Geriatric psychiatrists often receive referrals to determine if an elderly patient is either depressed or demented. Unfortunately, distinguishing between these two conditions is often not simple and precludes taking an “either/or” approach clinically. Moreover, mounting evidence suggests that these two disorders are not consistently mutually exclusive. Although depression is typically distinguished as a mood disorder in younger patients, there is greater recognition that depression in the elderly is a mood disorder and a cognitive disorder. Clinically significant depressive symptoms are present in 11% to 30% of elderly individuals,1–5 and impaired cognition is present in about 17% to 37% of geriatric adults.6–8
Studies show that rates of comorbid depression and cognitive impairment double every 5 years after 70 years, and by 85 years, the combination is evident in 25% of individuals.9 This combination of depression and cognitive impairment is concerning because the rate of adverse events in physical health, functional status, and mortality are increased in this population.10 It is imperative that psychiatrists develop skills in detection and treatment of depression and cognitive impairment because the group of individuals experiencing depression are likely to grow as the population ages in industrialized nations.
This is not to suggest that all depressed elderly people with resultant cognitive impairment have a separate cognitive condition destined to end in cognitive decline and dementia. Instead, we are suggesting that it is, in fact, possible to identify patients who experience cognitive impairment as a part of the depressive disorder, and this is a crucial step in diagnosis and treatment. This review will present clinical issues and key research with depression and cognitive impairment in the geriatric population. We will focus on a review of the literature on cognitive impairment in late-life depression, depression in cognitive disorders, comorbid depression and mild cognitive impairment, and comorbid depression and Alzheimer’s dementia. The resultant information will prepare us to develop a plan for assessing and predicting the prognosis of mood disorder and cognitive decline for a depressed, cognitive impaired elderly patient.
Depression is a mood disorder characterized by a constellation of symptoms, including sadness, decreased interest and pleasure in everyday activities, negative thoughts and self-perception, and disturbance in appetite, sleep, energy level, and thought process. When symptoms are present for more than 2 weeks, they are classified as a major depressive episode in the U.S.11 and international11a systems. Although clear criteria are required for a major depressive episode, subsyndromal forms of depression occur quite often in elderly adults, culminating in significant functional impairment. Diagnostic criteria encourage categorization of depression into severity and subtypes; however, any symptomatology that impairs either activities of daily living (ADLs) or cognition are considered clinically significant.12 Geriatric depression can appear quite heterogeneous.13 Throughout this article, the term “depression” will include depressive symptoms that, in combination, impair social functioning, cognition, or activities of daily living. We will make reference to major depression when it is important to make this clinical distinction.
The prevalence of depression is twice as high in women as in men.14 In community-based studies, 30% of individuals are estimated to experience depression first in late life (about 60 years), 40% first experience depression earlier in life, and 30% are difficult to reliably categorize because of reasons including poor retrospective recall about past depressive symptoms.15 Depression onset in late life is more often complicated by greater medical comorbidities, greater apathy, greater cerebrovascular pathology,16,17 more extensive cognitive impairment, and a stronger association to incident dementia.18 In contrast, early-onset depression is more frequently associated with psychiatric comorbidities, family history of mood disorder,19 and volume loss in the hippocampus when recurrent or untreated.20,21
Mild Cognitive Impairment
A precise definition of mild cognitive impairment (MCI) as a clinical entity is unclear, although, in general, MCI is thought to be the transitional state between normal cognition and clinically evident dementia. In fact, MCI is not a formal diagnostic entity but is used to describe a state of abnormal cognitive function that is not severe or pervasive enough to meet criteria for dementia. Currently, MCI would be classified by the Diagnostic and Statistical Manual of Mental Disorders as Cognitive Disorder, Not Otherwise Specified. MCI can remain a stable cognitive state, develop into Alzheimer’s disease or other forms of dementia, or can revert back to a normal cognitive state.22 There have been recent attempts to categorize MCI more broadly to include cognitive domains other than memory, and terms, such as amnestic compared with nonamnestic MCI and single cognitive domain compared with multiple domain MCI, have been proposed. Typically, multiple-domain MCI is more common than single domain.23 Importantly, mood disruption and symptoms are seen more commonly in multiple domain MCI in comparison with single domain amnestic MCI.23 Quite often, individuals with depression are excluded from MCI criteria. No consistent MCI criteria have been proposed and studied in elderly individuals with depression, even though MCI in depression may be a marker for persistent cognitive impairment. Furthermore, little is known about the possible course and prognosis of MCI in geriatric depression. Therefore, categorizing the cognitive symptoms of MCI in depression and examining change in MCI status over time is essential to our understanding of how some individuals are at increased risk of developing persistent cognitive impairment. Finally, comprehension of the cognitive course of MCI in depression is crucial in developing a broader clinical definition of this condition.
Prevalence reports of comorbid MCI and depression range between 25% and 50%.13,24 In comparison, studies of community samples report only a 3% to 6% prevalence of amnestic MCI.25 Recent studies demonstrate that clinically significant cognitive impairment or MCI developing during a depressive episode may persist after the episode is remitted.13,26 Some studies have shown that the magnitude of cognitive dysfunction in elderly depressives before treatment is associated with ongoing cognitive impairment after treatment,24,27 and this is seen especially in the domains of executive function and processing speed.28,29
Depression and Neurocognitive Function
Changes in neurocognitive function are often reported as a symptom of depression, including impaired concentration and slowed thinking; however, the presentation of cognitive deficits in the elderly can be quite heterogeneous from one individual to another. Many depressed individuals do not notice or report neurocognitive dysfunction nor are there any objective findings on formal assessment. However, research on neurocognitive function in depression has shown that depressed groups tend to show worse performance compared with non-depressed groups on several neuropsychological measures.30,31 The most consistent neurocognitive deficits have been shown to be in the domains of information processing speed,32 acquisition and retrieval of new information (ie, episodic memory),33–35 and in effortful tasks involving selective attention, response inhibition, and performance monitoring (ie, executive function).34,35 At times, patients exhibit underlying cognitive deficits in their subjective complaints, including that of those who struggle with executive dysfunction who may report difficulty in beginning new tasks or in multitasking. Family members may report ruminations with the same worries (usually negative) or increased apathy. As depressive symptoms become more severe (in particular apathy), executive and processing speed deficits seem to worsen.36 Nonetheless, deficits, including processing speed and executive dysfunction, occur more often when the first depressive episode occurs in late life. This is increasingly the case when apathy is prominent.35,37 It is commonly the case that when executive dysfunction, slowed processing, and apathy occur together in combination, these are associated with underlying cerebrovascular pathology to the frontal and subcortical regions of the brain.38,39 There is some evidence to suggest that those who have a history of earlier onset recurrent depression may have memory deficits that are more focally affected,40 and this is likely a result of reductions in hippocampal volume.21,41,42
A key clinical question is whether cognitive impairment resulting from depression resolves with successful treatment of depression. The recent evidence shows that cognitive performance improves; however, it may not achieve baseline levels of functioning. In one study, cognitive measures, including working memory, processing speed, episodic memory, and attention, were administered on five occasions over 12 weeks to elderly depressed patients and nondepressed controls.28 The elderly depressed patients were treated with either nortryptiline or paroxetine and did show improvement throughout the trial; however, the improved performance did not exceed that seen in the control group by practice alone. Therefore, it was concluded that cognitive performance in the depressed group did not normalize with response to treatment for depression. Similar results were found by the same group in 2006 when 45% of the patients continued to show cognitive impairment in the context of remission of depression at 1 year.43 In particular, deficits in processing speed, delayed memory, and visuospatial ability were most commonly found, and 94% of those impaired at baseline remained so 1 year later.
