo, both response and remission were comparable for the two groups. In addition, a separate analysis of adults (12 trials, 2635 patients) found that the improvement of rating scale scores for adults was nearly double that for geriatric patients.

●A subsequent randomized trial compared duloxetine with placebo in 299 patients aged 65 years or more [135]. For both groups, remission was comparable (approximately 50 percent).

Types of antidepressants

●SSRIs – SSRIs are considered first line for treatment of depressive disorders in older adults due to better tolerability, ease of use, and general safety, especially in overdose (table 7) [125]. Resolution of depressive symptoms, usually between four to six weeks, may take longer in older adults.

•Side effects – Potential side effects of SSRIs of special concern in older adults include Parkinsonism, akathisia, anorexia, sinus bradycardia, and hyponatremia [136]. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Hyponatremia'.)

We carefully monitor SSRIs in frail, older adults, especially those with extensive medical or neurologic comorbidity and/or polypharmacy because meta-analyses of cohort studies suggest an association between SSRIs and an increased risk for fragility fractures (fractures resulting from minimal trauma). (See "Drugs that affect bone metabolism", section on 'Antidepressants'.)

Citalopram causes dose-dependent QT interval prolongation that can lead to arrhythmias, so its maximum dose in patients >60 years of age should not exceed 20 mg per day [137,138]. Additional information about the citalopram warnings and cardiac effects of SSRIs is discussed separately, as are the pharmacology, administration, and other side effects of SSRIs. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

Although treating depression can reduce suicidal ideation, we monitor for suicide risk in early therapy with antidepressant medications, including SSRIs [75,139]. One study suggested an increased rate of suicide in males 66 years and older in the first month of treatment with an SSRI, compared with other antidepressant drugs; however, this effect was not seen during subsequent treatment [140]. (See 'Suicide' above.)

•Efficacy – Despite greater acceptance and clinical recommendations, SSRIs are probably not more efficacious than older antidepressants. Comparison studies in older adults show that the difference in clinical efficacy is small, the range of placebo response is broad, and a significant number of older adults retain significant residual depressive symptomatology [121,125,126]. For severe forms of melancholic and psychotic depression, SSRI agents may be less efficacious than other drugs or ECT [121,141].

●Serotonin-norepinephrine reuptake inhibitors – Serotonin-norepinephrine reuptake inhibitors (SNRIs), which include venlafaxine and duloxetine, are currently used as second-line agents for treatment failure with SSRIs (table 7).

These agents may also be useful in patients with comorbid pain, especially neuropathic pain. In a nine-week randomized study comparing duloxetine and placebo for treatment of major depression in patients over age 55, the duloxetine group had a greater treatment response for depression as well as reduction in overall pain, back pain, and pain while awake [142]. However, discontinuation due to adverse events was significantly greater in the duloxetine group (21 percent compared with 7 percent).

Few comparison studies exist between SSRIs and SNRIs in older adults. Frail nursing home patients showed a poorer tolerance to venlafaxine when compared with sertraline in one study [143].

The SNRIs are considered safe for use in most older populations, although both carry a dose-dependent risk for diastolic hypertension. In a study of older adults, venlafaxine extended-release (XR) was found to cause less gastrointestinal distress and agitation than the immediate release preparation [144].

The SNRIs, as well as SSRIs, have resulted in the serotonin syndrome, but more data are needed to identify risk factors for older patients [145]. Serotonin syndrome manifests as altered mental status, myoclonus, tremors, hyperreflexia, fever, and autonomic changes among other findings [146,147]. (See "Serotonin syndrome (serotonin toxicity)".)

The pharmacology, side effects, and general administration of SNRIs are discussed separately. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)

●Atypical antidepressants – Atypical antidepressants include agomelatine, bupropion, and mirtazapine (table 7). Few studies exist in populations of older adults [148].

