Late Life Depression: The Essentials and the Essential Distinctions

Abstract

Late life depression (LLD), a familiar syndrome, is not differentiated in the DSM-5. LLD can resemble depressive syndromes in younger adults but it differs in demographic characteristics, phenomenology, prognosis, treatment, suicide risk, relationship to other disorders, and etiology. Older depressed adults often present with fewer major depressive symptoms, less emphasis on mood disturbance, greater preoccupation with somatic or psychotic symptoms, and misleading cognitive deficits. LLD’s relationships with medical and neurocognitive symptoms and with inflammatory and immune factors are complex. Formal screening tools and biopsychosocial assessment informs diagnosis and treatment. Evidence supports the effectiveness of lifestyle interventions, several psychotherapies, and a variety of somatic treatment approaches. Comorbid medical disorders must be taken into account when planning treatment. In this article, the authors describe the characteristics of LLD, present an approach to assessment and management, and recommend that future DSM editions include a new specifier to differentiate LLD from other depressive syndromes.

In the extended family of DSM-5 diagnoses, late life depression (LLD) is the unacknowledged relative who awaits a formal invitation to the party. The DSM-5 states that “there are no clear effects of current age on the course or treatment response of major depressive disorder” (1); however, evidence suggests that there are multiple differentiated presentations of depression more characteristic of its appearance in later years. LLD shares features with depressive syndromes found among younger adults, but it also differs in many ways, not only in demographic characteristics but also in etiology, phenomenology, prognosis, acute treatment, maintenance treatment, suicide risk, and relationship to other medical and psychiatric disorders. Because of its differences from depression among younger adults, LLD risks going undetected or being mismanaged. In this overview, we highlight the essential characteristics of LLD and emphasize the most important differences between late life and earlier depression with the objectives of improving recognition and treatment of this common and debilitating disorder.

Demographic Characteristics

Depression is one of the more common psychiatric syndromes among older adults, and it presents in many guises. No official set of diagnostic criteria defines the diagnosis of LLD. By convention, this term typically denotes the presence of a depressive syndrome consistent with DSM criteria in an adult age 65 or older. The prevalence of major depressive disorder among community-dwelling older adults is estimated at 1%–4% (2). Taking various settings into consideration, another 10%–50% of older adults manifest clinically significant depressive symptoms below the threshold of major depressive disorder (3, 4). In primary care settings, higher rates of major depressive disorder are seen, an estimated 6%–9% (5). The highest rates of late life major depressive disorder are seen in long-term care facilities, where up to 25% of residents warrant that diagnosis; moreover, another estimated 30%–50% of residents manifest clinically significant depressive symptoms (6). Notably, LLD is an important antecedent to suicide in later life, which occurs at a higher rate than among the young. Depression is known to be the strongest risk factor for suicide among older adults (7). In 2000, the World Health Organization estimated suicide rates of men and women, age 75 and older, to be 50 and 16 per 100,000, respectively (8).

Although the prevalence of major depressive disorder is lower among older adults than among younger adults, milder depressive symptoms are more highly prevalent among older adults (2, 9). These clinically significant depressive symptoms, sometimes referred to as “minor depression,” can be a debilitating contributor to the psychiatric morbidity of the aging population (10).

Symptoms and Syndromes of LLD

The DSM-5 diagnosis of major depressive disorder provides a useful basic framework for detection of depression through the life cycle; however, the sensitivity and specificity of DSM-5 mood states and neurovegetative features differ between younger and older adults. Although the presentation of depressive episodes is heterogeneous at all ages, the “background noise” of symptoms reflecting age-associated medical burden and the frequent focus of older adults on somatic symptoms or psychotic concerns rather than depressed mood require clinicians to think beyond DSM-5 vegetative symptoms in diagnosing LLD. Disturbed sleep, energy, concentration, appetite, or activity among older adults can reflect various physiologic changes or medical disorders common to later life. As a result, the use of these symptoms in diagnosing LLD may lead to an overly inclusive approach that results in too many false positive diagnoses. However, when people with LLD fail to report mood changes characteristic of depression, which can occur for a variety of reasons, the diagnosis of LLD may be prematurely dismissed and a potential treatment opportunity lost.

An additional diagnostic consideration with LLD concerns the broad range of ages that make up “late life.” Older adults range from ages 65 to 100. Although the effects of age are individualized, increasing age amplifies the diversity of the older population and the symptoms, medical conditions, and functional status of individuals. The “young-old” group contains many individuals who perform at a high level in social and occupational domains, whereas the “old-old” group contains a much higher proportion of individuals who are retired, socially isolated, or compromised by impaired health and diminished function. Given the interactions between these variables and the phenomenology of mood disorders, LLD is not surprisingly a heterogeneous disorder with various presentations and disparate treatment needs.

