George S. Alexopoulos

Depression in the elderly

Summary In elderly people, depression mainly affects those with chronic medical illnesses and cognitive impairment, causes suffering, family disruption, and disability, worsens the outcomes of many medical illnesses, and increases mortality. Ageing-related and disease-related processes, including arteriosclerosis and inflammatory, endocrine, and immune changes compromise the integrity of frontostriatal pathways, the amygdala, and the hippocampus, and increase vulnerability to depression. Heredity factors might also play a part. Psychosocial adversity—economic impoverishment, disability, isolation, relocation, caregiving, and bereavement—contributes to physiological changes, further increasing susceptibility to depression or triggering depression in already vulnerable elderly individuals. Treatment with antidepressants is well tolerated by elderly people and is, overall, as effective as in young adults. Evidence-based guidelines for prevention of new episodes of depression are available as are care-delivery systems that increase the likelihood of diagnosis, and improve the treatment of, late-life depression. However, in North America at least, public insurance covers these services inadequately.

The vascular depression hypothesis: mechanisms linking vascular disease with depression

The ‘Vascular Depression’ hypothesis posits that cerebrovascular disease may predispose, precipitate or perpetuate some geriatric depressive syndromes. This hypothesis stimulated much research that has improved our understanding of the complex relationships between late-life depression (LLD), vascular risk factors, and cognition. Succinctly, there are well-established relationships between LLD, vascular risk factors and cerebral hyperintensities, the radiological hallmark of vascular depression. Cognitive dysfunction is common in LLD, particularly executive dysfunction, a finding predictive of poor antidepressant response. Over time, progression of hyperintensities and cognitive deficits predicts a poor course of depression and may reflect underlying worsening of vascular disease. This work laid the foundation for examining the mechanisms by which vascular disease influences brain circuits and influences the development and course of depression. We review data testing the vascular depression hypothesis with a focus on identifying potential underlying vascular mechanisms. We propose a disconnection hypothesis, wherein focal vascular damage and white matter lesion location is a crucial factor, influencing neural connectivity that contributes to clinical symptomatology. We also propose inflammatory and hypoperfusion hypotheses, concepts that link underlying vascular processes with adverse effects on brain function that influence the development of depression. Testing such hypotheses will not only inform the relationship between vascular disease and depression, but also provide guidance on the potential repurposing of pharmacological agents that may improve LLD outcomes.

Aging of Cerebral White Matter: A Review of MRI Findings

Cerebral aging is a complex and heterogeneous process that is associated with a high degree of inter‐individual variability. Structural magnetic resonance imaging (MRI) can be used to identify and quantify non‐disease‐related aging of the cerebral white matter.

Executive Dysfunction and the Course of Geriatric Depression

BACKGROUND Executive dysfunction is common in geriatric depression and persists after improvement of depressive symptoms. This study examined the relationship of executive impairment to the course of depressive symptoms among elderly patients with major depression. METHODS A total of 112 nondemented elderly patients with major depression participated in an 8-week citalopram trial at a target daily dose of 40 mg. Executive functions were assessed with the initiation/perseveration subscale of the Dementia Rating Scale and the Stroop Color-Word test. Medical burden was rated with the Cumulative Illness Rating Scale. RESULTS Both abnormal initiation/perseveration and abnormal Stroop Color-Word scores were associated with an unfavorable response of geriatric depression to citalopram. In particular, initiation/perseveration scores below the median (< or =35) and Stroop scores at the lowest quartile (< or =22) predicted limited change in depressive symptoms. Impairment in other Dementia Rating Scale cognitive domains did not significantly influence the outcome of depression. CONCLUSIONS Executive dysfunction increases the risk for poor response of geriatric depression to citalopram. Because executive functions require frontostriatal-limbic integrity, this observation provides the rationale for investigation of the role of specific frontostriatal-limbic pathways in perpetuating geriatric depression. Depressed elderly patients with executive dysfunction require vigilant clinical attention because they might be at risk to fail treatment with a selective serotonin reuptake inhibiting antidepressant.