Evidence supports the notion that there is a cohort of elderly depressed individuals with cognitive impairment that may be at increased risk for persistent cognitive deficits as measured on neuropsychological testing. Whether there are ongoing deficits on testing results in clinically apparent cognitive problems, such as MCI or dementia, are unknown. Recent studies suggest that the most important factor in answering this question lies in the cognitive domain that is affected. Prominent memory problems may be concerning for an underlying cognitive disorder. A recent study classified older individuals with “mild cognitive impairment of depression” (MCI-D), which is defined as a performance of 1.5 standard deviations or more below mean levels on one of eight memory measures on a neuropsychological battery.13 Here, among 67 patients who were depressed at baseline and in remission at 1 year, 54% met criteria for MCI-D again at follow-up. The odds of MCI-D diagnosis at 1 year were four times greater in those with baseline MCI-D than those without MCI-D at baseline. Another study investigating clinical outcomes of individuals with MCI and depression showed that of 115 individuals with amnestic mild cognitive impairment followed for a mean of 3 years, 85.4% of individuals with MCI with depression developed dementia, while only 32.9% of the nondepressed individuals developed dementia.44 In a recent cross-sectional study of remitted elderly depressed subjects by Bhalla et al,45 cognitive diagnoses were examined in 109 elderly subjects after response to depression treatment. The results of the study showed that after depression response, 48% of the remitted depressed subjects were diagnosed with either mild cognitive impairment or dementia in comparison with 28% of comparison subjects. Specifically, MCI was diagnosed in 38% of the remitted depressed subjects, while 26% of the comparison group was diagnosed with MCI. Dementia was diagnosed in 10% of the remitted depressed group, while only 2% of the comparison group was diagnosed with dementia. Investigation of executive dysfunction for risk of cognitive decline and dementia has been unclear. Impairment in the initiation/perseveration subscale of executive function has been associated with impairment of instrumental activities of daily living.46 It is uncertain if the functional decline correlates with cognitive decline and dementia. There is some evidence to suggest that executive impairment while depressed may affect the course of depression. In particular, in elderly individuals, executive deficits may decrease the response to depression.47,48 When patients have executive impairment and depression, specific treatments, such as problem solving therapy, may be more effective toward achieving treatment response.49
Cognitive Neuroscience of Depression
The contributions of neuroscience to our understanding of cognition have been important in recognizing how neural mechanisms in frontal and subcortical regions of the brain correlate with characteristics of cognition in depressed individuals. This new research allows us to further understand how cognitive impairments may be due to neurologic changes associated with depression. Depression is affected by many different neurologic regions within larger neural systems,50 but we will focus on four particular regions, including the orbitofrontal cortex (OFC), the anterior cingulated gyrus, the dorsolateral prefrontal cortex, and the hippocampus.
The OFC has been implicated in selective processing of affective stimuli and correlates with the evidence that depressed people exhibit a quicker response to sad words than to happy words.51 This region of the brain is shown to have a disproportionate response to negative feedback exhibited on tests of learning of stimulus-reward associations (ie, reversal learning).52 When depressed people receive negative feedback on tasks, they are more likely to have cognitive errors. Compared with nondepressed individuals, elderly depressed people exhibit smaller total OFC volumes, more prominent hyperintense lesions, and smaller OFC gray matter volumes in neuroimaging studies.53–54
The anterior cingulate gyrus (ACG) displays a cognitive role that includes appraisal of motivational content56 and initiation57 and suppression57a of behavior through conflict monitoring.58 This region of the brain is also implicated in the predisposition of depressed individuals to respond quicker to sad words than to happy words (affective processing bias) and also show an increased neural response in the rostral anterior cingulate.51 Furthermore, the ACG is implicated in working memory and spatial planning. While performing the Tower of London Task, depressed people show less activation of the ACG in comparison with non-depressed controls.59 Interestingly exhibited in depressed elderly people are bilateral reductions in volume of the ACG.55 Depressed individuals show decreased cerebral blood flow and metabolism in the subgenual ACG.60,61 The dorsolateral prefrontal cortex (DLPFC) serves a major cognitive role in implementing attentional control. In comparison with nondepressed controls, depressed individuals exhibit increased left DLPFC activation and decreased left cingulate activation (ie, Stroop test). Depressed individuals demonstrate a presumptive affective processing predisposition in the increased response of the DLPFC in the affective go/no-go task.51 Furthermore, the DLPFC is associated with higher-order cognitive functions, including response monitoring,62 planning,59a retrieval of episodic memory,63 and working memory.64 Reductions in perfusion have been demonstrated in the left superior frontal gyrus and right middle frontal cortex on planning tests, such as the Tower of London tasks in depressed compared with non-depressed individuals.65 Reduced metabolism in the DLPFC is found cognitively in depressed compared with nondepressed individuals.66,67 Finally, elderly depressives exhibit reduced volumes in the middle and superior frontal cortices55 and are correlated with microstructural changes in the white matter of the DLPFC.68 This may be a pertinent finding in late-life depression.
The hippocampus plays a crucial role in learning and recall, as well as a role in affective regulation. A reduction in hippocampal volume is shown in early-and late-life depression and is correlated with lower performance on tests of verbal and visual episodic memory.69 The hippocampus may also serve to regulate emotional responses to environmental stimuli.50 Results of imaging studies of the hippocampus in relation to depression have varied in that some have shown a reduced volume to correlate with depressed individuals,70,71 and some have not.72 Decreased hippocampal volumes are shown in earlier onset depression,41,42 recurrent depression,21,43 and longer duration of untreated depression.42 Finally, decreased hippocampal volume correlates with subsequent cognitive decline in geriatric depressed individuals.73,74
Vascular Changes and Depression
Cerebrovascular pathology has been associated with late-life depression. Subcortical ischemic changes on magnetic resonance imaging (MRI) have been implicated in depression pathology, specifically in late-age-onset depression.75–80 Accumulated evidence led to the construct of “vascular depression.”16,81 Depressed individuals with vascular pathology, compared with those without vascular pathology, tend to show higher levels of hypertension and cerebrovascular risk factors, are older, and have less family history of depression.34,68 In a study by Mast et al,82 it was shown that individuals with depression and cognitive impairment, and at least two cerebrovascular risk factors (diabetes, hypertension, or atrial fibrillation) who scored lower on measures of perseveration and initiation, demonstrated significantly higher levels of baseline and 18-month follow-up depressive symptomatology, compared with individuals with better cognitive performance and fewer cerebrovascular risk factors. This study suggests a greater possibility of developing depression in elderly people with more cerebrovascular risk factors and poorer executive function. These findings may be a result of structural neurologic changes. Kramer-Ginsberg et al82a showed greater amounts of deep white matter hyperintensities (DWMH) correlated with poor performance on executive and memory functions than individuals with and without depression and without DWMH. Increased hospitalization,83 slowed treatment response,84–87 increased functional impairment,73 and increased mortality88 have all been correlated with cerebrovascular pathology in depression.