•Bupropion – Bupropion is generally considered an activating agent, so it may be useful in patients who complain of lethargy, daytime sedation, or fatigue. Bupropion is contraindicated in patients with seizure disorders, concurrent use of benzodiazepines or other central nervous system depressants, alcohol detoxification, or prior or current diagnosis of bulimia nervosa. Dose-dependent diastolic hypertension is a concern in the older patient.

•Mirtazapine – Mirtazapine is also used as a second-line agent. Mirtazapine appears to be useful for older patients with insomnia, agitation or restlessness, and anorexia or weight loss. It may also be useful in patients with Parkinsonism, essential tremor, or nausea from chemotherapy, and is available as a rapidly dissolving sol-tab preparation [149].

Common side effects of mirtazapine include sedation, especially at initiation and at lower doses, appetite increase and weight gain, dry mouth, and constipation. The sedating effects of mirtazapine tend to diminish with acclimation and also tend to be less pronounced at higher doses where the noradrenergic effects predominate over the antihistaminergic effects.

•Agomelatine – Agomelatine was approved for use in Europe in 2009 but is not approved in the United States. A review identified only one controlled trial (unpublished) in older adults, in which 218 patients 60 years and older with major depression, were randomly assigned to agomelatine 25 mg per day or placebo for six weeks [150]. There was no significant difference in Montgomery Asberg Depression Rating Scale scores. In addition, the rate of response, defined by at least a 50 percent decrease in scores, did not differ significantly between agomelatine and placebo (46 versus 52 percent).

The pharmacology, side effects, and general administration of atypical antidepressants are discussed separately. (See "Atypical antidepressants: Pharmacology, administration, and side effects".)

●Serotonin modulators – Serotonin modulators include nefazodone, trazodone, and vilazodone.

Nefazodone is not commonly used because of concerns about hepatotoxicity. These concerns led to the voluntary removal of its brand (Serzone) in the United States and withdrawal from several countries outside the United States, including European countries and Canada. Nefazodone is available in a generic preparation in the United States. Nefazodone may be useful in patients who complain of insomnia, anxiety, or agitation. Common side effects include sedation and restlessness. It appears to have relatively good gastrointestinal tolerance. Nefazodone is a potent inhibitor of the cytochrome P450 3A4 isoenzyme, so significant drug-drug interactions may occur with macrolide antibiotics, cardiac antiarrhythmics, and other psychotropic agents.

Trazodone is rarely used solely as an antidepressant but is still commonly used as a soporific and mild sedative, especially at lower doses. Antidepressant effects tend to be seen only at higher doses, where concerns about orthostatic hypotension and excessive daytime sedation limit its use. Both nefazodone and trazodone have been associated with hyponatremia and trazodone has been associated with the rare but potentially serious side effect of priapism [146].

The pharmacology, side effects, and general administration of serotonin modulators are discussed separately. (See "Serotonin modulators: Pharmacology, administration, and side effects".)

●Tricyclic and tetracyclic antidepressants – While no longer considered first- or second-line agents for the treatment of depression in any age group, these agents may be useful for treatment failure with other antidepressants (table 7). A few studies suggest that cyclic antidepressants may have superior efficacy in older adults with melancholic or delusional depression, and these antidepressants are the only class shown to reduce the risk of relapse after a course of ECT [126,141,151].

Cyclic antidepressants must be used cautiously in patients with cardiac conduction abnormalities, arrhythmias, narrow angle glaucoma, urinary retention, or benign prostatic hyperplasia, and patients should be followed for development or worsening of orthostatic hypotension and constipation. Additionally, patients with Alzheimer-type dementia may experience worsening confusion due to anticholinergic side effects. Tricyclic and tetracyclic antidepressants are discussed separately. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects".)

●Monoamine oxidase inhibitors – This class of antidepressants is rarely used except when previously initiated and tolerated, or in the patient who is treatment resistant to all other antidepressants (table 8). Monoamine oxidase inhibitors (MAOIs) do have proven benefit, with some studies suggesting superior efficacy in atypical (reverse neurovegetative) depression, mixed anxiety-depressive states, and panic disorder, although limited research studies are found in older populations [152].