Microstructural White Matter Abnormalities and Remission of Geriatric Depression

OBJECTIVE White matter abnormalities may interfere with limbic cortical balance and lead to chronic depressive syndromes. The authors used diffusion tensor imaging to test the hypothesis that depressed elders who fail to achieve remission have microstructural white matter abnormalities in cortico-striato-limbic networks implicated in geriatric depression. METHOD The subjects were nondemented individuals with nonpsychotic major depression. After a 2-week placebo period, those subjects who had a Hamilton Depression Rating Scale (HAM-D) score of 18 or greater received escitalopram, 10 mg daily, for 12 weeks. Remission was defined as a HAM-D score of 7 or below for 2 consecutive weeks. Diffusion tensor imaging was performed at a 1.5 Tesla scanner, and voxel-based analysis of fractional anisotropy was conducted using age as the covariate. RESULTS Subjects who failed to achieve remission (N=23) had lower fractional anisotropy in multiple frontal limbic brain areas, including the rostral and dorsal anterior cingulate, dorsolateral prefrontal cortex, genu of the corpus callosum, white matter adjacent to the hippocampus, multiple posterior cingulate cortex regions, and insular white matter, relative to those who achieved remission (N=25). In addition, lower fractional anisotropy was detected in the neostriatum and midbrain as well as select temporal and parietal regions. CONCLUSIONS Lower fractional anisotropy in distributed cerebral networks is associated with poor antidepressant response of geriatric depression and may represent a neuroanatomical substrate that predisposes to this disorder.

Comorbidity of depression with other medical diseases in the elderly.

A major factor in the context of evaluating depression in the elderly is the role of medical problems. With aging there is a rapid increase in the prevalence of a number of medical disorders, including cancer, heart disease, Parkinsons disease, Alzheimers disease, stroke, and arthritis. In this article, we hope to bring clarity to the definition of comorbidity and then discuss a number of medical disorders as they relate to depression. We evaluate medical comorbidity as a risk factor for depression as well as the converse, that is, depression as a risk factor for medical illness. Most of the disorders that we focus on occur in the elderly, with the exception of HIV infection. This review focuses exclusively on unipolar disorder. The review summarizes the current state of the art and also makes recommendations for future directions.

Outcomes of Minor and Subsyndromal Depression among Elderly Patients in Primary Care Settings