Depression in Cognitive Disorders
Depressive symptoms are quite pronounced in several dementing illnesses. Most studies of Alzheimer’s disease, the most common form of dementia, report depressive symptoms in 30% to 50% of individuals, including low mood, social withdrawal, apathy, and suicidal ideation.89 The prevalence of individuals with Alzheimer’s disease diagnosed with major depression is inversely correlated with the severity of dementia with patients with mild (11.5%), moderate (10%), and severe depression (4.5%).90 Depressive symptoms are frequently observed in those with other types of dementia, including vascular dementia,91,92 dementia with Lewy bodies,93–94a Huntington’s disease95 and Parkinson’s disease.96,97 Depression seen in Parkinson’s disease is associated with earlier onset, more rapid decline in motor symptoms, greater cognitive impairment, and increased disability.93,96 A recent study by Geda et al98 compared neuropsychiatric symptoms in a population of people with MCI to those with normal cognition and determined that neuropsychiatric symptoms were significantly more prevalent in subjects with MCI (51%) than those with normal cognition (27%). The symptoms that most differentiate MCI from normal cognition, in descending order, were apathy (OR 4.53), then agitation (OR 3.60), then anxiety (OR 3.00), then irritability (OR 2.98), then depression (OR 2.78). Finally, Stepaniuk et al99 used data from the Canadian Study of Health and Aging to examine the relationship between neuropsychiatric impairment and prediction of MCI, dementia, and AD over 5-year time increments. Of all of the neuropsychiatric impairments, individuals with loss of interest were almost three times more likely to be diagnosed with MCI, those with personality changes and mood disruption were more than twice as likely to be diagnosed with MCI, and those with depression were twice as likely to be diagnosed with MCI. Overall, only loss of interest and depression were shown to correlate significantly with the prediction of MCI, dementia, and Alzheimer’s dementia when controlling for initial cognitive status.
There is clearly a close relationship between depression and dementia, and six hypotheses have been proposed to account for this connection.100 The first two hypotheses are unlikely because little evidence exists to support them. The first is that treatments for depression are a risk factor for dementia. The second is that depression occurs as a reaction to cognitive decline. Jorm100 suggests that the following four hypotheses may be better substantiated. The first suggests that depression brings to the surface the clinical manifestations of dementing processes. Put another way, this idea considers that depression may affect the threshold for manifesting clinical dementia instead of affecting the pathological processes involved in either vascular or Alzheimer’s dementia. This concept brings to the forefront “brain reserve” in which those who have a greater brain reserve (ie, larger size, higher education) may exhibit signs and symptoms of dementia later because they are more able to compensate for neuron loss.
The next hypothesis proposes that dementia and depression share similar risk factors. This particularly applies to patients with cerebrovascular pathology. Cerebrovascular disease and development of late-life depression share a well-established association. MRI studies have found subcortical ischemic changes may be a factor in geriatric depression with late age of onset.76–80 This evidence progressed to the description of MRI-defined vascular depression.16,81 Recent studies showed in elderly depressives with worsening cerebrovascular pathology on MRI a correlation with cognitive decline and dementia, specifically of the non-Alzheimer’s type.101
The fifth hypothesis suggests that depression is a prodromal syndrome of dementia. The evidence debates if depression is a risk factor or a prodromal syndrome of dementia. These are two different approaches because many study findings suggest a history of depression does confer increased risk of a later diagnosis of dementia.102–105 This includes when depressive episodes occur greater than 10 years before cognitive decline.103,104 In some studies, closer inspection of the magnitude of risk ratios show decreasing risk with increasing length of time between onset of depression and diagnosis of dementia. These results support the notion that late-onset depression is a prodrome of dementia. It is our opinion that depression as a risk factor for or a prodrome of dementia are both possible, and that both theories help to explain the heterogeneity of etiology and clinical presentation of these conditions. The next pertinent step includes delineating the factors that cause depression to become a risk factor for dementia and identifying the factors that cause depression to develop into the prodromal syndrome.
Finally, Jorm100 proposed depression leads to a glucocorticoid cascade causing damage to the hippocampus. The literature suggests a link between stress of depression, glucocorticoid excess, and neurotoxicity.106 This model proposes the stress of depression causes higher cortisol levels. The prolonged length of exposure to cortisol causes hippocampal atrophy leading to increased cognitive deficits. As the hippocampus progressively atrophies, cognitive impairment gradually worsens to clinical dementia. Jorm states there is minimal evidence to support this final hypothesis, and the available evidence has been mixed in studies of depression.100
In summary, we would highlight each of the last four hypotheses as plausible, placing particular emphasis on the hypotheses that depression may be a risk factor or prodrome of dementia. The underlying neurobiology is not fully understood, and cerebrovascular pathology and excess glucocorticoid leading to toxic levels in the hippocampus are possible etiologies. Further studies are crucial to develop clarity in our understanding of depression and dementia.
Assessment of Depression in Cognitively Impaired Individuals
Cognitive impairment is quite common, as noted above, in patients with late-life depression. Therefore, the astute clinician should expect this scenario when receiving referrals for geriatric patients with depression. However, the degree of cognitive impairment may help to determine how to proceed in evaluating depressive symptoms in cognitively impaired adults. The first scenario occurs when patients demonstrate cognitive impairment of depression. The level of cognitive impairment is typically mild, and individuals may be slower when answering questions. However, their answers are typically accurate and are likely to carry a negative valence. Therefore, although the interview may take a longer length of time, it is similar to an interview of a cognitively intact individual.
A more complex diagnostic picture occurs when a depressed patient presents with obvious cognitive impairment. Distinguishing between the mood and cognitive components is more difficult but may not be necessary. However, diagnosis is crucial in developing a treatment plan. A differential diagnosis for cognitively impaired depressed elderly individuals includes major depression with cognitive impairment of depression, major depression with cognitive disorder not otherwise specified, major depression with dementia, and dementia with depression. Separating these possibilities can become quite complicated, but a three-step approach can prove to be effective. The first step entails distinguishing depressive symptoms more characteristic of mood disruption rather than cognitive impairment. Then, the second step is to handle reporting inaccuracies. Finally, the third step is to use a rating scale sensitive to mood symptoms in elderly individuals and cognitive impairment.
Much of the evidence of depressive symptoms found in patients with cognitive disorders arises from the Alzheimer’s disease literature. Depressive symptoms in individuals with Alzheimer’s disease and major depression were investigated across levels of severity of cognitive impairment.90 Patients with mild dementia were more likely to exhibit depressive symptoms, including low energy (55%), depressed mood (54%), anhedonia (51%), and sleep disturbance (48%). Less common symptoms of depression in individuals with mild dementia were appetite changes (39%), tearfulness (31%), and hopelessness (19%). Therefore, when assessing for depression, one may target disruptions in mood, inability to experience pleasure, poor energy, and changes in sleep pattern. Apathy is often seen in early Alzheimer’s disease, and it is unclear whether or not to consider this symptom when diagnosing major depression in this population. Koenig et al106a consider including apathy as a symptom of depression in diagnosing medically ill elderly patients with major depression, although one can feel more justified when apathy is accompanied by other symptoms of depression as outlined above when diagnosing major depression.
Particular attention must be paid when evaluating depression as a symptom of dementia to findings with a predominance of symptoms of amotivation in patients with early dementia, including loss of energy, lack of interest, and struggles with concentration.107 Fluctuation is often seen in depressive symptoms before the actual diagnosis of dementia.80,108 Criteria for “depression of Alzheimer’s disease” have been considered as a result of these reports.109 This suggests that at least three depressive symptoms are present for at least 2 weeks with a core required symptom being depressed mood or decreased ability to experience pleasure or positive affect. The “Depression in Alzheimer’s Disease Study-2” (DIADS-2), a randomized, placebo-controlled, multicenter trial to evaluate the efficacy and safety of sertraline for the treatment of depression in Alzheimer’s disease, is currently testing this proposed criteria.110 Sertraline was better than placebo in DIADS-1 for treatment of major depression in Alzheimer’s disease.111 If DIADS-2 shows that sertraline is more efficacious, it may be unnecessary to differentiate between depression of dementia or depression and dementia because both require treatment and are effectively treated with antidepressants.
