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Clinicians will likely encounter increasing numbers of older adults with late-life depression. Advances in our understanding of the neurobiology can help inform diagnosis and prognosis.
Late-life depression (LLD) can be defined as depression that occurs after the age of 60 years, although onset and definition of cutoff may vary. There are many subtypes of depressive illness that are the same in both younger and older adults. The focus in this article is on unipolar depressive disorders.
It is important to distinguish early-onset depression (EOD) with recurrent depressive episodes in later years from late-onset depression (LOD), in which a depressive illness develops for the first time in later life, because the neurobiological underpinnings, presentations, and illness courses differ (Table 1). Symptoms in older adults with EOD who have recurrent depressive episodes in later life appear to differ substantially on various aspects from symptoms in persons with LOD; in older adults with LOD, depressive illness appears to develop in the context of primary medical or neurological illnesses, such as heart disease or stroke (vascular etiology), dementia (neurodegeneration), or increasing medical burden (chronic inflammation or stress overload).
Epidemiology of LLD
In DSM-5, the core symptoms and criteria for MDD remain the same regardless of age. A new category termed “Persistent Depressive Disorder” captures both chronic depression and dysthymic disorder, but the immediate significance of this terminology change in the older adult population is unknown. An inability to find scientifically meaningful differences between these two conditions led to their combination with specifiers included to identify different pathways to the diagnosis and to provide continuity with DSM-IV. Finally, the grief exclusion for MDD has been eliminated, meaning that the diagnosis can be made in patients who experience severe and persistent depression as a consequence of bereavement and they can be treated.
Although depression is not a consequence of normal aging, depressive disorders are common in later life. Rates of MDD are by and large lower in healthy community-dwelling elderly persons than in younger adult populations, ranging from 1% to 3%.1 However, these rates rise in different settings and with increasing medical and psychiatric comorbidity as well as with various social conditions.
Subthreshold depression (SubD) in later life encompasses minor depression, subsyndromal depression, dysthymia, brief recurrent depressive disorder, and non-dysphoric depression. In general, the prevalence of SubD in older adults is higher than that of MDD.
SubD in later life is not a benign condition, and it has been linked to various negative medical and psychosocial outcomes, including impaired physical functioning, more disability days, poorer self-rated health, and greater use of psychotropic medications.2,3 Moreover, SubD is a risk factor for subsequent conversion to MDD, and it may be associated with suicidal ideation; thus, it requires careful surveillance.
Neurobiology of LLD
Over the past 2 decades, a vast literature on the neurobiology of depression has provided many intriguing insights, giving rise to theories of pathogenesis and novel interventions. New techniques in molecular genetics, neuroimaging, and bioinformatics, among others, have increased our understanding of the relevant neurobiological mechanisms involved in the expression of complex psychological thought, cognitive function, and social behavior. These advances are being applied to the study of LLD. Table 2 describes currently prevailing etiological theories and some consistently related neuroimaging findings; relevant cognitive findings are also shown.
Cognitive impairment in LOD appears to be more common and more impairing than in EOD. These deficits may reflect the direct effects of the primary psychiatric disorder, the consequences of repeated depressive episodes, prodromal states of dementia or other neurodegeneration, vulnerabilities from associated conditions such as vascular or inflammatory processes, medication effects, or the changes associated with aging.
The distinction in onset appears to reflect different vulnerabilities across the age span. In EOD, genetic load appears to be higher. The cumulative effects of long-term exposure to hypercortisolemia via hypothalamic-pituitary-adrenal axis activation over repeated episodes may manifest with particular changes in vulnerable brain areas, such as the hippocampus. These changes may subsequently be associated with an increased risk of cognitive impairment. Conversely, in LOD, different mechanisms, such as neuroinflammation, vascular insults, and neurodegeneration, may be responsible.