Context The spectrum of depressive illness includes milder forms, about which we know relatively little. Content Older patients selected from 10 primary care practices for depressive symptoms had major depression, minor or subsyndromal depression, or were not depressed. After 1 year, depression symptom severity was closely associated with the initial depression diagnosis. Patients with minor or subsyndromal depression had a much higher incidence of major depression than nondepressed patients, but most were no longer depressed or still had minor or subsyndromal depression. Cautions Approximately 29% of patients withdrew before the end of the study. Implications Minor or subsyndromal depression causes substantial morbidity and is a risk factor for major depression. The Editors Depressive conditions in later life are a major public health problem because they are common and associated with considerable morbidity (1-10). However, most elderly persons who have clinically significant depressive symptoms do not meet diagnostic criteria for major depression or dysthymic disorder (4, 7, 11). Terms such as minor, subsyndromal, or subthreshold depression have been used to describe such sub-major depressive conditions. In younger adults, minor and subsyndromal depression are associated with greater cumulative functional disability than major depression (12); they probably exist along a dimensional spectrum of symptomatic severity (11, 13, 14), sometimes (but not always) representing a prodromal or residual phase of a major mood disorder. In older persons, minor and subsyndromal depression are seen in various settings more commonly than major depression (1, 4, 11, 15-17) and are associated with similar functional morbidity. Most elderly persons with depressive symptoms never see mental health specialists but do see their primary care physicians (18). Because there is limited evidence to support specific treatments for minor and subsyndromal depression (19, 20), it is important for primary care physicians to initiate treatment primarily for patients at highest risk for poor outcomes. However, there are few published longitudinal data from primary care settings to guide identification of such patients. Previous observational studies did not include patients with minor or subsyndromal depression (21, 22) or distinguish them from those with major depression (23, 24). One previous study (25) found that patients with minor depression had outcomes that were poorer than those of persons who were not depressed. Outcomes were not universally poor, however, and were better than those of patients with major depression. The researchers noted that these findings required replication in a larger and more diverse sample. Furthermore, little is known about predictors of geriatric depression outcomes in patients in primary care settings. Studies that reported a predictive role for medical illness burden (26) rarely focused on primary care, and many used self-reports of medical illness that were subject to confounding by depression (27). Small-vessel brain disease may contribute to the pathogenesis of some forms of depression seen later in life (28-31); cerebrovascular risk factors are associated with depression outcomes in other settings (32-35), but their role remains unclear in primary care (35, 36). Psychosocial factors, such as functional disability, social support, and stressful life events, contribute to depression in younger adults and to more severe depression in senior citizens, but their role in elderly patients in primary care settings is generally unknown (2, 37). We hypothesized that 1) patients with minor or subsyndromal depression have an intermediate outcome in severity and diagnosis of depression, medical burden, and functional status compared with patients who have major depression and those who are not depressed and 2) initial overall medical burden, particularly cerebrovascular risk factors, are independently associated with outcomes of depression in elderly patients. We tested these 2 hypotheses in a large, multisite sample of elderly primary care patients who were followed for 1 year. We also explored functional status, social support, and stressful life events as outcome predictors. Methods Patient Sample and Randomization Protocol The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) was a randomized trial of a collaborative care intervention for geriatric depression (38) in patients of primary care practices in greater New York City, and Philadelphia and Pittsburgh, Pennsylvania. Within matched pairs, practices were randomly assigned to an intervention group or a usual care (control) group. This study used only data from patients in 10 usual care practices; these sites comprised 2 academic practices and 8 community-based practices, 1 of which served primarily African-American patients. All patients received usual care from their primary care physicians; the physicians were initially educated about published treatment guidelines (39) and, for ethical reasons, were notified when a patient met research criteria for a depression diagnosis (40). The institutional review board of each of the 3 participating universities approved the research protocol and its formal written consent procedures. Recruitment Procedures As described elsewhere (38), the patients who participated in PROSPECT were recruited to generate a demographically representative sample. Depressive conditions were oversampled to increase the power to examine depression outcomes without precluding the ability to examine specific predictors because the relationships between variables over time were not affected by the enriched sample. Protocol eligibility requirements included age of 60 years or older, ability to give informed consent in English, and a score of 18 or higher on the Mini-Mental State Examination (41). We oversampled for depressive symptoms by using the Center for Epidemiologic Studies Depression Scale (42); all patients with scores of greater than 20 (43) and a random sample of 5% of patients with scores of 20 or less were approached for study participation. In addition, patients with scores of 20 or less who were not included in the latter random sample were recruited if they responded positively to supplemental questions about previous depressive episodes or treatment. Research personnel at the practice interviewed consenting patients in person. Patients received telephone assessments at 4 and 8 months and an in-person interview 1 year after the baseline evaluation. Of the 622 usual care patients completing intake measures, 441 (70.9%) completed 1-year follow-up visits. The withdrawal rate probably reflected the lack of direct benefits offered to patients in this observational study. The group of patients who completed 1-year evaluations contained fewer cigarette smokers at baseline than the group that did not complete follow-up (13.3% vs. 19.7%; chi-square = 3.9; P= 0.047); other demographic and baseline clinical characteristics of the groups were not significantly different. Study Measures All study measures were obtained from patient interviews that were conducted by trained research associates; study psychiatrists reviewed patient responses. We measured the primary outcome of depressive symptom severity by using the 24-item examiner-rated Hamilton Rating Scale for Depression (Ham-D) (44). We used the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual for Mental Disorders, fourth edition) (SCID) to make depression diagnoses (45, 46). The intraclass correlation coefficient of research associates across the 3 study sites was 0.97 for the Ham-D and 0.92 for the SCID, and reliability was monitored throughout the study to prevent drift. Patients were classified into 1 of 3 diagnostic groups: major depression (n= 122), minor or subsyndromal depression (n= 205), or nondepressed (n= 114). Patients were assigned to the major depression group if they met SCID criteria for current major depression. To receive a diagnosis of minor or subsyndromal depression, a patient needed to have at least 2 SCID-defined depressive symptoms, of which 1 symptom had to be depressed mood or anhedonia. The symptoms had to be present at threshold (that is, meeting DSM-IV criteria for severity and 2-week duration) or subthreshold (that is, present but not meeting the threshold criterion) levels. The nondepressed category comprised all other patients. The minor or subsyndromal depression group included patients who 1) met DSM-IV criteria for dysthymic disorder; 2) did not meet the criteria for dysthymic disorder or minor depression (nonDSM-IV subsyndromal depression); and 3) had minor depression as defined by PROSPECT criteria. Modified from the DSM-IV appendix criteria, the PROSPECT criteria require 4 threshold depressive symptoms, a Ham-D score of 10 or higher, and a symptom duration of 4 weeks or more. Secondary analyses compared outcomes between the patients with PROSPECT-defined minor depression and those with nonDSM-IV subsyndromal depression; separate analysis of the patients with dysthymic disorder was precluded by the subgroups small size. We rated the cumulative severity of specified cerebrovascular risk factors (presence of antihypertensive therapy, cardiovascular disease, diabetes mellitus, cigarette smoking, atrial fibrillation, and left ventricular hypertrophy) by the weighted sum of points that were obtained from the American Heart Associations chart for predicting stroke risk, which is derived from the Framingham Heart Study (47). According to this measure, womens scores for antihypertensive therapy are based on a patients systolic blood pressure (range, 0 to 6); because blood pressure measurements were not available, we assigned a score of 3 if the patient used antihypertensive therapy and a score of 0 if they did not. The Charlson Comorbidity Index was used as a validated measure of overall medical