Along with concentrating on depressive symptoms, the pattern of depressive episodes may be helpful in disentangling major depression from depression in dementia. If the symptoms of depression precede cognitive impairment, the diagnosis is more likely a major depression. Increasing intensity of depressive symptoms in the context of cognitive impairment may point to a major depression as well, but cognition may become more impaired as a result of depression leading to concern for dementia with depression. If the clinical picture presents where distinctive depressive symptoms worsen over a course of weeks to months, treatment for major depression is indicated. Prior episodes of depression may be unhelpful in separating major depression from depression in dementia since a history of depression has correlated with depression in Alzheimer’s disease.112,112a Finally, a historical report of family history of mood disorder of a first-degree relative has been shown to be a risk factor for depression in Alzheimer’s disease.113
Then, the second step in the three-pronged approach to separating mood disorder from cognitive impairment is to be aware of and minimize inaccuracies in reporting of symptoms. A reliable collateral source should be consulted to include reports of behavior and thoughts of death or suicidality. This is typically a family member in the outpatient setting; however, in patients who are institutionalized, the clinician may contact a member of the staff (ie, nurse, nurse’s aide, healthcare technician) who regularly works with the patient. A recent study by Chopra et al114 assessed the correlation between the symptom reports of the patient, collateral source, and the clinician’s diagnosis of depression in cognitive impairment using the Geriatric Depression Scale-15. The study reported several conclusions, including that a patient’s report of the motivational symptom of loss of interest correlated highest with a clinician’s diagnosis of major depression, whereas the same symptom significantly increased the odds of disagreement with the report of the collateral source. However, a patient’s report of negative cognitions significantly decreased the odds of disagreement with the collateral source. Overall, this study showed that there was poor agreement between the patient’s report and the collateral report of depressive symptoms in those with early to moderate impairment except in the question about memory impairment.
The third step in assessing for mood disruption in cognitively impaired individuals is to utilize a mood scale sensitive to cognitive impairment. Many geriatric psychiatrists prefer the Cornell Scale for Depression in Dementia.115 This scale allows any discrepancies or loss of relevant information in report from patients and informants, as well as the well-recognized fluctuation of symptoms in depression. As a result, multiple complementary sources of information must corroborate each symptom. This allows a high sensitivity and interrater reliability.115 Another more ambiguous option in diagnosis includes remaining obscure about the diagnosis while not using a scale and attempting an empirical trial of antidepressant medication. This approach can typically be avoided by using this proposed, three-step, systematic approach to formulate a clinically informed opinion of the etiology of depressive symptoms. In some cases, however, the etiology and diagnosis can remain more dubious. When one cannot make a confident diagnosis, it is reasonable to assume a mood disorder is present and treat the mood disorder aggressively. The risk-benefit analysis in the context of an unknown mood disorder typically favors treating with the potential for significantly improved mood and potentially improved cognitive symptoms as this usually outweighs the risk of side effects of psychotropic medications.
Assessment of Cognitive Impairment in Late-Life Depression
Whether or not the depressive symptoms are a risk factor or a prodrome to dementia, the key issue is that cognitive function must be assessed to appropriately manage depression. Therefore, it is important to be able to differentiate between major depression and depression in Alzheimer’s dementia, as well as to understand the options for brief and comprehensive cognitive evaluation of depression in late life. One must take care to appropriately rule out medical causes and medications that may cause cognitive impairment or masquerade as physical and behavioral symptoms of depression.
Comparison of Features of Major Depression Versus Depression in Alzheimer’s Dementia
A patient’s report of depressive symptoms can inform the clinician whether the depressive characteristics are indicative of a dementia prodrome. Useful clinical symptoms are described by Olin et al.116 First, depressed elderly patients with cognitive impairment are more likely to report the full constellation of a mood episode, whereas depression in AD is usually less severe. Second, higher levels of subjective cognitive complaints are observed in depressed patients than in AD. Third, although depression in AD typically follows a slower progressive course, major depression exhibits a more rapid, mood-congruent cognitive impairment. Finally, cognitive impairment occurs in AD in the domains of language impairment, agnosia impairment, and apraxias, but cognitive impairment in depression is strongly associated with effortful tasks. Therefore, depression in Alzheimer’s dementia may present with marked irritability and social withdrawal with fewer symptoms than would be required for a diagnosis of major depression.89,116 Bartolini et al117 showed that deficits in motivation, such as apathy, are more predictive of dementia rather than somatic or mood-related symptoms. Therefore, this may be evidence of a surfacing prodrome of dementia. Furthermore, apathy has been disputed as a distinct clinical entity from depression in several neurological disorders117a as shown by Starkstein et al118 in a study showing that 13% of patients with AD experienced apathy without depression. Finally, as cognitive impairment progresses, depressive symptoms may diminish while somatic complaints may escalate.119
Pharmacologic Management of Cognitive Impairment in Late-Life Depression
In general, when an individual demonstrates cognitive impairment that is consistent with acute depression, pharmacologic management of cognitive symptoms is not started. Furthermore, the methodical clinician will start one medication at a time so as not to complicate the clinical picture, monitor for side effects (especially gastrointestinal complaints), and manage adverse events. Treatment becomes more complex when dementia is suspected as well as depression in an elderly patient, and depending on the level of severity of the dementia, an acetylcholinesterase inhibitor or N-methyl-D-aspartic acid (NMDA) receptor antagonist may be justified. It is common, however, to approach the case in a stepwise fashion and initiate, first, an antidepressant and titrate to a therapeutic level before adding an agent for cognitive impairment.
It is imperative for the clinician to recognize that symptoms of dementia can adversely affect the patient’s response to treatment for depression. Specifically, executive functions, including diminished initiation and perseveration, are deficits that correlate with lower acute response rates to pharmacological treatment.120,121 These symptoms can predict recurrent depression over a 2-year period. However, executive impairment has not led to recurrent depression in all studies.121a Therefore, depression and executive deficits may exist separately in some elderly people; however, the combination of depression and executive deficits may be evidence of a common underlying etiology in the fronto-striatal system. A recent study by Lu et al22 presents new evidence that in patients with amnestic MCI with depressive symptoms, donepezil may delay progression to AD. The study assessed 756 patients with MCI and stratified into depressed (defined as BDI at least 10) or not depressed (defined as BDI less than 10) and measured the length of time until progression to dementia while taking donepezil. The results showed that the patients progressing to dementia were significantly fewer at 1.7 years, 2.2 years, and fewer but not significant at 2.7 years. This also suggests donepezil may protect against the increased risk of progression to AD caused by depression. Of note, this was not a result of improvement in depressive symptoms because there was virtually no change in BDI throughout the study. In conclusion, the clinician must recognize that cognitive impairment can significantly affect the treatment of depression in elderly individuals, thus requiring more frequent monitoring of patient response.
