Introduction

There has been a considerable increase in the number of older individuals in the United States, with those over the age of 85 representing the fastest growing segment of the population ( ). The global population has also seen an increase in the proportion of older individuals, especially among developing countries ( ). We must appreciate this demographic change by recognizing the many biopsychosocial elements unique to this diverse population. As clinicians and researchers, we must always remain vigilant to the ever-changing and specific needs of our patients. This will require particular focus on the complex network of associations and relationships that govern the everyday lives of people. This is crucial when discussing mental health, especially in the older patient population. The mental health of older individuals has profound consequences for not only quality of life but also morbidity and mortality. This is deeply concerning given that many psychiatric disorders are often underdiagnosed and therefore untreated in geriatric patients ( ; ; ; ; ; ; ; ). Even when recognized, some psychiatric disorders have prolonged and tortuous treatment courses. This is often the case for late-life depression (LLD). In general, it has been determined that depression is among one of the leading causes of disability-adjusted life years (DALYs) in the world ( ). It is well known that depression has devastating health consequences in older adults that include but are not limited to social deprivation, decreased quality of life, cognitive decline, and suicide ( ).

The development of psychiatric disorders later in life has significant health consequences for these individuals. There are complex bidirectional interactions that occur between medical and psychiatric diseases that often leads to worse outcomes overall ( ; ; ). As an example, there is significant worsening of cardiovascular outcomes in patients with coronary heart disease and comorbid depression ( ). It has also been determined that patients with depression are at increased risk of diabetic complications due to worse glycemic control ( ). This remains relevant when discussing healthcare outcomes for geriatric patients given their increased burden of medical disease in combination with the historical under recognition of psychiatric disorders ( ; ; ). In addition to the unique health burden assumed by aging populations, there are many psychosocial factors that influence the overall wellbeing of geriatric patients ( ). It has been determined that psychological and social variables such as environmental mastery, sense of purpose, and autonomy were crucial elements related to the diagnosis of major depression in older individuals ( ; ). In addition to unique psychosocial stressors experienced later in life, older individuals are also at increased risk for depression due to age specific biologic changes ( ; ). There is mounting evidence that supports unique pathophysiology for LLD with wide-ranging medical etiologies ( ). This has profound consequences for disease presentation, clinical course, symptom management, treatment response, and prognosis ( ; ). In this chapter, we will focus primarily on LLD with particular emphasis on treatment resistance.

Epidemiology

There are many epidemiological studies that exclude older adults, focusing more on younger populations when investigating psychiatric disorders ( ). This is due to the misconception that psychiatric disorders are rare in older individuals ( ). Although there is epidemiological evidence suggesting an overall lower rate of depression among this population, we must consider how underdiagnosis impacts the validity of these studies. It has been well documented that depression in geriatric patients is often not recognized, underdiagnosed, and inadequately treated ( ; ; ; ; ; ; ; ). There is data to suggest that depression in older adults is not fully assessed due to differences in clinical presentation when compared to younger individuals ( ; ; ). There is a paucity of training leading to poor clinical competency in the area of geriatric depression which has further exacerbated the level of underdiagnosis ( ). In addition, we must also be cognizant of changes in diagnostic criteria or algorithms over time and how this can impact prevalence data ( ; ). Therefore, late-life depression has the potential to be higher than traditionally reported in the geriatric population.

In general, there is a 20% lifetime prevalence for major depressive disorder ( ). In terms of psychiatric disorders presenting later in life, depression remains one of the most frequent diagnoses with the majority of individuals having no previous psychiatric history ( ; ; ). It has been determined that over 50% of elderly patients with depression are experiencing their first episode ( ; ). The overall prevalence of major depression in adults over the age of 65 was roughly 1% with rates of 1.5% in women and 0.5% in men ( ). Depressive symptoms do not preclude the diagnosis of other psychiatric diseases and are not mutually exclusive. There is evidence to suggest that depression occurring later in life increases the risk of developing other psychiatric disorders. This is particularly true when considering alcohol use disorder, which is three to four times more likely to occur in the setting of geriatric depression ( ). These psychiatric comorbidities may contribute to increased treatment resistance in geriatric depression. For example, comorbid anxiety is associated with poorer treatment response ( ). Treatment nonresponse in geriatric depression has also been associated with clinical factors such as higher baseline depressive severity, longer duration, more guilt, and greater functional impairment ( ).

There are many sociodemographic factors to consider when discussing depression ( ; ; ). Some of these risk factors specific to LLD include but are not limited to social isolation, bereavement, low income or educational level, divorced or separated marital status, sleep problems, and prior history of depression ( ; ). Moreover, low level of perceived social support has been shown to be one of the risk factors for poor response to psychotherapy in LLD ( ).