Assessment and diagnosis
Although DSM-5 criteria for mood disorders are not age-specific, challenges to diagnosis of depressive illness in the elderly are well recognized (Table 3). Older persons are more likely to focus on bodily complaints rather than psychological distress. The stigma of mental illness remains high with some older cohorts, although more recent evidence suggests that this attitude may be changing. With a higher prevalence of medical comorbidity in older age, distinguishing neurovegetative symptoms of depression from symptoms of medical illness or the adverse effects of medications can be difficult. Moreover, LLD may be seen as a consequence of accumulating losses across physical, functional, and social domains rather than as an actual disorder that needs to be treated.
To improve assessment and reliability of diagnosis in older adults, several strategies can be useful. First, privacy and confidentiality (absent any serious safety or emergency concern) must be ensured. Second, psychological distress should be normalized, but not overemphasized. Third, collateral information from available family, friends, or other caregivers should be solicited if the patient consents. Discussion with at least the primary care physician should be attempted, and treatments, if offered, should be coordinated among all caregivers. Lastly, although there is currently no evidence for routine screening for LLD, targeted screening of high-risk individuals may be useful. For targeted screening to work, a systematic plan of surveillance and ability to provide care must be in place. Risk factors for the development of LLD are shown in Table 4. The differential diagnosis of LLD is broad and should rule out medical, neurological, and other psychiatric disorders as well as adverse effects of medications and life circumstances (eg, bereavement, loneliness, or financial distress).
Numerous screening instruments exist for the assessment of depression. The following have been specifically studied and validated for use in older adults: the Patient Health Questionnaire-9 (PHQ-9), the Geriatric Depression Scale, the Cornell Scale for Depression in Dementia, and the Center for Epidemiological Studies-Depression. Because of ease of use and reliability across settings and older populations, the PHQ-9 appears well-suited for routine application. Screening instruments are helpful for case-finding and surveillance, but they are not the sole basis for making a diagnosis and should be followed by a clinical interview. Some instruments-eg, the PHQ-9-may also be used to assess symptom severity or to guide treatment decisions.
If a patient screens positive, a clinical interview to clarify any questions and explore for complications (eg, a home safety issue, suicidal intent or access, or psychosis) is necessary. At this point, an explicit therapeutic alliance, which follows the principles of patient-centered care, should be formed and take into account the patient’s understanding of depressive illness, address any fears or concerns of diagnosis or management, set expectations for treatment, and respect the patient’s care values.
Because depressive symptoms can be seen in a variety of medical conditions and depressive disorders are highly comorbid in common medical illnesses, a thorough review of current and past medical history and review of current medications and supplements-both prescribed and over-the-counter-will be needed. Older adults who present often for evaluation of relatively minor or vague somatic complaints should raise suspicion for an underlying depressive disorder. Similarly, pain that appears unresponsive to usual measures or a new symptom of insomnia should prompt a screen for depression. Older adults will also need to be screened for abuse, misuse, and inappropriate use of medications, alcohol, medical marijuana and, in some circumstances, illicit substances.
If duration and criteria for MDD are not met, consideration should be given to a diagnosis of SubD and a return visit in 2 to 4 weeks to review stability of symptoms is indicated. Documentation of symptoms to be systematically measured with mood and functional scales will facilitate communication with the patient, family, and other caregivers; help direct follow-up and type of intervention selected; and guide treatment choices to ensure optimal outcomes.
A 74-year-old man with an ailing wife presents with worsening back pain and headaches, lack of energy, and insomnia. On examination, he has hypertension and because of poor appetite, he has recently lost 10 lb. He lacks motivation to take his medications regularly and endorses poor concentration and memory lapses. He no longer socializes, and he worries about his wife and blames himself for not doing more around the house. He adds, “When she goes, it’ll be my time too.” He has access to firearms.