Nonpharmacologic Intervention for Depression and Cognitive Impairment
Nonpharmologic management of depression in elderly individuals is imperative because many patients are unable to tolerate the medications because of adverse effects and because many do not respond to the medications.122 However, there is also evidence to suggest that psychotherapy is an important piece in management of depression because the combination of medication and either cognitive behavioral therapy or interpersonal therapy often produce better symptom improvement and better maintenance of response than either medication or therapy alone.123–125 Intolerability and subtherapeutic response to medications may be seen more often in elderly individuals with cognitive deficits, and this suggests that certain psychotherapeutic approaches may diminish the cognitive impairment associated with depression. In particular, Alexopoulos et al49 showed that in depressed elderly adults with deficits in executive function, in a 12-week trial of problem-solving therapy compared with supportive therapy, individuals receiving problem-solving therapy showed greater remission rates and lower functional disability. The focus on practical problem-solving therapies was shown to be the essential therapeutic agent, which is advantageous to individuals with perseverative thinking and other executive deficits, which may otherwise suppress effective coping and problem solving. Finally, psychoeducation of the caregiver can significantly reframe unattainable expectations of the patient as well as diminish anxiety and unreasonable expectations of the caregiver.
Older depressed people often exhibit depression and cognitive impairment. This can present a complex clinical scenario that cannot be easily compartmentalized into separate diagnoses or treatment. Cognitive impairment as a result of geriatric depression can resolve with treatment of depression in some cases. Despite those whose cognitive impairment improves, executive function and memory may not completely resolve with treatment of depression. Furthermore, elderly subjects can exhibit depressive symptoms that may be more of a prodrome for progression to dementia. These issues can significantly complicate treatment of depression and cognitive impairment. However, a gradual approach to evaluation, including assessment of mood changes, cognitive impairment, and referral for cognitive assessment can effectively inform diagnosis and treatment.
- Kivela SL, Pahkala K, Laippala P. Prevalence of depression in an elderly population in Finland. Acta Psychiatr Scand. 1988;78(4):401–413. doi:10.1111/j.1600-0447.1988.tb06358.x [CrossRef]
- Gallo JJ, Lebowitz BD. The epidemiology of common late-life mental disorders in the community: themes for the new century. Psychiatr Serv. 1999;50(9):1158–1166.
- Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population: the Cache County study. Arch Gen Psychiatry. 2000;57(6):601–607. doi:10.1001/archpsyc.57.6.601 [CrossRef]
- Copeland JR, Beekman AT, Braam AW, et al. Depression among older people in Europe: the EURODEP studies. World Psychiatry. 2004;3(1):45–49.
- Lee Y, Shinkai S. Correlates of cognitive impairment and depressive symptoms among older adults in Korea and Japan. Int J Geriatr Psychiatry. 2005;20(6):576–586. doi:10.1002/gps.1313 [CrossRef]
- Koenig HG, Blazer DG. Epidemiology of geriatric affective disorders. Clin Geriatr Med. 1992;8(2):235–251.
- Rait G, Fletcher A, Smeeth L, et al. Prevalence of cognitive impairment: results from the MRC trial of assessment and management of older people in the community. Age Ageing. 2005;34(3):242–248. doi:10.1093/ageing/afi039 [CrossRef]
- Graciani A, Banegas JR, Guallar-Castillón P, Dominguez-Rojas V, Rodríguez-Artalejo F. Cognitive assessment of the non-demented elderly community dwellers in Spain. Dement Geriatr Cogn Disord. 2006;21(2):104–112. doi:10.1159/000090509 [CrossRef]
- Arve S, Tilvis RS, Lehtonen A, Valvanne J, Sairanen S. Coexistence of lowered mood and cognitive impairment of elderly people in five birth cohorts. Aging (Milano). 1999;11(2):90–95.
- Mehta KM, Yaffe K, Langa KM, Sands L, Whoo ey MA, Covinsky KE. Additive effects of cognitive function and depressive symptoms on mortality in elderly community-living adults. J Gerontol A Biol Sci Med Sci. 2003;58(5):M461–M467.
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders [text revision]. 4th ed. American Psychiatric Association: Washington, DC.; 2000.
- Dilling H, Mombour W, Schmidt MH. International Classification of Mental and Behavioral Disorders. Huber: Bern, Switzerland; 1991.
- Koenig HG, Blazer DG. Mood disorders. In: Textbook of Geriatric Psychiatry. Blazer DG, Steffens DC, Busse EW, eds. American Psychiatric Publishing: Arlington, VA; 2004:241.
- Lee JS, Potter GG, Wagner HR, Welsh-Bohmer KA, Steffens DC. Persistent mild cognitive impairment in geriatric depression. Int Psychogeriatr. 2007;19(1):125–135. doi:10.1017/S1041610206003607 [CrossRef]
- Blazer DG. Mood Disorders: Epidemiology. New York: Lippincott, Williams, & Wilkins; 2000.
- Blazer DG. Depression in late life: Review and commentary. J Gerontol A Biol Sci Med Sci. 2003;58(3):249–265.
- Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154(4):497–501.
- Krishnan KR, Hays JC, Tupler LA, George LK, Blazer DG. Clinical and phenomenological comparisons of late-onset and early-onset depression. Am J Psychiatry. 1995;152(5):785–788.
- Schweitzer I, Tuckwell V, O’Brien J, Amees D. Is late onset depression a prodrome to dementia?Int J Geriatr Psychiatry. 2002;17(11):997–1005. doi:10.1002/gps.525 [CrossRef]
- Lyness SA, Eaton EM, Schneider LS. Cognitive performance in older and middle-aged depressed outpatients and controls. J Gerontol. 1994;49(3):129–136.
- Bell-McGinty S, Butters MA, Meltzer CC, Greer PJ, Reynolds CF, Becker JT. Brain morphometric abnormalities in geriatric depression: Long-term neurobiological effects of illness duration. Am J Psychiatry. 2002;159(8):1424–1427. doi:10.1176/appi.ajp.159.8.1424 [CrossRef]
- Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8):1516–1518. doi:10.1176/appi.ajp.160.8.1516 [CrossRef]
- Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL. Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 2009;72(24):2115–2121. doi:10.1212/WNL.0b013e3181aa52d3 [CrossRef]
- Jak AJ, Bangen KJ, Wierenga CE, Delano-Wood L, Corey-Bloom J, Bondi MW. Contributions of neuropsychology and neuroimaging to understanding clinical subtypes of mild cognitive impairment. Int Rev Neurobiol. 2009;8481–103.
- Adler G, Chwalek K, Jajcevic A. Six-month course of mild cognitive impairment and affective symptoms in late-life depression. Eur Psychiatry. 2004:19(8)502–505. doi:10.1016/j.eurpsy.2004.09.003 [CrossRef]
- Ganguli M, Dodge HH, Shen C, DeKosky ST. Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology. 2004;63(1):115–121.
- Reischies FM, Neu P. Comorbidity of mild cognitive disorder and depression – a neuropsychological analysis. Eur Arch Psychiatry Clin Neurosci. 2000;50(4):186–193. doi:10.1007/s004060070023 [CrossRef]
- Butters MA, Becker JT, Nebes RD, et al. Changes in cognitive functioning following treatment of late-life depression. Am J Psychiatry. 2000;157(12):1949–1954. doi:10.1176/appi.ajp.157.12.1949 [CrossRef]
- Nebes RD, Pollock BG, Houck PR, et al. Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double-blind clinical trial with nortriptylineand paroxetine. J Psychiatr Res. 2003;37(2):99–108. doi:10.1016/S0022-3956(02)00085-7 [CrossRef]
- Murphy CF, Alexopoulos GS. Longitudinal association of initiation/perseveration and severity of geriatric depression. Am J Geriatr Psychiatry. 2004;12(1):50–56.