Notably, these presentations include at least the following entities: recurrence of earlier onset major depressive disorder (9); the syndrome of subsyndromal depression, with symptoms too few for major depression; depression lacking a prominent low mood (i.e., depression without sadness) (11); depression with emphasis on somatization, including concern about pain, bodily dysfunction, or cognition; depression with psychotic features; depressive symptoms secondary to general medical conditions; depressive symptoms secondary to substance or medication use; and depressive symptoms associated with neurocognitive disorders. Episodes of depression that represent a late life recurrence of a longstanding mood disorder are grouped with other LLD depressive syndromes; however, these episodes may represent a significantly different condition because most LLD episodes are not preceded by earlier episodes (12). One study reported that as many as 71% of the older adults with depression enrolled in a home health care program were experiencing their first episode of depression (13). LLD in the context of bipolar disorder, which is less frequent than unipolar LLD, is beyond the scope of this article and has been recently reviewed elsewhere (14).

Etiologic Theories

Multiple factors can contribute to LLD. In any affected individual, one or more of these might be the most critical to recognize or address. The most prominent of the proposed contributors to LLD are illustrated in Figure 1 and discussed in the subsequent text.

FIGURE 1.

Factors that contribute to late life depression

Immune and Inflammatory Mechanisms

Dysregulation of the immune system, as a consequence of age or disease, appears to be an important factor in LLD (15). The multiple mechanisms by which aging alters immune function are referred to collectively as “immunosenescence” (16). Increased levels of proinflammatory mediators with aging have been demonstrated in several cross-sectional studies (17). Evidence also suggests that a muted or inhibited immune response contributes to the maladies associated with an aging immune system. Proinflammatory changes in particular can alter communication between the peripheral and central nervous system immune systems (18), dampened the normal anti-inflammatory response, and facilitate a chronic proinflammatory state in the brain which leads to production of proinflammatory cytokines and harmful reactive oxygen and nitrogen species (18).

Immunosenescence can be further exacerbated by adverse psychosocial factors. In particular, evidence is increasing that psychosocial stressors can stimulate proinflammatory molecules such as elevated interleukin‐6 (IL‐6), tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) (19). A proinflammatory milieu is also promoted by adverse lifestyle factors such as a diet high in sugar or saturated fat content, smoking, or increased body mass index. The proinflammatory cytokine, IL-6, has been consistently found to be increased in depressive disorders, and treatment with antidepressants significantly decreases peripheral levels of IL-6 (20). Elevated IL-6 levels in the cerebrospinal fluid have been correlated with increased suicide risk and with attempt severity (21). Meta-analysis has shown that peripheral levels of other inflammatory molecules such as TNF-α, IL‐13, IL‐18, IL‐12, soluble IL‐2 receptor, IL‐1 receptor antagonist, and soluble TNF receptor 2 were elevated in individuals with major depression compared with control groups.

Besides looking at peripheral markers, a cross-sectional positron emission tomography study used F-FEPPA ligand to measure the association of translocator protein total distribution volume (TSPO VT), a marker of microglial activation, with the duration of untreated major depressive disorder. A positive association between the duration of illness and TSPO VT was found (22). Alternatively, studies of healthy participants demonstrate that classic depressive symptoms can be induced by infusing endotoxin, which triggers cytokine release (23). Although the exact role of each of these inflammatory molecules and processes is still not fully understood, clear evidence exists to show that these immune mediators are dysregulated and sometimes correlated to disease severity in depressive disorders.

Cardiovascular Mechanisms

Aging is associated with increased vascular dysfunction (24). As people age, two major changes affect the arteries: large artery stiffening and endothelial dysfunction. Stiffening of the large arteries diminishes elasticity and compliance (25). Endothelial dysfunction is associated with a significant increase in the production of a wide range of cytokines, exacerbating the heightened inflammatory state of the aging vasculature (26). The vascular hypothesis of depression proposes “cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes” (27). Vascular depression, named for this hypothesis, is characterized by executive dysfunction, psychomotor retardation, disability disproportional to the severity of depression, and greater relapse risk (28). Presence of moderate to severe white matter hyperintensities on neuroimaging studies, interpreted as corresponding to cerebral small vessel disease, is a typical feature of vascular depression (29). These white matter changes are also associated with a slower response to citalopram treatment (30), a finding suggestive of slower antidepressant responsiveness in general.

Cerebrovascular Disease

In individuals with disrupted cerebrovascular function as a result of cerebrovascular accident (CVA or stroke), depression is common and described as “poststroke depression” (PSD). Every year, more than 795,000 CVAs occur in the United States (31), and about one-third of affected individuals develop PSD (32). In contrast to vascular depression, PSD is a disorder of larger blood vessels. It develops in the weeks and months following a CVA and can continue for many years (33). The correlation of PSD with CVA lesion location is controversial, but left hemispheric location or proximity to the frontal pole have been proposed as probable PSD risk factors (34). Bilateral basal ganglia damage appears to be associated with apathetic depression (32). Current research approaches are moving beyond a focus on lesion location to consider the effect of CVA on larger brain networks using techniques such as diffusion tensor imaging. Along these lines, one study has linked poststroke apathy to damage to the genu and splenium of the corpus callosum, left anterior corona radiata, and white matter of the frontal gyrus, thereby interconnecting brain regions involved in tasks such as decision making, emotional regulation, and reward-processing (35).