Patients treated with MAOIs require special dietary and medication restrictions to prevent the serotonin syndrome and hyperadrenergic crisis. Because of potential severe side effects, these medications are best prescribed by a psychiatrist or clinician with extensive experience in use of these medications. Aside from these concerns, these medications are surprisingly well tolerated in older adults. Common side effects include orthostatic hypotension, activation, and insomnia. In contrast to tricyclic antidepressants, these medications are relatively devoid of cardiac conduction effects.

The pharmacology, side effects, and general administration of monoamine oxidase inhibitors are discussed separately. (See "Monoamine oxidase inhibitors (MAOIs): Pharmacology, administration, safety, and side effects".)

Adjunctive medications

●Methylphenidate – For patients with late-life major depression, simultaneously prescribing an antidepressant with methylphenidate at the onset of treatment may improve outcomes. A 16-week randomized trial enrolled patients (n = 143; mean age 70 years) with major depression who were free of psychotropic medications for at least two weeks and assigned them to receive citalopram plus methylphenidate, citalopram plus placebo, or methylphenidate plus placebo [153]. Electrocardiograms were performed at baseline, and patients with atrial or ventricular arrhythmias or acute ischemic features were excluded. Citalopram doses ranged from 20 to 60 mg/day and methylphenidate from 5 to 40 mg/day. Improvement was greater and occurred more quickly with combination treatment than either citalopram monotherapy or methylphenidate monotherapy. In addition, discontinuation of treatment due to side effects appeared to be comparable for the three groups. It is worth noting that stimulants can lead to adverse cardiac effects, and that the maximum dose of citalopram recommended by the US Food and Drug Administration for patients age >60 years is 20 mg/day. (See "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Citalopram'.)

●Aripiprazole – For patients with treatment-resistant late-life depression, multiple randomized trials indicate that adjunctive aripiprazole can be efficacious:

•A 12-week trial compared add-on aripiprazole with placebo in patients (n = 181) who did not initially remit with open label venlafaxine [154]. Aripiprazole was started at 2 mg per day and titrated up as needed and tolerated to a target dose of 10 mg per day (range 2 to 15 mg per day; median final daily dose 7 mg). Remission occurred in more patients who received aripiprazole than placebo (44 versus 29 percent). However, aripiprazole caused more akathisia (26 versus 12 percent of patients) and Parkinsonism (17 versus 2 percent). Weight gain was also greater with active drug than placebo (1.9 versus 0.0 kg).

•A subsequent, 10-week trial enrolled 413 patients who had not responded to adequate treatment with a mean of two antidepressants (eg, duloxetine, escitalopram, or venlafaxine), and randomly assigned them to augmentation with aripiprazole or switching to extended-release bupropion [155]. Aripiprazole was started at 2 mg per day and titrated up as needed and tolerated to a maximum dose of 15 mg per day. Bupropion was started at 150 mg per day and titrated up as needed and tolerated to a maximum dose of 450 mg per day. Improvement was greater with adjunctive aripiprazole than switching to bupropion. However, adverse effects that appeared to be greater with aripiprazole than bupropion included akathisia (11 and 2 percent of patients), fatigue (9 and 1 percent), and weight gain (15 and <1 percent).

Information about adjunctive second-generation antipsychotics for the general population of patients with treatment-resistant depression is discussed separately. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics".)

●Cholinesterase inhibitors – Cholinesterase inhibitors in older adults with late-life depression and cognitive impairment require close monitoring. Although they may help to preserve cognitive function, they do not appear to improve depressive symptoms when used as adjuncts to antidepressants. In a review of four randomized trials, cholinesterase inhibitors as adjunctive treatment with antidepressants provided no clear benefit [156]. In the largest trial, donepezil was compared with placebo as an add-on maintenance treatment with an antidepressant in patients aged 65 years and older [157]. Cognitive functioning was superior with donepezil at one year but not two years. However, donepezil appeared to increase the risk of recurrence of major depression. In addition, cholinesterase inhibitors may provoke symptoms (eg, dysphoria) that mimic depression.