- Veiel H. A preliminary profile of neuropsychological deficits associated with major depression. J Clin Exp Neuropsychol. 1997;19(4):587–603. doi:10.1080/01688639708403745 [CrossRef]
- Zakzanis KK, Leach L, Kaplan E. On the nature and pattern of neurocognitive function in major depressive disorder. Neuropsychiatry Neuropsychol Behav Neurol. 1998;11(3):111–119.
- Sheline YI, Barch DM, Garcia K, et al. Cognitive function in late life depression: relationships to depression severity, cerebrovascular risk factors and processing speed. Biol Psychiatry. 2006;60(1):58–65. doi:10.1016/j.biopsych.2005.09.019 [CrossRef]
- Beats BC, Sahakian BJ, Levy R. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychol Med. 1996;26(3):591–603. doi:10.1017/S0033291700035662 [CrossRef]
- Boone K, Lesser B, Miller B, et al. Cognitive functioning in a geriatric depressed population: relationship of presence and severity of depression to neuropsychological scores. Neuropsychology. 1995;9:390–398. doi:10.1037/0894-422.214.171.1240 [CrossRef]
- Austin MP, Mitchell P, Wilhelm K, et al. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia?Psychol Med. 1999;29(1):73–85. doi:10.1017/S0033291798007788 [CrossRef]
- Palmer BW, Boone KB, Lesser IM, Wohl MA, Berman N, Miller BL. Neuropsychological deficits among older depressed patients with predominantly psychological or vegetative symptoms. J Affect Disord. 1996;1:17–24. doi:10.1016/0165-0327(96)00059-6 [CrossRef]
- Feil D, Razani J, Boone K, Lesser I. Apathy and cognitive performance in older adults with depression. Int J Geriatric Psychiatry. 2003;18(6):479–488. doi:10.1002/gps.869 [CrossRef]
- Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. “Vascular depression” hypothesis. Arch Gen Psychiatry. 1997;54(10):915–922.
- Krishnan KR, Taylor WD, McQuoid DR, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry. 2004;55(4):390–397. doi:10.1016/j.biopsych.2003.08.014 [CrossRef]
- Rapp MA, Dahlman K, Sano M, Grossman HT, Haroutunian V, Gorman JM. Neuropsychological differences between late-onset and recurrent geriatric major depression. Am J Psychiatry. 2005;162(4):691–698. doi:10.1176/appi.ajp.162.4.691 [CrossRef]
- MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function and hippocampal volume in major depression. Proc Natl AcadAm Acad Sci. 2003;100(3):1387–1392. doi:10.1073/pnas.0337481100 [CrossRef]
- Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19(12):5034–5043.
- Bhalla RK, Butters MA, Mulsant BH, Begley AE, Zmuda MD, Schoderbek B. Persistence of neuropsycologic deficits in the remitted state of late-life depression. Am J Geriatr Psychiatry. 2006;14(5):419–427. doi:10.1097/01.JGP.0000203130.45421.69 [CrossRef]
- Modrego PJ, Ferrandez J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurology. 2004;61(8):1290–1293. doi:10.1001/archneur.61.8.1290 [CrossRef]
- Bhalla RK, Butters MA, Becker JT, et al. Patterns of mild cognitive impairment after treatment of depression in the elderly. Am J Geriatr Psychiatry. 2009;17(4):208–316. doi:10.1097/JGP.0b013e318190b8d8 [CrossRef]
- Kiosses DN, Klimstra S, Murphy C, Alexopoulos GS. Executive dysfunction and disability in elderly patients with major depression. Am J Geriatr Psychiatry. 2001;9(3):269–274.
- Alexopoulos GS, Kiosses DN, Heo M, Murphy CF, Shanmugham B, Gunning-Dixon F. Executive dysfunction and the course of geriatric depression. Biol Psychiatry. 2005;58(3):204–210. doi:10.1016/j.biopsych.2005.04.024 [CrossRef]
- Alexopoulos GS, Kiosses DN, Murphy C, Heo M. Executive dysfunction, heart disease burden, and remission of geriatric depression. Neuropsychopharmacology. 2004;29(12):2278–2284. doi:10.1038/sj.npp.1300557 [CrossRef]
- Alexopoulos GS, Raue P, Arean P. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11(1):46–52.
- Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion. I: The neural basis of normal emotion perception. Biol Psychiatry. 2003;54(5):504–514. doi:10.1016/S0006-3223(03)00168-9 [CrossRef]
- Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ. The neural basis of mood-congruent processing biases in depression. Arch Gen Psychiatry. 2002;59(7):597–604. doi:10.1001/archpsyc.59.7.597 [CrossRef]
- Murphy FC, Michael A, Robbins TW, Sahakian BJ. Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance. Psychol Medicine. 2003;33(3):455–467. doi:10.1017/S0033291702007018 [CrossRef]
- Lai TJ, Payne M, Byrum CE, Steffens DC, Krishnan KR. Reduction of orbital frontal cortex volume in geriatric depression. Biol Psychiatry. 2000;48:971–975. doi:10.1016/S0006-3223(00)01042-8 [CrossRef]
- MacFall JR, Payne ME, Provenzale JM, Krishnan KR. Medical orbital frontal lesions in late-onset depression. Biol Psychiatry. 2001;49:803–806. doi:10.1016/S0006-3223(00)01113-6 [CrossRef]
- Ballmaier M, Toga AW, Blanton RE, et al. Anterior cingulate, gyus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. Am J Psychiatry. 2004;161(1):99–108. doi:10.1176/appi.ajp.161.1.99 [CrossRef]
- Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulated cortex to behavior. Brain. 1995;118(Pt 1):279–306. doi:10.1093/brain/118.1.279 [CrossRef]
- Németh G, Hegedüs K, Molnár L. Akinetic mutism associated with bicingular lesions: clinicopathological and functional anatomical correlates. Eur Arch Psychiatry Neurol Sci. 1988;237(4):218–222. doi:10.1007/BF00449910 [CrossRef]
- Paus T, Petrides M, Evans AC, Meyer E. Role of the human anterior cingulated cortex in the control of oculomotor, manual, and speech responses: a positron emission tomography study. J Neurophysiol. 1993;70(2):453–469.