Non-Neurodegenerative Medical Illnesses

The bidirectional relationship between LLD and medical illness is an especially important consideration because of the high medical burden among older adults and the frequent ambiguity of symptom etiology. Research has shown that many medical diseases induce or mimic depressive symptoms. Conversely, depression can manifest itself in somatic symptoms or exacerbation of medical illness. Among the medical conditions associated with depressive symptoms, the most frequent are cardiopulmonary disorders, cerebrovascular disease, endocrine conditions, autoimmune disorders, neoplasms, and neurological conditions.

Some 80% of older individuals live with at least one chronic health condition, and 50% have two or more. Therefore, the co-occurrence of depressive and medical symptoms is not unexpected. The frequency of co-occurrence, however, suggests more than coincidence. The prevalence of major depressive disorder among patients with coronary heart disease is estimated to be between 15% and 23% (36). Among people with diabetes mellitus, the prevalence of major depressive disorder is estimated to be 12%; moreover, subsyndromal depressive symptoms are reported to be present in 15%–35% (37). One meta-analysis found the mean prevalence of meaningful depressive symptoms to be 8%–24% in patients with cancer and the prevalence of major depressive disorder to be 13% (38). Among patients with multiple sclerosis, the estimated prevalence of major depression is reported to be between 19% and 54% (39). Although major depressive disorder is common in individuals with medical illness, the prevalence of subsyndromal symptoms is even higher. Milder depressive symptoms contribute to a self-perception of poorer health and can affect self-care and the course of a patient’s medical illness.

The evaluation of depression in an individual with comorbid medical illness requires considerable clinical judgment when deciding which symptoms might best be attributed to one or the other etiology. Excess disability related to depression or depressive disturbances of mood, energy, appetite, sleep, and interest can be falsely attributed to a medical disorder, obscuring the presence of a potentially treatable mood disorder contribution.

Neurodegenerative Disorders

The neurocognitive disorders deserve special attention in a discussion of medical disorders associated with depressive symptoms. Here, again, the relationship is bidirectional and can be ambiguous. Some evidence supports the idea that depression is a risk factor for the development of dementia, or major neurocognitive disorder as it is now termed. Depression can also be a consequence of cognitive decline, both as a psychological reaction to self-observed diminished function and also as a physiological consequence of neurodegenerative changes. In some cases, the onset of depressive symptoms reflects a prodromal phase of dementia (40). Cognitive symptoms attributed to a primary mood disorder have been labeled “pseudodementia,” a term that is appropriately giving way to a more accurate designation, the “dementia syndrome of depression.” This newer term validates cognitive symptoms in depression as genuine dysfunction rather than purely psychodynamic or factitious. Controversy exists as to whether depression-related cognitive symptoms represent unmasking of a latent cognitive decline, because some longitudinal studies have reported a high rate of subsequent dementia among patients whose depressive episodes included acutely reversible cognitive symptoms (41).

In contrast to the treatment of depressive symptoms associated with the dementia syndrome of depression, the treatment outcome for depressive symptoms accompanying a primary dementia is often disappointing. Despite some positive studies, the preponderance of evidence, including a large recent study, suggests that antidepressants have limited value in this endeavor (14, 42). For clinicians, a general consideration is to evaluate the response to treatment and avoid prolonging an ineffective antidepressant trial when the target of treatment, depressive symptoms in a person with dementia, is failing to respond despite a reasonable trial.

Epigenetic and Genetic Factors

The contribution of epigenetic and genetic factors to the risk for LLD is an area of current growing interest. A sizable French investigation (the European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT]) of neuropsychiatric disorders in 302 participants age 65 and older suggested that a decrease in methylation of a specific serotonin transporter gene (SLC6A4) might increase the risk for LLD (43). Another meta-analysis has linked two additional genes that affect hippocampal plasticity and stress reactivity, apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF), with LLD (44). Although the number of genetic studies is limited at present, current evidence suggests that the genetic associations of LLD may differ from those in younger adults (45).

Depression-Executive Dysfunction Syndrome

The depression-executive dysfunction syndrome (DEDS) attributes a characteristic depressive syndrome (with specific cognitive and mood manifestations and a poorer response to antidepressant treatment) to the disruption of frontostriatal-limbic pathways among older adults (15, 46, 47). The etiology of this condition can be vascular but can also include other causes. The clinical profile of DEDS is characterized by apathy; anhedonia; trouble with planning, initiating, and completing goal-directed activities; lack of insight; suspiciousness; and pronounced disability (15). Apathy, in this syndrome, has been associated with damage to cortical-subcortical networks associated with emotion regulation, reward, and goal-directed behavior (48).