●Other – Other add-on medications that can be used with antidepressants in treatment-resistant late-life depression include lithium and triiodothyronine. (See "Unipolar depression in adults: Treatment with lithium" and "Unipolar depression in adults: Augmentation of antidepressants with thyroid hormone".)

Quetiapine monotherapy — Although monotherapy with the second-generation antipsychotic quetiapine may be effective for major depression, the risk of short- and long-term side effects is such that quetiapine is not a first- or second-line treatment. Evidence for the efficacy of quetiapine includes a nine-week randomized trial that compared quetiapine extended-release monotherapy (50 to 300 mg per day, median dose 159 mg per day) with placebo in 335 patients with late-life, nonpsychotic major depressive disorder [158]. Remission occurred in more patients who received quetiapine than placebo (45 versus 17 percent). Discontinuation of treatment following an adverse event occurred in more than twice as many patients who received quetiapine (10 versus 4 percent). Common side effects of quetiapine included sedation, dry mouth, and extrapyramidal symptoms. Although these findings indicate that quetiapine extended release may have some utility for major depression, ongoing concerns remain about safety issues and side effects, especially with long-term treatment. The use of second-generation antipsychotics as adjunctive treatment for major depressive disorder that does not respond to antidepressant monotherapy is discussed separately. (See "Unipolar depression in adults: Treatment with second-generation antipsychotics".)

Neurostimulation — Several brain stimulation procedures for treating major depression are clinically available or under investigation. An overview of these procedures is discussed separately. (See "Unipolar depression in adults: Overview of neuromodulation procedures".)

Electroconvulsive therapy — ECT remains an important and viable treatment option in older adults. ECT is used for patients who have not responded to adequate antidepressant trials and patients with severe major depression that is life-threatening or significantly impairs functioning [41,159-162]. Indications for use, description of the procedure, morbidity, and risk assessment for ECT are discussed separately. (See "Overview of electroconvulsive therapy (ECT) for adults" and "Technique for performing electroconvulsive therapy (ECT) in adults" and "Medical evaluation for electroconvulsive therapy".)

Other brain stimulation therapies — Other brain stimulation therapies have been evaluated for treatment of medication-resistant depression; these therapies include repetitive transcranial magnetic stimulation, deep brain stimulation, and vagus nerve stimulation. However, there are no randomized trials that have demonstrated the benefit of these modalities in older adults. Neuromodulation is discussed in more detail separately. (See "Unipolar depression in adults: Overview of neuromodulation procedures" and "Unipolar depression in adults: Indications, efficacy, and safety of transcranial magnetic stimulation (TMS)", section on 'Older adult' and "Unipolar depression in adults: Treatment with surgical approaches".)

Other interventions

Exercise — We encourage older adults with depression to engage in regular physical activity and exercise. Exercise can supplement standard treatment with medications or psychotherapy for all individuals with depression and may be used as a "stand-alone" treatment for those with mild depression. The role of exercise in the initial management of older individuals with major depression is similar to that in the general population and is discussed separately. (See "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Role of supplemental treatments'.)

●Regimens and types of exercise – We encourage patients to choose between aerobic, resistance, and mind-body types of exercise. Aerobic activities include walking, running, or swimming, and resistance training involves nonaerobic muscle strengthening (ie, lifting weights). Mind-body interventions that have been studied for treating depression include yoga and tai chi [163]. Data from meta-analyses of randomized trials suggest that aerobic, resistance, and mind-body types of exercise have comparable efficacy for treating depression in older adults [164-167].

Specific exercise regimens are similar to those in the general population of adults with depression and are discussed separately. (See "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Suggested regimen'.)