There are studies revealing 50%–60% of patients overall do not achieve adequate response following initial treatment for depression ( ). Other studies revealed that between 29% and 46% of patients with depression did not achieve therapeutic effect from antidepressant medications even after adequate dose and duration ( ). One study had determined that only 19% of elderly individuals with depressive disorders were on antidepressant medications ( ). It was found that treatment resistance was present in roughly 18%–40% of the elderly population ( ). There are some survey data that report even higher rates with nearly 55%–88% of elderly patients with major depression not responding to selective serotonin reuptake inhibitor (SSRI) or SNRI medication ( ).

Pathophysiology

There is growing evidence to suggest that late life depression (LLD) has multiple potential etiologies which contributes to its unique presentation when compared to depression occurring earlier in life. It has been well documented that comorbid medical disease can impact the accurate diagnosis and treatment of depression due to confounding symptomatology ( ; ). There are cerebrovascular, metabolic, inflammatory, immune, neurocognitive, and genetic changes that can influence both the clinical presentation and treatment response of LLD ( ; ). There are also specific neural structures and cerebral networks that have been implicated in the pathophysiology of LLD ( ). The conglomeration of these elements provides insight into mechanisms that potentially govern treatment resistance of depression within the geriatric population.

This hypothesis proposes that cerebrovascular disease plays a critical role in the development of depression in older individuals. The development of LLD secondary to these changes has been given the term “vascular depression” ( ). This was originally suggested due to the increased prevalence of depression among individuals with stroke and other cerebrovascular risk factors (CVRFs) ( ; ). This is supported by neuroimaging studies. There is notable gray matter atrophy in the frontal and hippocampal regions of the brain along with subcortical lacunes, micro infarcts, and micro hemorrhages seen in patients with LLD ( ). Of note, the rates of clinically defined vascular depression (35.2%) and poststroke depression (36.4%) are similar among geriatric patients ( ). It is believed that the underlying pathophysiology of vascular depression involves hypoperfusion and inflammation that leads to the development of white matter lesions (WMLs) that disrupt neural systems such as the cortico-striato-pallido-thalamo-cortical (CSPTC) pathway among others ( ). As an example, consider the “depression-executive dysfunction (DED)” hypothesis which results from abnormal communication between limbic and dorsal cortical structures resulting from lesions in white matter networks ( ). There is evidence to suggest that WML burden is related to treatment resistance in LLD and is associated with poor response to antidepressant medications with nonremission, early relapse, and recurrence ( ). This is supported by imaging studies demonstrating that white matter integrity in particular networks is associated with poor response to antidepressant medications, specifically those involved in serotonin reuptake inhibition ( ).

There are also investigations focusing on the relationship between neurocognitive disorders and LLD ( ). It has been suggested that frontal-subcortical abnormality leads to depressive mood symptoms in patients with dementia and that 10%–30% of elderly individuals with Alzheimer’s disease experienced depressive mood symptoms ( ). It has been found that the default mode, executive control, and salience networks are involved in LLD. Of these networks, abnormal functioning of the default mode network (DMN) appears to be involved with Alzheimer’s disease pathology. It was found that moderate-severe treatment resistance in patients with LLD had amyloid PET findings similar to patients with confirmed Alzheimer’s disease ( ). The amyloid burden in these patients was located in the precuneus, parietal, temporal, and occipital areas. This has led researchers to believe that treatment resistance in LLD might represent a prodrome to Alzheimer’s disease and reflect its early changes ( ).

There are other various age-related inflammatory, metabolic, immune and genetic processes that influence neural networks impacting the development of treatment resistance in LLD. There was an association between the presence of a single nucleotide polymorphism (SNP) which encoded for IL-1β and treatment response to antidepressant medication ( ). There have been genetic studies that have demonstrated an association between specific serotonin receptors and response to antidepressant medications. The study revealed that homozygous gene expression of the serotonin 2A-receptor led to an increased treatment response to citalopram. ¹

Additionally, patients with elevated levels of TNF-α did not respond well to escitalopram. Interestingly, patients also responded poorly to escitalopram if they had elevated baseline CRP levels, with greater response found in patients with low baseline levels (CRP < 1 mg/L). ¹ The contrary was true when considering nortriptyline. It was found that patients had a greater response to the medications with elevated levels of CRP and responded poorly with lower levels. ¹ There have also been studies focused on insula metabolism and how this impacts treatment response to escitalopram in patients with LLD. A positron emission-based study found that insula hypometabolism was associated with a poor response to escitalopram with hypermetabolism leading to more a favorable response. ¹ These studies provide further insight into the challenges faced with developing an effective treatment plans for patients with LLD.