A meta-analysis concluded that among the domains of executive functions, planning and organization were the ones significantly associated with poor response to antidepressant treatment (46). In addition to executive dysfunction predicting poorer response to antidepressants, a marker of executive dysfunction (decreased brain activation measured by functional magnetic resonance imaging during the Wisconsin Card Sorting Task) predicted poor outcome to a psychotherapeutic intervention (cognitive-behavioral psychotherapy) among individuals with LLD (49).

Dysfunctional Reward Processing

Abnormalities in the reward processing system characterized by a reduction in reward responsiveness have also been suggested as a contributing factor (50); this finding is further discussed in the Psychotherapy section in relationship to the role of Engage therapy.

Psychosocial Factors

Adverse life events, lack of social support, loneliness, and lower income are among the psychosocial risk factors associated with LLD (51). Loneliness, even in prepandemic times, has been identified as an important stressor in later life. In a large longitudinal cohort study of older adults, 43% reported feeling lonely (52). In another study, the long-term trajectory of depression was affected by loneliness in a cohort of elderly Finnish adults (53). The mechanisms underlying the association between loneliness and LLD are not entirely clear, but various theories have been proposed. Perceived isolation or loneliness results in increased sympathetic tone, increased systemic inflammation, and decreased sleep (54), which, in turn, exacerbate depressive symptoms. During the later years of life, when social interactions may be restricted, disruption of the dyadic relationship takes on a particular importance in exacerbating depression; this relationship must also be taken into account when implementing treatment interventions. Complex persistent bereavement disorder overlaps symptomatically with LLD, or can co-occur, and both disorders have been associated with increased morbidity and mortality. Following the loss of a spouse, the period of greatest relative mortality risk occurs between 7 and 12 months after the event (55).

Bereavement is one of the psychosocial stressors that increases suicide risk. Assessment of suicide risk, which is an essential component in the evaluation on an individual with LLD, is therefore very important when bereavement has occurred. Suicide risk can be reduced by recognizing reduced social support, by screening for suicidal ideation or behavior, and by enrolling high-risk individuals in appropriate follow-up (such as that described in the innovative Prevention of Suicide in Primary Care Elderly: Collaborative Trial [PROSPECT], which evaluated suicide risk in a primary care setting to prevent adverse outcomes) (7).

Other Factors

Prescribed medications, sometimes helpful for a medical condition or believed to reduce symptoms such as insomnia, may inadvertently contribute to the symptoms of LLD. Angiotensin-converting enzyme (ACE) inhibitors, beta blockers, corticosteroids, and other medications used by many older adults have been linked with initiation or exacerbation of depressive symptoms (56). The effect of aging on the hormonal internal milieu is also significant. Postmenopausal loss of normal estradiol cycling has been proposed to increase depressive symptoms in LLD via effects on neurotransmitter and mood regulatory systems. Specific estrogen receptor polymorphisms have been associated with heightened depression risk among older women, and maintenance of normal estrogen levels is important for several brain regions vulnerable to age-related changes (e.g., the prefrontal cortex and hippocampus) (57).

One review has called attention to the possibility that this hormonal change is growing in importance as increased life expectancy prolongs the duration of postmenopausal life (58). Testosterone, too, may play a role in mood regulation, and testosterone levels appear to be of significance in both men and women. Augmentation with low-dose testosterone, in one trial, improved depressive symptoms among women (59), although the association between depression and low testosterone in other studies has been inconsistent (60, 61). Among hypogonadal men with depression, exogenous supplementation of testosterone has been reported to be beneficial (62, 63).

Assessment

Comprehensive biopsychosocial assessment is warranted when an older adult presents with depressive symptoms. Evaluation begins with a careful history of prior episodes and risk factors, delineation of symptoms, exclusion of symptom-inducing or treatment-complicating medical diseases or toxins (including medications and recreational substances), and identification of acute suicide risk. Laboratory evaluation, to rule out treatable medical disorders that mimic depression, routinely includes the complete blood count (CBC), comprehensive metabolic panel, and thyroid-stimulating hormone (TSH). When clinically indicated, additional tests such as estradiol and testosterone levels as well as vitamin D (64), vitamin B12 (65, 66), or folate (67, 68) levels are also checked. C-reactive protein levels can assess the presence of an ongoing inflammatory process. On the basis of the history and physical examination, one may also consider neuroimaging and sleep assessment for selected patients.

Objective assessment of depressive symptoms using an appropriate rating scale can help to guide and monitor effective treatment. Table 1 provides a list of instruments that can be used to screen and track treatment outcomes among older individuals. Providers are encouraged to use the tools that are best suited to their patients and practice settings. Each instrument has a relatively high and comparable degree of sensitivity and specificity, but these measures vary depending on the studied populations; a detailed summary of these variations is beyond the scope of this article. In addition, a cognitive screening test such as the Saint Louis University Mental Status Examination (69) or the Montreal Cognitive Assessment (70) should be part of the routine assessment of LLD because of the frequent co-occurence of cognitive symptoms among people with LLD. The presence of these symptoms may indicate the prodrome of a neurocognitive disorder (71). Regardless of whether these symptoms are prodromal to neurocognitive decline, their presence may be clinically significant, and their response to treatment may be important to measure.