●Expected benefit – Data from meta-analyses of randomized trials suggest that exercise reduces depressive symptoms in older individuals with and without established major depression [165-175]. As an example, in a meta-analysis of 15 trials of 596 participants aged ≥65 with clinical depression, exercise interventions were superior to control interventions for achieving symptom improvement, and the clinical benefit was moderate to large [164].

Exercise has shown efficacy for improving depressive symptoms in older adults in a range of settings and patient populations. Data from meta-analyses of randomized trials indicate that exercise reduces depressive symptoms in older adults with frailty and cognitive impairment and those living in the community and in long-term care facilities [165,167-169,176].

●Duration of benefit – Depression-related benefits of exercise appear to persist in older individuals who continue to exercise for the long term. A trial of 438 adults aged 60 years or older with osteoarthritis evaluated three-month supervised exercise programs followed by 15 months of home exercise with ongoing support from the exercise leader [177]. Participants randomized to aerobic exercise experienced a reduction in depressive symptoms, compared with a control group that received health education. In the subset of participants with major depression (n = 98), the reduction in depressive symptoms persisted at 18-month follow-up (40 versus 20 percent).

Exercise for the treatment of depression and physical activity in older adults more generally, including assessment of individuals with cardiovascular contraindications to physical activity, are discussed separately. (See "Major depressive disorder in adults: Treatment with supplemental interventions", section on 'Exercise and physical activity' and "Physical activity and exercise in older adults".)

Bright light — Bright light therapy may be beneficial for older individuals with depression with and without seasonal affective disorder. A three-week randomized trial compared bright light treatment with placebo in 89 older patients with nonseasonal major depression. Response (improvement from baseline ≥50 percent) occurred in more patients who received bright light (58 versus 34 percent), which was well-tolerated [178]. The use of bright light therapy for nonseasonal depression in the general population is discussed separately. (See "Unipolar depression in adults: Investigational and nonstandard treatment", section on 'Bright light therapy'.)

Systems-level interventions

Collaborative care — Collaborative care programs emphasize patient education and use nonphysician mental health professionals or depression care managers to integrate psychiatric and primary care and augment medication management with evidence-based, brief psychologic/psychosocial interventions such as problem-solving treatment or behavioral activation. These programs (also called integrative care and care management) for older adults with depression can improve a variety of outcomes [179,180]. As an example, the 12-month, multisite Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) program compared collaborative care with usual care in 1801 primary care patients with late life major depression and/or persistent depressive disorder (dysthymia), and found that cost effectiveness and improvement of symptoms (including suicidal ideation), physical functioning, and quality of life were greater with collaborative care [76,101,103]. In addition, the benefits were sustained one year after termination of the collaborative intervention [181]. Other trials have found comparable results [75,182,183].

Collaborative care appears to improve general medical outcomes as well as depression. Patients at one of the IMPACT study sites were followed for eight years, including 168 patients without cardiovascular disease at baseline [184]. Cardiovascular events (fatal or nonfatal myocardial infarction or stroke) occurred in fewer patients who received collaborative care than usual care (28 versus 47 percent).

In addition, collaborative care programs may decrease all-cause mortality in late-life depression. A randomized trial compared collaborative care with usual care in 396 older primary care patients with major depressive disorder as well as 203 patients with minor depression [185]. The study also enrolled 627 patients without depression. Collaborative care involved depression care managers (social workers, nurses, or psychologists) who were supervised by psychiatrists and worked with primary care physicians to provide antidepressants and/or psychotherapy for depression; increase antidepressant doses or switch antidepressants when indicated; and monitor symptoms, side effects, and adherence to treatment. Patients were treated for up to 24 months and followed for a median of 98 months, during which time 405 patients died. The primary findings were as follows:

●Among patients with major depression, the risk of death was 24 percent less with collaborative care than with usual care (hazard ratio [HR] 0.76, 95% CI 0.57-1.00).