Clinical presentation

The clinical diagnosis of geriatric depression, or late-life depression (LLD), is based on the same criteria as depression in younger individuals. The Diagnostic and Statistical Manual for Mental Disorders Fifth Addition (DSM 5) indicates that an individual must display five of nine criteria, including depressed affect, for a 2-week period in order to be diagnosed with a major depressive episode. These criteria include anhedonia, change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, inappropriate guilt or worthlessness, decreased concentration, recurrent thoughts of death or passive or active suicidal ideation (DSM 5).

Symptoms of depression in late life are more similar to early life than they are dissimilar . However, clinical presentation of depression can be different in patients of advanced age, and symptom frequency and severity may vary. Quality and duration of sleep changes later in life regardless of depression, making insomnia much more likely in LLD than hypersomnia, which can be a symptom of depression earlier in life ( ). A significant decrease in appetite and resultant weight loss are also very common in late life depression, more so than earlier in life. Individuals over age 65 with depression often have multiple medical comorbidities that can contribute to worsening mood. Additionally, they may also present with physical symptoms that make underlying depression more likely to remain undiagnosed ( ). Examples of these presenting complaints include cognitive or memory issues, fatigue, weight loss, pain, social withdrawal, increased substance or medication intake.

Cognitive impairment is a presenting symptom that is associated with LLD. In the past, the cognitive decline noted in depressed patients was termed pseudodementia , indicating that the cognitive impairment would fully resolve with treatment of the depression. However, this is no longer an accurate term since it has been determined that the cognitive impairment is as real and potentially irreversible as that caused by any other etiology . Additionally, these patients are at higher risk of developing dementia in the future ( ). Cognitive impairment may be a symptom of depression, or, alternatively, patients with a higher predisposition for, or in the early stages of, Alzheimer’s dementia, vascular dementia and other major neurocognitive disorders may be more likely to develop depression. The directionality of this association remains unclear.

When evaluating geriatric patients for depression, cognitive impairment may make it more difficult for them to report symptoms themselves. It is often helpful to obtain history from caretakers or family members during an assessment. In addition to history-taking, a comprehensive evaluation for late like depression includes administering symptom rating scales and completing a cognitive examination, a medication review, and laboratory testing ( ). Rating scales that are commonly used to assess symptoms as quantitatively as possible are the Geriatric Depression Scale (GDS) and the Personality Health Questionnaire 9 (PHQ-9) ( ). A cognitive examination includes administering a screening tool like the Mini Mental Status Examination (MMSE). It is also important to review medications since polypharmacy and specific medications used to treat other illnesses could be contributing to low mood. Laboratory testing for nutrient deficiencies, anemia, or changes in thyroid hormone are recommended in order to assess for easily reversible medical conditions that could be contributing to depressive symptoms ( ).

The course of geriatric depression is often chronic and resistant to treatment. In a study published in 2015, 61% of geriatric participants had chronic depressive symptoms over a 2-year period, even with treatment throughout the entire study . In a study done by , remission was achieved in one third of all elderly patients treated with an antidepressant. This demonstrates the high rate of treatment-resistance in this population. Additionally, in a study done by , over half of the depressed elderly patients who achieved symptom remittance experienced recurrence . Due to the difficulty in treating late life depression a wide variety of treatment options must be considered.

Current treatment options

Pharmacotherapy for the treatment of LLD includes antidepressants that are used for depression in all ages. SSRIs are first line, as they are in younger patients with depression. In a review done in 2018, specific SSRIs sertraline and paroxetine and an SNRI, duloxetine, were effective for symptom improvement in LLD. Vortioxetine, a newer antidepressant, also demonstrated efficacy ( ). Escitalopram and sertraline have been recommended over other SSRIs due to less risk of adverse effects or interactions with other medications ( ).

However, the results demonstrating the efficacy of antidepressant monotherapy is mixed. In a metaanalysis including 15 randomized controlled trials, antidepressants were found to be ineffective in patients over 65 years of age . Antidepressants have also been shown to decrease in efficacy as age increases ( ). The reason for this difference in efficacy of antidepressants based on age remains unclear. It could be due to the increased number of medical comorbidities that contribute to depressive symptomatology, or physicians’ concerns about increasing doses of psychotropic medication in patients of advanced age on multiple other medications, making them less likely to increase a medication to the dose necessary for symptom remission ( ).

When first line medications prove to be ineffective other treatments are considered. These include adjunct treatment with lithium or atypical antipsychotics, electroconvulsive therapy, transcranial magnetic stimulation, and ketamine. Lithium augmentation has been investigated and in one study had an overall response rate of 42% ( ). In another study, lithium augmentation was more effective for geriatric patients with depression than younger adults ( ). Atypical antipsychotics are also used as augmentation agents. Some patients with late-life depression may benefit from the addition of SGAs. Aripiprazole has been shown to be efficacious, and adverse events of SGAs were not serious in elderly patients ( ).