TABLE 1.

Instruments used to screen for late life depression^a

Instrument	Who administers?	No. of items	Time required for administration (minutes)	In public domain?
SELFCARE (D)	Self	12	5–7	Yes
Center for Epidemiological Studies Depression Scale	Self	20	20	Yes
Center for Epidemiological Studies Depression Scale-10	Self	10	10	Yes
Geriatric Depression Scale-Long Form	Self	30	5–7	Yes
Geriatric Depression Scale-Short Form	Self	15	5–7	Yes
Patient Health Questionnaire-2	Self	2	5	Yes
Patient Health Questionnaire-9	Self	9	5	Yes
Cornell Scale for Depression in Dementia	Provider	19 + 19	20	Yes
Beck Depression Inventory	Self	21	10	No
Hamilton Depression Rating Scale	Provider	21	20	Yes
Montgomery-Åsberg Depression Rating Scale	Provider	10	20–30	Yes

^aMore information and links to instruments are available at https://www.apa.org/depression-guideline/assessment.

Treatment Approach

Psychosocial and somatic treatment interventions have each been shown to be effective in treating LLD. Nonpharmacological strategies, alone or with somatic therapies, should be strongly considered and discussed when planning initial treatment because they can be highly effective and are preferred by many patients.

Physical Activity

Encouraging appropriate physical activity is both preventive and therapeutic with respect to LLD. Physical inactivity among older adults is associated with depression and cognitive deficits, whereas greater midlife physical activity is linked with lower depressive symptomatology in later life. A study of 140 patients showed that engagement in physical activity was associated with lower levels of depression and anxiety (72). Exercise has been shown to reduce inflammation and oxidative stress (73). Evidence indicates that physical exercise can be comparable with antidepressant medication in achieving therapeutic response rates (74, 75); moreover, the addition of exercise to pharmacological treatment is linked to higher and faster remission rates in LLD (76). Although aerobic activity has been consistently shown to be effective in LLD (77), the dose-response relationship has yet to be fully established (78).

Restful Sleep

Reduced ability to initiate and maintain sleep, especially after age 50, is part of the normal aging process (79). Disturbed sleep, however, is also a characteristic feature of depression that may even anticipate mood symptoms during a depressive episode. When both sleep disturbance and mood symptoms are present, the trajectory of depression is likely to include longer and more severe episodes as well as higher relapse rates (80). In addition, incomplete resolution of insomnia portends relapse of other depressive symptoms (81). Consequently, addressing insomnia, discussing sleep hygiene, and incorporating sleep measures into follow-up care are crucial ingredients of LLD care. In pilot studies, newer nonpharmacologic modalities such as brief behavioral treatment for insomnia show promise in effectively treating insomnia among older adults (82).

Appropriate Nutrition and Microbiome Health

A growing body of research supports and characterizes the clinical significance of a gut-brain axis and elucidates a possible contribution of gut microbiome dysfunction to depressive symptoms. This relationship may reflect the association between inflammatory states and gut barrier health (83). Additional evidence suggests that alterations in the gut microbiome affect serotonin levels in the central and peripheral nervous system. Probiotics have been shown to improve depressive symptoms, decrease levels of inflammatory markers, and increase serotonin availability (84). These compelling data suggest the value of additional research among patient populations.

Additional Lifestyle Factors

Smoking is associated with higher rates of depression among older adults compared with those who have never smoked (85). For this and other health reasons, smoking cessation should be encouraged and assisted. At-risk and problem drinking of alcohol also elevate the potential for depressive symptoms. The co-occurrence of alcohol use disorders and depression increases the potential for poor mental and general health outcomes among older adults. Alcohol dependence is both a risk factor for LLD and an obstacle to effective treatment (70). Addressing alcohol misuse in late life is important. Targeted screening that takes into account alcohol consumption and life context can help to identify older adults at higher risk for excessive or problematic drinking (86), which is a problem in its own right that also undermines treatment of LLD.

Psychotherapy and Somatic Treatment Interventions

Psychotherapy

Evidence-based psychotherapies, alone or with pharmacotherapy, are recommended for older individuals with mild to moderate depression (70); they are also recommended for individuals with inadequate or adverse response to therapeutic doses of antidepressants or who are at risk for drug interactions secondary to polypharmacy, which is a particularly important concern among older adults. However, cognitive and sensory impairments as well as access issues such as therapist unavailability, impaired patient mobility, and limited transportation options can interfere with this form of treatment. Randomized controlled trials have provided support for the efficacy of several psychotherapeutic approaches, which can be chosen and customized on the basis of individual needs and resources. Cognitive-behavioral therapy (CBT), problem-solving therapy (PST), interpersonal therapy (IPT), and Engage therapy (87) have been shown effective in treating LLD (88). Each of these approaches is amenable to delivery within a time frame that is customized for the individual, in briefer sessions if necessary and in a problem-focused manner.