●The risk of death for patients with major depression who received collaborative care and patients who were not depressed was comparable (HR 1.1, 95% CI 0.8-1.4). By contrast, mortality with usual care was greater (nearly twice as high) for patients with major depression, compared with patients without depression (HR 1.9, 95% CI 1.6-2.3).

●For patients with minor depression, collaborative care did not affect the risk of mortality.

The elements of collaborative care are also helpful in psychiatric practices. A six-month randomized trial compared care management plus pharmacotherapy with pharmacotherapy alone in 57 older patients, who were treated for depressive disorders in a psychiatric clinic [186]. Care management consisted of eight telephone calls from a psychologist, who educated patients about depression, treatment options, and adherence; monitored symptoms and adverse events; and reminded patients about their next visit to the clinic. Remission occurred in more patients who received care management plus pharmacotherapy than pharmacotherapy alone (55 versus 29 percent).

Additional information about collaborative care in mixed age populations is discussed separately. (See "Major depressive disorder in adults: Approach to initial management", section on 'System-level interventions and collaborative care'.)

Home-based care — Home-based interventions for mildly depressed, older patients with limited mobility or access to care may be helpful. However, the availability of home-based interventions is limited.

Evidence supporting the efficacy of home-based care includes the following [187]:

●A four-month randomized trial compared at-home care with a waiting list control condition in 208 older African Americans with depressive symptoms [188]. The active treatment was administered by social workers and included referrals for medical and social services, education about depression and stress reduction, and behavioral activation. Remission of symptoms occurred in more patients in the intervention group than the waiting list group (44 versus 27 percent).

●A one-year randomized trial compared home-based treatment with usual care in 138 patients with either minor depression or persistent depressive disorder (dysthymia) [111]. The home-based program was administered by social workers and included eight sessions of problem-solving therapy and behavioral activation, as well as recommendations to patients' physicians about use of antidepressants; usual care included a letter to patients' physicians about the depression diagnosis. Remission was greater in patients who received home-based care than usual care (36 versus 12 percent).

Family support — Family members and caregivers should be involved in the care of patients with late-life major depression and be educated about the signs and symptoms, treatment, and prognosis of the illness [179]. The family can provide information about symptoms that the patient may not reveal and can encourage adherence to treatment. Family meetings for assessment and treatment of patients with major depression are discussed separately. (See "Unipolar depression in adults: Family and couples therapy".)

PREVENTION — 

Efforts to prevent late-life depression have included the use of omega-3 fatty acids; however, the evidence indicates this treatment is not effective. As an example, a five-year randomized trial compared omega-3 fatty acids with placebo in more than 18,000 patients (mean age 68 years) without depression [189]. Active treatment consisted of eicosapentaenoic acid 465 mg/day and docosahexaenoic acid 375 mg/day. Depressive symptoms were comparable in the two groups.

Omega-3 fatty acids have also been studied for treating acute major depression. (See "Unipolar depression in adults: Investigational and nonstandard treatment", section on 'Omega-3 fatty acids'.)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Coping with high drug prices (The Basics)")

●Beyond the Basics topic (see "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and diagnosis

•Impact – Late-life depression often goes undetected and has a significant adverse impact on quality of life, outcomes of medical disease, health care utilization, and morbidity and mortality. The majority of older adults with depression initially present to primary care, often with somatic complaints. (See 'Introduction' above.)

•Risk factors – Depression is not a normal consequence of aging. Healthy independent older adults have a lower prevalence rate of major depression than the general population. Rates increase greatly with medical illness, particularly cancer, myocardial infarction, and neurologic disorders, such as stroke and Parkinson disease. (See 'Risk factors' above.)

•Suicide – Suicide rates are approximately twice as high in older adults, with the rate highest for Caucasian males over 85 years of age. Most older adults who commit suicide have seen a clinician within the previous month. (See 'Suicide' above.)