Two weeks later, although denying sadness, he endorses a lack of enjoyment in his usual activities; he no longer takes pleasure in visiting with his grandchildren and admits to being more irritable than usual. With medication, his blood pressure is normal. His pain resolved with physical therapy and intermittent use of non-opioid analgesics, but his insomnia and fatigue persist as does his poor appetite. He has not shaved in over a week. His laboratory test results are negative, a 12-lead ECG shows normal sinus rhythm and rate, and a brief physical examination shows mild temporal wasting and decreased strength.
Brief cognitive testing on the Montreal Cognitive Assessment (MoCA) shows he can draw a clock but requires prompting to complete other items. His score is 27/30 and he lost 1 point each on alternating trail making, attention (vigilance), and short-term memory recall. His PHQ-9 score is 19, which indicates moderately severe depression.
There are no medical or medication issues that contribute to his depression, and treatment is warranted. Although he denies suicidal thinking, he has acute risk factors that must be addressed, such as insomnia and caregiver stress as well as firearms in the home.
He accepts a referral to a social worker for additional resources needed at home to help him care for his ailing wife and agrees to attend group psychotherapy, available at his local senior center once a week. He also avails himself of phone peer-counseling. His daughter is holding his gun for safekeeping. Although initially reluctant, he starts antidepressant treatment and is being seen in the office every 2 weeks to ensure adherence, address any adverse effects, and complete mood scales. After 10 weeks, on a repeated MoCA he scores 30/30 and his PHQ-9 score is 3, indicating no significant depression. He still worries about his wife but feels capable of providing for her needs and seeking help if he begins to feel overwhelmed.
Depending on the diagnosis of depression and severity of impairment, a variety of treatment interventions can be considered. For milder cases of depression, supportive measures and watchful waiting may suffice, since the evidence of benefit from pharmacotherapy is limited. When watchful waiting is being used, it is essential not to overlook systematic reassessment with a validated mood instrument. On the other hand, this may be an ideal time for intervention to prevent deterioration and development of more serious forms of depression.
Nonsomatic interventions can be particularly useful for addressing milder forms of depression, and patient acceptance rates are usually high. Nonsomatic treatment may be better suited to older adults with multiple medical problems or who take multiple medications, for whom the concern for polypharmacy, drug-drug interactions, or susceptibility to adverse effects may be high. Recent studies of complementary and alternative medicine approaches have shown promise, although it is important to remember that botanicals and over-the-counter supplements can also have adverse effects or interact with prescribed medications.4,5
Although acupuncture is widely practiced for other ailments, the data for its use in LLD remain limited. However, preliminary evidence suggests a potential benefit when it is used alone or combined with other methods or medication.
Exercise improves cardiovascular function, releases endogenous endorphins, and improves cognition and mental stimulation. The effect size may be comparable to that of psychotherapy in select populations of older adults. Motivation to exercise is usually the main obstacle, so methods such as behavioral activation or motivational interviewing to ensure adherence are often needed. Mindfulness approaches, encompassing meditation, mindful awareness, T’ai Chi Chih, and yoga, have also shown some preliminary utility in addressing depressive and anxiety symptoms-especially insomnia and pain-in older adults.
The evidence for St John’s wort is mixed: it may be effective in milder forms of depressive illness but is not effective in more severe forms. Furthermore, the use of St John’s wort may be problematic because of its inhibition of monoamine oxidase and induction of the liver enzyme system.
A necessary cofactor in the synthesis of various neurotransmitters, S-adenosyl-L-methionine (SAM-e) is a naturally occurring compound synthesized from the amino acid L-methionine. Preliminary evidence suggests that SAM-e may have potential as an augmentation strategy in patients with incomplete responses to antidepressants; however, randomized controlled trials (RCTs) in older populations are needed.
Omega-3 fatty acids have been extensively studied in a variety of conditions and are essential for normal human development and cellular function throughout the life span. Most studies have focused on younger adults with depression. Notwithstanding, preliminary evidence suggests potential benefit in LLD, although given the antithrombotic properties of fish oil, a better understanding of safety in older populations is needed.