CBT, which is based on the premise that inaccurate beliefs lead to maladaptive thoughts and behaviors, is an established and effective approach to treating LLD. In CBT, the therapist is an interactive coach and teacher, helping a patient to identify and alter dysfunctional cognitions while also encouraging behavioral activation and the scheduling of pleasant events. A recent multicenter study showed CBT, with modifications, to be effective in treating LLD (89). These modifications concern both the delivery of treatment and the content of sessions (90). Older adults sometimes find it easier to participate in shorter but more numerous sessions. Engagement with the issues can be enhanced through use of summarization and symptom assessment. Behavioral interventions should target the concerns most relevant to older adults, such as counteracting loneliness through an increase in social engagement.

PST conceptualizes depression as a consequence of a skill deficit. Acting as a sort of project manager and coach, the PST therapist helps a patient with depression to learn and apply new skills or to utilize abilities that were not learned or have fallen into disuse (91). The PST therapist teaches effective problem-solving techniques by providing a structured approach for defining a goal, planning a strategic solution, and monitoring progress toward success, which can be used in diverse populations (92). In one studied cohort, PST was significantly more efficacious than supportive therapy in reducing suicidality among older adults with major depressive disorder and significant executive dysfunction (93). This and other evidence suggest that PST may even have a role in treating older adults with depression and mild degrees of cognitive impairment (94).

IPT was designed to address depression arising from alterations in one’s interpersonal environment. It focuses on one or two of four areas frequently encountered in LLD: role transitions (significant life change), role disputes (conflict with a partner or another person), death of a loved one (complicated grief), and interpersonal deficits (isolation and loneliness or lack of a purpose) (95). Individuals with LLD often blame themselves inaccurately, and an IPT therapist can help the individual reframe the reactions to life changes as treatable life disruptions rather than moral failures. Redefining problems in this way reduces self-blame and clarifies the relationship between depressive symptoms and life events. Identifying and processing the precipitating circumstances with IPT can counteract depressive symptoms.

Engage therapy claims to differ from other psychotherapies as a result of its grounding in the principles of the Research Domain Criteria (RDoC) initiative, an effort to integrate multiple levels of evidence (genetics, molecules, cells, circuitry, behavior, physiology, and self-report) to explore basic elements of functioning to better understand and treat mental illness. Engage therapy postulates that depression reflects dysfunction of the positive valence (reward) system, and it uses reward exposure as its principal intervention to depressive symptoms (96). In RDoC terms, the commonly encountered barriers to treatment response are negativity bias (negative valence system dysfunction), apathy (arousal system), or emotional dysregulation (cognitive control dysfunction). Strategies targeting these dysfunctions are added when needed. For example, methods for addressing negativity bias can include discussing or writing alternative positive explanations to negative thoughts. Strategies for addressing apathy can consist of prompts to initiate action plans or even reminders from others. Emotional dysregulation can be countered by mindfulness activities such as meditation or deep breathing (96).

An additional promising related nonpharmacologic approach, computerized cognitive remediation, uses computer software designed to provide training in cognitive control and to enhance responsiveness of the reward system (97). This type of approach is personalized and continuously adapts its level of difficulty on the basis of the individual’s aptitude, both at baseline and through the course of treatment; this approach also provides consistent supportive feedback to avoid frustration or discouragement (15).

Pharmacotherapy

Despite research demonstrating the importance of psychosocial factors, the treatment of LLD in specialty settings or primary care very often relies upon the use of pharmacotherapy. Studies have shown that among older individuals with moderate to severe depression, antidepressants are more efficacious when compared with placebo (81). Any of the FDA-indicated antidepressants may be used, with a reported response rate of 50%–65% in randomized controlled trials with intention to treat compared with a 25%–30% response to placebo treatment. The intention to treat remission rate with treatment is lower: 30%–40% versus 15% for placebo (98). Individual risks and benefits are likely to vary as a result of pharmacokinetic and pharmacodynamic differences that affect the interaction between patient and medication. In cases of treatment resistance, augmentation strategies and coprescribing have successfully been used. Table 2 lists some of the commonly used antidepressants and augmenters in LLD with typical dosing ranges (99–106).

TABLE 2.