•Minor depression – Minor depression in late life is more prevalent than major depression, has significant health consequences, and responds to treatment. (See 'Other depressive disorders' above.)

•Psychotic depression – Delusional (psychotic) depression is a very severe illness and can be lethal. Cognitive deficits may be pronounced and similar to dementia. However, both depressive symptoms and cognitive impairment respond to treatment with antidepressants, distinguishing these patients from those with Alzheimer disease and secondary depression. (See 'Major depression' above.)

•Vascular depression – Depression associated with cerebrovascular disease is characterized by psychomotor retardation, anhedonia, greater frontal executive dysfunction, and poor insight. (See 'Risk factors' above.)

•Screening – Depression in older adults can be challenging to diagnose. Depression screening can help identify individuals who need further evaluation and treatment. (See "Screening for depression in adults", section on 'Older patients (ages 65 and older)'.)

●Treatment

•Psychotherapy – Psychotherapy is effective in older adults, although for moderate to severe depression in late life, pharmacotherapy or a combination of pharmacotherapy and psychotherapy is recommended. (See 'Psychotherapy' above.)

•General principles of pharmacotherapy – Medication monotherapy is preferred in older adults in order to minimize drug side effects and drug-drug interactions. Initial medication dose should be adjusted for the older adult, typically halving the usual starting dose for younger patients but full therapeutic doses are often required to achieve the desired responses. (See 'Medication selection and management' above.)

All medications typically take four to six weeks to show efficacy; in older patients, a full antidepressant response may not occur until 8 to 12 or even 16 weeks of therapy. Long-term treatment may be necessary to prevent recurrence. (See 'Medication selection and management' above and 'Duration of treatment' above.)

Patients should be contacted or seen within one or two weeks of initiating medication to discuss tolerance and adjust the dose as indicated. They should have an office visit within two to four weeks of treatment to assess response, monitor for side effects, and address any complications or deterioration. (See 'Medication selection and management' above.)

•Selective serotonin reuptake inhibitors (SSRIs) – SSRIs are first-line antidepressants because of safety and tolerability. In patients aged 60 years and above, the maximum recommended dose of citalopram is 20 mg per day due to concerns about dose-dependent QT interval prolongation that can lead to arrhythmias. (See 'Types of antidepressants' above and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)

•Serotonin-norepinephrine reuptake inhibitors – Venlafaxine and duloxetine are frequently used as second-line agents and may be particularly helpful in patients with depression and neuropathic pain. (See 'Types of antidepressants' above.)

•Atypical antidepressants – Mirtazapine may be useful for patients with insomnia, agitation, restlessness, or anorexia and weight loss. (See 'Types of antidepressants' above.)

•Tricyclic antidepressants – Tricyclic antidepressants are third- or fourth-line therapy in older adults due to significant arrhythmic side effects, as well as anticholinergic effects causing urinary retention, orthostasis, and possible exacerbation of dementia. These drugs, when necessary, are probably best managed by a psychiatrist or clinician with special expertise and experience in managing these medications in older adults. (See 'Types of antidepressants' above.)

•Monoamine oxidase inhibitors – Monoamine oxidase inhibitors can be used for depression that is resistant to other agents. This class of drugs has not been well studied in older adults. They should be prescribed by a psychiatrist or clinician with special expertise and experience with these medications because of their serious side effect profile. (See 'Types of antidepressants' above.)

•Collaborative care – For older primary care patients with major depression, improvement of symptoms (including suicidal ideation), physical functioning, and quality of life is greater and mortality is lower with collaborative care than with usual care. (See 'Collaborative care' above.)

•Electroconvulsive therapy – Electroconvulsive therapy (ECT) is used more frequently in older patients than in younger patients and may be effective for the older patient who is intolerant of medications or not responding to adequate medication trials. ECT is generally well tolerated in the older patient, although it causes transient memory loss. (See "Unipolar major depression in adults: Indications for and efficacy of acute electroconvulsive therapy (ECT)", section on 'Older age'.)