Diverse psychotherapies are available for patients with LLD, and they can be applied in the same modalities (eg, individual, group) and settings used in younger populations with some modifications. The effectiveness of various forms of psychotherapy for LLD should not be overlooked, but access to qualified trained psychotherapy practitioners may be limited. Other challenges to using psychotherapy in older adults include the potentially slower time to onset of benefit, the need for multiple office visits, the need to adapt techniques in the face of physical or primary sensory impairment, and psychological resistance.
Neuroplasticity-based computerized cognitive remediation (NBCCR) has shown promising results.6 This treatment focuses on brain networks implicated in LLD, specifically, hypometabolism in the dorsal neocortical structures and hypermetabolism of limbic structures. The intervention tasks target and activate these dorsal neocortical structures to enhance their function, leading to improvement in depression symptoms. Replication studies in larger independent samples of older adults are warranted.
Pharmacotherapy for LLD takes into consideration pharmacokinetic and pharmacodynamic changes associated with aging and illness, the need to avoid polypharmacy when possible, and close monitoring for adverse effects. Starting at a lower than usual dose and slowly titrating to a therapeutic dose is recommended; adequate dosage and trial duration are essential. In addition, keep in mind that treatment response may take up to 16 weeks.7 Treatment adherence for this length of time can be difficult for any patient.
In general, SSRIs may take longer to work in older adults (10 to 12 weeks) than in younger adults (6 to 8 weeks). Lower rates of response were found among older men, with increasing age, and with a longer duration of current index episode.8 Importantly, those patients with higher baseline severity and a first episode of illness appeared to have higher response rates.
The recent Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) placebo-controlled study of sertraline and mirtazapine for depression in dementia showed no difference in depression outcome.9 However, one study showed that mirtazapine, but not sertraline, was cost-effective in this population when the impact on unpaid caregivers and quality of life were considered.10 Findings from the Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) trial indicate that sertraline was not more effective than placebo in reducing depression or improving cardiovascular status in patients with depression and heart failure.11 A recent meta-analysis suggests that response to antidepressants in the oldest age-group may be less robust or poorly sustained.12 Notwithstanding, on the basis of extant evidence, all currently available antidepressants are equally effective in LLD.
Because of their improved tolerability and safety profile, SSRIs are considered first-line therapy.13,14 Data on the efficacy of newer agents (levomilnacipran ER, vilazodone, vortioxetine) for LLD are limited or lacking.15,16 Table 5 lists agents for treatment of LLD, although the evidence base is limited.
Late-life treatment-resistant depression
Guidance on next steps after an older adult with LLD fails to respond to a first SSRI trial is based mainly on expert consensus. The exact prevalence of late-life treatment-resistant depression (TRD) is unknown, although findings indicate that as many as 40% of older adults have chronic depression if they are not successfully treated; medically frail patients are at higher risk.17 Risk factors for late-life TRD include LOD, chronic depression, significant residual symptoms without full inter-episode functional recovery, and significant psychiatric or medical comorbidity.
Poorer treatment response has been seen with comorbid neurodegenerative disorder.9,18 Results from a recent study showed that discontinuation of antidepressant treatment in patients with dementia and neuropsychiatric symptoms led to an increase in depression symptoms.19 The effects of combining antidepressants or adding an adjunctive nonantidepressant medication have not been fully explored. Finally, the adjunctive use of psychotherapy, in particular cognitive-behavioral therapy, problem-solving therapy, interpersonal psychotherapy and, possibly, NBCCR, as well as other nonsomatic therapies may increase efficacy.
When these options have not worked, consider neuromodulation interventions. Data are most robust for electroconvulsive therapy (ECT) but are generally lacking or still questionable for vagus nerve stimulation (VNS) and transcranial magnetic stimulation (TMS).20,21 While VNS is FDA-approved for TRD in all adults, the pivotal trials did not include many older adults and reports of benefit are mainly anecdotal. Response may take up to 6 months or 1 year, which makes VNS unsuitable for immediate definitive response. Moreover, the cost of the procedure and follow-up visits can be prohibitive because it is not covered by Medicare.