Another newer treatment for depression is intravenous ketamine, which has also been considered for use in LLD that does not respond to other medications. A few case reports have looked at ketamine for treatment-resistant depression in patients of advanced age. In a 2017 review of these case reports by da Frota Ribeiro, two showed evidence of leading to improvement without significant side effects. The relative safety of intravenous ketamine in the elderly was demonstrated in further studies by the mild, transient adverse effects seen by this patient group ( ). However, in another study by Bryant et al., the geriatric population was unable to maintain an antidepressant response to intravenous ketamine over time, signifying that ketamine may have diminished efficacy for the elderly . Whether this is a viable treatment option for the geriatric population remains unclear.

When choosing a treatment regimen for patients with LLD, it is important to weigh the benefits of starting medication with the risks of adverse effects. SSRIs are first-line for depression for all age groups and are generally thought to have a more favorable side effect profile than the older classes of antidepressants: tricyclics and monoamine oxidase inhibitors. SSRIs do not have the cardiac and anticholinergic adverse effects of tricyclic antidepressants, which makes them safer for elderly patients. However, there is still concern that paroxetine could have adverse outcomes in the geriatric population due to anticholinergic properties; however, studies show no increases in mortality, dementia risk, or cognitive measures ( ). Also, SSRIs have been associated with increased risk of falls and osteoporosis ( ). Duloxetine, an SNRI, has also been associated with increased risk of falls due to its possible drug-drug interactions ( ). Aripiprazole, which has been shown to be effective for augmentation for treatment-resistant LLD, comes with the risk of akathisia and parkinsonism . It is crucial that the risk of side effects be carefully weighed with the benefits of treatment, especially in a population with higher rates of medical comorbidities and polypharmacy that can worsen outcomes.

Electroconvulsive shock therapy is treatment option when pharmacologic agents lack sufficient efficacy or are not well tolerated. New data add to the evidence demonstrating that ECT is a highly effective, safe, and well-tolerated antidepressant treatment option for geriatric patients ( ). In a study published in 2016 investing right unilateral ultra-brief ECT for elderly patients, there was a 61% remission rate ( ). However, the study did not include specifically treatment-resistant participants, and the efficacy for this group is likely to be less. Although concerns have been raised for the adverse effects associated with ECT in the geriatric population, the use of anesthesia poses the most risk, as opposed to the ECT itself ( ).

Transcranial magnetic stimulation is another nonpharmacological option for treatment-resistant depression that can be considered for LLD. In a study in 2019 looking at the use of this procedure on patients of advanced age, participants receiving bilateral rTMS experienced greater remission rates (40%) compared to unilateral (0%) or sham (0%) groups. Response to rTMS in the Hamilton Depression Rating Scale scores similarly favored the efficacy of bilateral rTMS ( ).

Future directions

In a review of refractory LLD, the overall response rate for all active pharmacological treatments investigated was 52% ( ). This leaves much room for improvement in our treatment of depression in this population. Current research must be evaluated in order to identify shortcomings and to design studies aimed at filling the gaps. Three future priority areas identified in a review in 2016 were focusing on patient-centered and culturally sensitive care, involving caregivers outside of the traditional healthcare team, and choosing different care settings ( ). Paying close attention to ethnic and cultural differences when research is conducted is especially important, since presentation of depression in the elderly can vary widely, and therefore, treatment must be personalized. For example, suicidal ideation and hopelessness are symptoms more commonly expressed by White British than Black Africans and South Asians ( ).

In addition to improved cultural awareness when determining future treatment options, the advances being developed in neuroscience and neuroimaging techniques should be utilized. Functional magnetic resonance imaging (fMRI) has recently been used more to compare individuals with late life depression to healthy controls ( ). Using fMRI techniques to identify areas of the brain that are functioning abnormally in late life depression will help develop treatment options to specifically target these specific areas.

In addition to the use of neuroimaging to create a better diagnostic understanding of late life depression, the role of biomarkers, genetics and hormone levels in disease pathophysiology should also be further investigated. In a recent 2020 study, single nucleotide polymorphisms in CYP19A1, an enzyme implicated in the conversion of androgen to estrogen, were associated with increased risk of late life depression ( ). Elevations in the biomarker C-reactive protein (CRP) have also been shown to be associated with late life depression, and variants in the CRP gene can alter susceptibility to the development of the disorder ( ). Further research to better understand the clinical and treatment implications of these findings is imperative in order to create new and more specific treatments that will have better efficacy than our current management for patients of advanced age.