Antidepressants and augmenters commonly used in the pharmacotherapy of late life depression^a

Antidepressant class and medication	Typical dose (mg/day)
SSRI
Citalopram	10–20
Escitalopram	5–20
Fluoxetine	10–40
Sertraline	50–200
Vortioxetine	10–20
Vilazodone	10–40
Paroxetine	10–30
SNRI
Venlafaxine	75–225
Desvenlafaxine	25–50
Duloxetine	30–120
Levomilnacipran	20–120
TCA
Nortriptyline	20–150
Desipramine	50–200
MAOI
Tranylcypromine	30–60
Phenelzine	60–90
Selegiline (Emsam)b	3–6c
Miscellaneous antidepressants
Bupropion	100–300
Mirtazapine	15–45
Esketamine	84d
Agomelatinee (104)	25–50
Antipsychotic-antidepressant
Quetiapine	100–600
Antidepressant combinations
SRI+mirtazapinef
SRI+bupropionf
Bupropion+mirtazapinef
Augmenters
Lithium carbonate (105)g
Triidothyronine (106)	25–50h
Methylphenidate (107)	2.5–5i
Aripiprazole (108)	10–15
Brexpiprazole (109)	1–3
Testosteroneb (110)	100–200j

^aSSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamine oxidase inhibitor; SRI, serotonin reuptake inhibitor.

^bAvailable for transdermal administration.

^cPer 24 hours.

^dTwice per week.

^eNot available in the United States.

^fIn combination, doses up to individual agent maximum levels can be used with caution and appropriate monitoring.

^gDosed to target ≥0.5 mmol/L.

^hDosed in micrograms.

ⁱTwice per day.

^jIntramuscular/weekly.

It is not our goal here to offer specific guidance regarding choice of antidepressant, an exhaustive list of antidepressants, or the procedure for dosing and monitoring treatment, all of which have been reviewed extensively elsewhere (107). General pharmacotherapy principles in LLD include choosing a medication with an eye to potential adverse effects, starting at a low dose, increasing gradually to optimal benefit, and discontinuing after nonresponse or appropriate response and maintenance.

Treatment-resistant depression often requires the use of an augmenter or combination intervention, whereas depression with psychotic features usually requires the combination of an antidepressant with an antipsychotic medication. After remission is achieved, relapse and recurrence rates are diminished by maintenance pharmacotherapy. The focus in successful treatment of LLD must reach beyond treatment of the individual episode and take into account the long-term view, which includes maintenance therapy for prevention of future episodes. In the context of recurrent LLD episodes, extended maintenance pharmacotherapy has been suggested, and limited evidence is available to help the clinician assess the optimal time for antidepressant discontinuation (108).

As in the adult population, careful management of adverse effects is an essential element of successful pharmacotherapy. Selective serotonin reuptake inhibitors are commonly associated with gastrointestinal side effects, changes in weight, hyponatremia, sexual dysfunction, and bruising; they are much less frequently associated with some more serious adverse effects, including gastrointestinal bleeding and cardiac arrhythmias. Tricyclic antidepressant (TCA) use has been associated with sedation, postural hypotension, and anticholinergic side effects such as blurred vision, constipation, urinary retention, and confusion. Less frequent but more severe events include delirium and cardiac conduction disturbances, including ventricular arrhythmias that account for the lethality of TCA overdose.

Broadly, antidepressant side effects can be anticipated on the basis of the medications’ pharmacokinetic characteristics and the pharmacodynamic properties of the medications listed in Table 3; practitioners can anticipate and monitor parameters accordingly. In general, our recommendation is that for older individuals with LL D whose symptoms are managed with antidepressants, providers should consider obtaining a baseline electrocardiogram, CBC, and basic metabolic panel before initiating medications. These parameters can be reviewed after dose titration or as clinically indicated.

TABLE 3.

Pharmacologic basis of adverse medication effects in the pharmacotherapy of late life depression^a

Medication property	Possible clinical consequences
NE reuptake blockade	Tremors, tachycardia, erectile and ejaculatory dysfunction, elevated blood pressure
Serotonin reuptake blockade	GI symptoms, sexual dysfunction, EPS, bruising and bleeding, bone mass density loss
Dopamine reuptake blockade	Activation, aggravation of psychosis
Histamine H1 receptor antagonism	CNS depressant potentiation, sedation, weight gain, hypotension
Muscarinic receptor antagonism	Blurred vision, dry mouth, constipation, urinary retention, cognitive dysfunction
NE α1 receptor antagonism	Some antihypertensive potentiation, postural hypotension, dizziness, reflex tachycardia

^aNE, norepinephrine; GI, gastrointestinal; EPS, extrapyramidal symptoms; CNS, central nervous system.

Neuromodulation

Electroconvulsive therapy (ECT) remains an effective but underused treatment option for LLD (109, 110). ECT is especially useful among individuals with antidepressant intolerance or nonresponse; it is also beneficial when treating LLD associated with delusions, catatonia, and mania (87). The acute antidepressant efficacy of ECT has repeatedly been shown superior to other antidepressant treatment modalities, including pharmacotherapy and psychotherapy. Because of its rapid effect, ECT is the treatment of choice for patients who are urgently ill, including those with psychosis and strong suicidal ideation from depression. ECT treatment of LLD can be associated with transient memory disturbance and significant posttreatment relapse rates; however, the procedure is considered relatively safe for older adults and has been demonstrated to be one of the most effective treatment options for LLD (111). No definitive guideline has identified the optimal number of ECT treatments for patients with LLD. One influential suggestion, from the 2009 Prolonging Remission In Depressed Elderly (PRIDE) study, is to provide at least four additional maintenance ECT treatments following a successful course of ECT, with further treatments as clinically indicated (112).