In the US, TMS is available as repetitive TMS (rTMS) and deep TMS (dTMS). Although TMS efficacy has been demonstrated in treatment of MDD in adult populations, some controversy exists as to benefit for older adults. Pivotal TMS trials included older adults but excluded the oldest old and those with significant medical comorbidity. Indeed, initial reports suggested that older age might be a predictor of nonresponse to rTMS, possibly because of age-related atrophy of the dorsal prefrontal cortex where the stimulus is applied and the subsequent inability of the magnetic pulse to reach its target.
Findings suggest that age or prefrontal atrophy per se may not be the determining factors of nonresponse to rTMS in LLD.22 Response rates to rTMS were negatively correlated with age and positively correlated with higher frontal gray matter volumes. Also, disrupted white matter tracts in pathways connecting the >left dorsolateral prefrontal cortex (ie, the stimulation site) and other neurocircuitry targets, such as the left anterior cingulate cortex, might be selectively associated with poorer response to rTMS.23
dTMS is also available for use in the treatment of MDD. RCTs included older but generally healthier adults up to age 65, so applicability and benefit in older and more medically frail cohorts remain to be shown. Nonetheless, studies of dTMS suggest additional cognitive improvements independent of effects on mood, which may be particularly relevant to older adults with LLD. Higher apathy scores may be a predictor of nonresponse to dTMS, suggesting that better targeting in LLD subgroups may be possible. Combining either rTMS or dTMS with antidepressants may also be beneficial.
Finally, for severe, unremitting depression associated with marked physical or functional impairment, and for which a rapid definitive response is needed, ECT remains the gold standard. Numerous meta-analyses and reviews point to the safety and efficacy of ECT in LLD and, in fact, older age may be a predictor of response.24 ECT can be particularly beneficial in older adults with suicidal, psychotic, or catatonic depression. With medical evaluation and optimization, ECT may be the most effective treatment for medically frail older adults.
While acute responses are well recognized, an ongoing problem with ECT regardless of patient age is the high risk of relapse after completion of the index series. Maintenance strategies include combination pharmacotherapy (dual-action antidepressant such as a TCA, venlafaxine, or mirtazapine plus lithium); maintenance ECT (treatments at decreasing frequency necessary to maintain response); and combinations of medications, ECT and, possibly, other neuromodulation interventions. Trials of ECT for maintenance and to better characterize potential biomarkers of ECT response are under way.
Clinicians will likely encounter increasing numbers of older adults with LLD. Advances in our understanding of the neurobiology of LLD can help inform diagnosis and prognosis. Targeted screening using a validated instrument appropriate for the patient population and setting is a useful strategy for identifying and systematically following individuals at high risk for LLD. Ensuring that the patient understands the diagnosis and treatment options will maximize safety and outcomes.
Both somatic and nonsomatic interventions should be considered, although, in general, specific efficacy data of benefit in older adults or more medically compromised groups are often limited or the results modest. For milder cases of depression, watchful waiting may be appropriate; however, nonpharmacological approaches appear to be well-tolerated, beneficial, and potentially sufficient to prevent further deterioration. Once a patient converts to or presents with more moderate to severe depression, pharmacotherapy, combined medication and psychotherapy, or some forms of neuromodulation can be considered.
Dr Espinoza is Clinical Professor in the department of psychiatry and biobehavioral sciences at the Geffen School of Medicine at UCLA. He is also Director of the Geriatric Psychiatry Fellowship Training Program, Medical Director of the ECT Program, and Associate Director of the UCLA Longevity Center. Dr Kaufman is Assistant Clinical Professor in the department of psychiatry and biobehavioral sciences at the Geffen School of Medicine at UCLA.
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