- Carter CS, MacDonald AM, Botvinick M, et al. Parsing executive processes: strategic vs. evaluative functions of the anterior cingulate cortex. Proc Natl Acad Sci U S A. 2000;97(4):1944–1948. doi:10.1073/pnas.97.4.1944 [CrossRef]
- Elliott R, Baker SC, Rogers RD, et al. Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography. Psychol Med. 1997;27(4):931–942. doi:10.1017/S0033291797005187 [CrossRef]
- Dagher A, Owen AM, Boecker H, Brooks DJ. Mapping the network for planning: a correlational PET activation study with the Tower of London task. Brain. 1999;122:1973–1987. doi:10.1093/brain/122.10.1973 [CrossRef]
- Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12(6):527–544. doi:10.1016/S0924-977X(02)00102-5 [CrossRef]
- London ED, Simon SL, Berman SM, et al. Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry. 2004;61(1):73–84. doi:10.1001/archpsyc.61.1.73 [CrossRef]
- Blakemore SJ, Rees G, Frith CD. How do we predict the consequences of our actions? A functional imaging study. Neuropsychologia. 1998;36(6):521–529. doi:10.1016/S0028-3932(97)00145-0 [CrossRef]
- Rugg M, Fletcher PC, Chua PM, Dolan RJ. The role of the prefrontal cortx in recognition memory nd memoryfor source: an fMRI study. Neuroimage. 1999;10:520–529. doi:10.1006/nimg.1999.0488 [CrossRef]
- Owen AM, Herrod NJ, Menon DK, et al. Redefining the functional organization of working memory processes within human lateral prefrontal cortex. Eur J Neurosci. 1999;11(2):567–574. doi:10.1046/j.1460-9568.1999.00449.x [CrossRef]
- Goethals I, Audenaert K, Jacobs F, et al. Blunted prefrontal perfusion in depressed patients performing the Tower of London task. Psychiatry Res. 2005;139(1):31–40. doi:10.1016/j.pscychresns.2004.09.007 [CrossRef]
- Biver F, Goldman S, Delvenne V, et al. Frontal and parietal metabolic disturbances in unipolar major depression. Biol Psychiatry. 1994;36(6):381–388. doi:10.1016/0006-3223(94)91213-0 [CrossRef]
- Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B. Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol Med. 2003;33(7):1277–1284. doi:10.1017/S0033291703007931 [CrossRef]
- Taylor WD, MacFall JR, Payne ME, et al. Late-life depression and microstructural abnormalities in dorsolateral prefrontal cortex white matter. Am J Psychiatry. 2004;161(7):1293–1296. doi:10.1176/appi.ajp.161.7.1293 [CrossRef]
- Hickie I, Naismith S, Ward PB, et al. Reduced hippocampal volumes and memory loss in patients with early-and late-onset depression. Br J Psychiatry. 2005;186:197–202. doi:10.1192/bjp.186.3.197 [CrossRef]
- Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A. 1996;93(9):3908–3913. doi:10.1073/pnas.93.9.3908 [CrossRef]
- Frodl T, Meisenzahl EM, Zetzsche T, et al. Hippocampal and amygdale changes in patients with major depressive disorder and healthy controls during 1-year follow-up. J Clin Psychiatry. 2004;65(4):492–499.
- Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ. Volumetric analysis of the prefrontal cortex, amygdale, and hippocampus in major depression. Neuropsychopharmacol. 2004;29(5):52–959.
- Steffens DC, Bosworth HB, Provenzale JM, MacFall JR. Subcortical white matter lesions and functional impairment in geriatric depression. Depress Anxiety. 2002;15(1):23–28. doi:10.1002/da.1081 [CrossRef]
- O’Brien JT, Lloyd A, McKeith I, Gholkar A, Ferrier N. A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatry. 2004;161(11):2081–2090. doi:10.1176/appi.ajp.161.11.2081 [CrossRef]
- Krishnan KRR, Goli Z, Ellinwood EH, Franz RD, Blazer DG, Nemeroff CB. Leukoencephalopathy in patients diagnosed as major depressive. Biol Psychiatry. 1988;23:519–522. doi:10.1016/0006-3223(88)90025-X [CrossRef]
- Coffey CE, Figiel GS, Djang WT, Saunders WB, Weiner RD. White matter hyperintensity on magnetic resonance imaging: clinical and neuroanatomic correlates in the depressed elderly. J Neuropsychiatry Clin Neurosci. 1989;1(2):135–144.
- Figiel GS, Krishnan KR, Doraiswamy PM, Rao VP, Nemeroff CB, Boyko OB. Subcortical hyperintensities on brain magnetic resonance imaging: a comparison between late-age onset and early onset elderly depressed subjects. Neurobiol Aging. 1991;12(3):245–247. doi:10.1016/0197-4580(91)90104-R [CrossRef]
- Salloway S, Malloy P, Kohn R, et al. MRI and neuropsychological differences in early-and late-life-onset geriatric depression. Neurology. 1996;46(6):1567–1574.
- Kumar A, Bilker W, Jin Z, Udupa J, Gottleib G. Age of onset of depression and quantitative neuroanatomic measures: absence of specific correlates. Psychiatry Res. 1999;91(2):101–110. doi:10.1016/S0925-4927(99)00021-9 [CrossRef]
- deGroot JC, deLeeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry. 2000;57:1071–1076. doi:10.1001/archpsyc.57.11.1071 [CrossRef]
- Steffens DC, Krishnan KR. Structural neuroimaging and mood disorders: recent findings, implications for classification, and future directions. Biol Psychiatry. 1998;43(10):705–712. doi:10.1016/S0006-3223(98)00084-5 [CrossRef]
- Mast BT, Yochim B, MacNeill SE, Lichtenberg PA. Risk factors for geriatric depression: the imiportance of executive functioning within the vascular depression hypothesis. J Gerontol A Biol Sci Medical Sci. 2004;59(12):1290–1294.
- Kramer-Ginsberg E, Greenwald BS, et al. Neuropsychological functioning and MRI signal hyperintensities in geriatric depression. Am J Psychiatry. 1999;156(3):438–444.
- Yanai I, Fujikawa T, Horiguchi J, Yamakawi S, Touhouda Y. The 3-year course and outcome of patients with major depression and silent cerebral infarction. J Affect Disord. 1998;47:25–30. doi:10.1016/S0165-0327(97)00148-1 [CrossRef]
- Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B. Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biol Psychiatry. 1995;37(3):151–160. doi:10.1016/0006-3223(94)00174-2 [CrossRef]
- Simpson SW, Jackson A, Baldwin RC, Burns A. 1997 IPA/Baye Research Awards in Psychogeriatrics. Subcortical hyperintensities in late-life depression: acute response to treatment and neuropsychological imipairment. Int Psychogeriatr. 1997;9:257–275. doi:10.1017/S1041610297004432 [CrossRef]
- Steffens DC, Conway CR, Dombeck CB, Wagner HR, Tupler LA, Weiner RD. Severity of subcortical matter hyperintensity predicts ECT response in geriatric depression. J ECT. 2001;17(1):45–49. doi:10.1097/00124509-200103000-00009 [CrossRef]
- Steffens DC, Pieper CF, Bosworth HB, et al. Biological and social predictors of long-term geriatric depression and outcome. Int Psychogeriatr. 2005;17(1):41–56. doi:10.1017/S1041610205000979 [CrossRef]
- Levy RM, Steffens DC, McQuoid DR, Provenzale JM, MacFall JR, Krishnan KR. MRI lesion severity and mortality in geriatric depression. Am J Geriatr Psychiatry. 2003;11(6):678–682.
- Zubenko GS, Zubenko WN, McPherson S, et al. A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer’s disease. Am J Psychiatry. 2003;160(5):857–866. doi:10.1176/appi.ajp.160.5.857 [CrossRef]
- Lopez OL, Becker JT, Sweet RA, et al. Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J Neuropsychiatry Clinical Neurosci. 2003;15(3):346–353.
- Park JH, Lee SB, Lee TJ, et al. Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2007;23(2):67–73. doi:10.1159/000097039 [CrossRef]
- Sultzer DL, Levin HS, Mahler ME, High WM, Cummings JL. A comparison of psychiatric symptoms in vascular dementia and Alzheimer’s disease. Am J Psychiatry. 1993;150(12):1806–1812.
- Ballard C, Holmes C, McKeith I, et al. Psychiatric morbidity in with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry. 1999;156(7):1039–1045.
- Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lewy body disease: a clinicopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups. Neurology. 1996;47(5):1148–1152.
- Papka M, Rubio A, Schiffer RB. A review of Lewy body disease, an emerging concept of cortical dementia. J Neuropsychiatry Clin Neurosci. 1998;10(3):267–279.
- Folstein S, Abbott MH, Chase GA, Jensen BA, Folstein MF. The association of affective disorder with Huntington’s disease in a case series and in families. Psychol Med. 1983;13(3):537–542. doi:10.1017/S0033291700047966 [CrossRef]
- Tandberg E, Larsen JP, Aarsland D, Cummings JL. The occurrence of depression in Parkinson’s disease. A community-based study. Arch Neurology. 1995;53(6):175–179.