Repetitive transcranial magnetic stimulation (rTMS) is an additional neuromodulatory approach that has consistently been reported as safe and well tolerated with minimal cognitive adverse effects and a low dropout rate. Evidence of efficacy of rTMS in treating patients with LLD who have failed antidepressant treatments, including patients with treatment-resistant vascular depression (113), has generated interest in its use as a first line treatment. Many clinicians and patients see it as an alternative to medications suitable for individuals hesitant to undergo or unable to tolerate ECT. Older individuals require some modifications of rTMS administration, such as adjustment of the treatment schedule and the use individualized treatment protocols. Identification of factors predictive of rTMS response will further improve its therapeutic potential (114). Deep rTMS is a technical refinement that compensates for age-associated brain atrophy, which increases the distance of the brain from the applied magnetic field. A recent study showed that delivery of deep rTMS using an H1 coil over the dorsolateral and ventrolateral prefrontal cortex achieved a higher remission rate than sham rTMS (40.0% vs. 14.8%) and may be especially suitable for use among patients with treatment-resistant LLD (115).

Collaborative Care

Given the shortage of geriatric psychiatrists and the prevalence of LLD, researchers have explored methods for improving the recognition and management of LLD in primary care settings. The IMPACT study, which is one of the larger treatment trials for LLD, showed that a collaborative care model can increase the effectiveness of treating LLD in primary care settings. Older adults are more likely to seek depression treatment from a primary care provider than from a mental health specialist; however, treatment as usual in primary care may is less efficacious than collaborative treatment in the primary setting that incorporates guidance from a depression care specialist.

Results from the IMPACT study showed that at 12 months, about half of the primary care patients receiving collaborative care for depression reported at least a 50% reduction in depressive symptoms compared with only 19% of those in usual care. Surveys conducted 1 year after the study showed that the benefits of the IMPACT intervention persisted at follow-up assessment (116). Other collaborative care models, some of which engage community health workers, have also been successful. These models present an effective and affordable approach that can improve engagement of different racial-ethnic minority groups within the LLD population (117).

Concluding Comments

Depression is not a normative aspect of the aging process, but it is an often overlooked or undertreated psychiatric disorder among older adults. The consequences of failing to recognize and adequately treat LLD include impaired functional capacity and diminished quality of life. In later life, the most frequent psychiatric antecedent of suicide is depression. People with LLD are most often identified and treated in primary care settings. Whether in primary care or specialized settings, attentive and comprehensive assessment is required to avoid a missed diagnosis or ineffective treatment plan. Early detection and management are both desirable and challenging.

Older adults are especially vulnerable to suboptimal outcome because of age-associated variant presentations, medical comorbid conditions, cognitive impairment, and social determinants that interfere with treatment. LLD is amenable to lifestyle interventions, psychotherapy, or somatic approaches, including antidepressant therapy and neurotherapeutic approaches. Appropriate management is associated with reasonably high rates of response and remission, although maximal improvement may be more limited or require a longer duration of treatment. Individuals with vascular depression or the depression-executive dysfunction syndrome, for example, have been shown to respond less fully and more slowly to conventional antidepressant pharmacotherapy (15, 30).

Given the common presentation of treatment resistance among patients with LLD, further research is needed to guide clinicians who treat older adults with depression who fail to respond well to typical initial approaches. Psychotherapy plays a valuable role and can be modified to target the special needs of older adults. Antidepressants have been shown effective, but side effects require attentive management. Augmentation and coprescribing strategies effective in younger adults are used in treating people with resistant LLD, but further evaluation among older adults is needed to propose evidence-based pathways for management. Additional areas for investigation include the potential preventive value of lifestyle interventions such as physical and mental activity, nutrition, social engagement, and management of sleep disturbances.

As primary care practitioners increase their competence in treating LLD, the psychiatrist’s role is often consultative. Psychiatrists are in a unique position to assist and educate primary care colleagues in recognizing and treating LLD in its various manifestations. A psychiatric perspective can be valuable in identifying important medical and psychosocial determinants that are less amenable to pharmacotherapy but must be addressed to achieve an optimal outcome.

Because LLD can vary from the depressive syndromes seen among younger adults with respect to detection and management, it may be valuable to call attention to its distinct characteristics in the classification of mood disorders. Currently, several variants of major depressive disorder with differential presentations or treatment requirements are highlighted through the use of specifiers such as “with anxious distress,” “with mixed features,” “with melancholic features,” “with atypical features,” “with mood-congruent psychotic features,” “with mood-incongruent psychotic features,” or “with peripartum onset.” Inclusion of a specifier for “with late life onset” in future DSM editions would emphasize the uniqueness of LLD and remind clinicians that this particular mood disorder syndrome may be associated with different approaches to prognosis, risk assessment, evaluation, acute treatment, and follow-up care.