- Weintraub D, Stern MB. Psychiatric complications in Parkinson disease. Am J Geriatr Psychiatry. 2005;13(10):844–851.
- Geda YE, Roberts RO, Knopman DS, et al. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry. 2008;65(10):1193–1198. doi:10.1001/archpsyc.65.10.1193 [CrossRef]
- Stepaniuk J, Ritchie LJ, Tuokko H. Neuropsychiatric impairments as predictors of mild cognitive impairment, dementia and Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2008;23(4):326–333. doi:10.1177/1533317508317351 [CrossRef]
- Jorm AFHistory of depression as a risk factor for dementia: an updated review. Aust N Z J Psychiatry. 2001;35(6):776–781. doi:10.1046/j.1440-1614.2001.00967.x [CrossRef]
- Steffens DC, Potter GG, McQuoid DR, Mac-Fall JR, Payne ME, Burke JR. Longitudinal magnetic resonance imaging vascular changes, apolipoprotein E genotype, and development of dementia in the neurocognitive outcomes of depression in the elderly study. Am J Geriatr Psychiatry. 2007;15(10):839–849. doi:10.1097/JGP.0b013e318048a1a0 [CrossRef]
- Broe GA, Henderson AS, Creasey H, et al. A case-control study of Alzheimer’s disease in Australia. Neurology. 1990;40(11):1698–1707.
- Green RC, Cupples LA, Kurz A, et al. Depression as a risk factor for Alzheimer disease: the MIRAGE study. Arch Neurol. 2003;60(5):753–759. doi:10.1001/archneur.60.5.753 [CrossRef]
- Speck CE, Kukull WA, Brenner DE, Bowen JD, McCormick WC, Teri L. History of depression as a risk factor for Alzheimer’s disease. Epidemiology. 1995;6(4):366–369. doi:10.1097/00001648-199507000-00006 [CrossRef]
- Steffens DC, Plassman BL, Helms MJ, Welsh-Bohmer KA, Saunders AM, Breitner JC. A twin study of late-onset depression and apolipoprotein E epsilon 4 as risk factors for Alzheimer’s disease. Biol Psychiatry. 1997;41(8):851–856. doi:10.1016/S0006-3223(96)00247-8 [CrossRef]
- Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr Rev. 1986;7(3):284–301. doi:10.1210/edrv-7-3-284 [CrossRef]
- Koenig HG, George LK, Bercedis PL, Pieper CF. Depression in the medically ill hospitalized older adults: prevalence, characteristics and course of symptoms according to six diagnostic schemes. Am J Psychiatry. 1997;154(10):1376–1383.
- Berger AK, Fratiglioni L, Forsell Y, Winblad B, Backman L. The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology. 1999;53(9):1998–2002.
- Lyetsos CG, Steele C, Baker L, Galik E, Kopunek S, Steinberg M. Major and minor depression in Alzheimer’s disease: Prevalence and impact. J Neuropsychiatry Clin Neurosci. 1997;9(4):556–561.
- Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC. Provisionial diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002;10(2):125–128.
- Martin BK, Frangakis CE, Rosenberg PB, Mintzer JE, Katz IR, Porsteinsson AP. Design of Depression in Alzheimer’s Disease Study-2. Am J Geriatr Psychiatry. 2006;14(11):920–930. doi:10.1097/01.JGP.0000240977.71305.ee [CrossRef]
- Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C. Treating depression in Alzheimer’s disease: Efficacy and safety of sertraline therapy, and the benefits of depression reduction: The DIADS. Arch Gen Psychiatry. 2003;60(7):737–746. doi:10.1001/archpsyc.60.7.737 [CrossRef]
- Harwood DG, Barker WW, Ownby RL, Dura R. Association between premorbid history of depression and current depression in Alzheimer’s disease. J Geriatr Psychiatry Neurol. 1999;12:72–75. doi:10.1177/089198879901200206 [CrossRef]
- Migliorelli R, Teson A, Sabe L, Petracchi M, Leiguarda R, Starkstein S. Prevalence and correlates of dysthymia and major depression among patients with Alzheimer’s disease. Am J Psychiatry. 1995;152(1):37–44.
- Lyketsos CG, Tune LE, Pearlson G, Steele C. Major depression in Alzheimer’s disease: An interaction between gender and family history. Psychosomatics. 1996;37(4):380–389.
- Chopra MP, Sullivan JR, Feldman Z, Landes RD, Beck C. Self-, collateral-and clinician assessment of depression in persons with cognitive impairment. Aging Ment Health. 2008;12(6):675–683. doi:10.1080/13607860801972412 [CrossRef]
- Alexopoulos GS, Abrams RC, Young RC, Young RC, Shamoian CA. Cornell Scale for depression in dementia. Biol Psychiatry. 1998;23(3):271–284. doi:10.1016/0006-3223(88)90038-8 [CrossRef]
- Olin JT, Katz IR, Meyers BS, Schneider LS, Lebowitz BC. Provisional diagnostic criteria for depression of Alzheimer’s disease: rationale and background. Am J Geriatr Psychiatry. 2002;10:129–141.
- Bartolini M, Coccia M, Luzzi S, Provinciali L, Ceravolo MG. Motivational symptoms of depression mask preclinical Alzheimer’s disease in elderly subjects. Dement Geriatr Cogn Disorders. 2005;19(1):31–36. doi:10.1159/000080968 [CrossRef]
- Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci. 1998;10:314–319.
- Starkstein SE, Petracca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer’s disease. Am J Psychiatry. 2001;158(6):872–877.
- Gilley DW, Wilson RS, Bienias JL, Bennett DA, Evans DA. Predictors of depressive symptoms in persons with Alzheimer’s disease. J Gerontol B, Psychol Sci Soc Sci. 2004;59(2):75–83.
- Kalayam B, Alexopoulos GS. Prefrontal dysfunction and treatment response in geriatric depression. Arch Gen Psychiatry. 1999;56(8):713–718. doi:10.1001/archpsyc.56.8.713 [CrossRef]
- Potter GG, Kittinger JD, Wagner HR, Steffens DC, Krishnan KR. Prefrontal neuropsychological predictors of treatment remission in late-life depression. Neuropsycopharmacology. 2004;29(12):2266–2271. doi:10.1038/sj.npp.1300551 [CrossRef]
- Butters MA, Bhalla RD, Mulsant BH, et al. Executive functioning, illness course, and relapse/recurrence in continuation and maintenance treatment of late-life depression: is there a relationship?Am J Geriatr Psychiatry. 2004;12(4):387–394.
- Lyketsos CB, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA. 2002;288(12):1475–1483. doi:10.1001/jama.288.12.1475 [CrossRef]
- Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazadone, the cognitive behavioral analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462–1470. doi:10.1056/NEJM200005183422001 [CrossRef]
- Lenze EJ, Dew MA, Mazumdar S, et al. Combined pharmacotherapy and psychotherapy as maintenance treatment for late-life depression: effects on social adjustment. Am J Psychiatry. 2002;159(3):466–468. doi:10.1176/appi.ajp.159.3.466 [CrossRef]
- Lynch TR, Cheavens JS, Cukrowicz KC, Thorp SR, Bronner L, Beyer J. Treatment of older adults with comorbid personality disorder and depression: a dialectical behavioral therapy approach. Int J Geriatr Psychiatry. 2007;22(2):131–143. doi:10.1002/gps.1703 [CrossRef]