Reducing Suicidal Ideation and Depression in Older Primary Care Patients: 24-Month Outcomes of the PROSPECT Study

OBJECTIVE The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) evaluated the impact of a care management intervention on suicidal ideation and depression in older primary care patients. This is the first report of outcomes over a 2-year period. METHOD Study participants were patients 60 years of age or older (N=599) with major or minor depression selected after screening 9,072 randomly identified patients of 20 primary care practices randomly assigned to provide either the PROSPECT intervention or usual care. The intervention consisted of services of 15 trained care managers, who offered algorithm-based recommendations to physicians and helped patients with treatment adherence over 24 months. RESULTS Compared with patients receiving usual care, those receiving the intervention had a higher likelihood of receiving antidepressants and/or psychotherapy (84.9%-89% versus 49%-62%) and had a 2.2 times greater decline in suicidal ideation over 24 months. Treatment response occurred earlier on average in the intervention group and increased from months 18 to 24, while no appreciable increase in treatment response occurred in the usual care group during the same period. Among patients with major depression, a greater number achieved remission in the intervention group than in the usual-care group at 4 months (26.6% versus 15.2%), 8 months (36% versus 22.5%), and 24 months (45.4% versus 31.5%). Patients with minor depression had favorable outcomes regardless of treatment assignment. CONCLUSIONS Sustained collaborative care maintains high utilization of depression treatment, reduces suicidal ideation, and improves the outcomes of major depression over 2 years.

Comorbidity of late life depression: an opportunity for research on mechanisms and treatment.

Late life depression principally affects individuals with other medical and psychosocial problems, including cognitive dysfunction, disability, medical illnesses, and social isolation. The clinical associations of late life depression have guided the development of hypotheses on mechanisms predisposing, initiating, and perpetuating specific mood syndromes. Comorbidity studies have demonstrated a relationship between frontostriatal impairment and late life depression. Further research has the potential to identify dysfunctions of specific frontostriatal systems critical for antidepressant response and to lead to novel pharmacological treatments and targeted psychosocial interventions. The reciprocal interactions of depression with disability, medical illnesses, treatment adherence, and other psychosocial factors complicate the care of depressed older adults. Growing knowledge of the clinical complexity introduced by the comorbidity of late life depression can guide the development of comprehensive treatment models. Targeting the interacting clinical characteristics associated with poor outcomes has the potential to interrupt the spiral of deterioration of depressed elderly patients. Treatment models can be most effective if they focus on amelioration of depressive symptoms, but also on treatment adherence, prevention of relapse and recurrence, reduction of medical burden and disability, and improvement of the quality of life of patients and their families.

Use of the Cornell Scale in Nondemented Patients

The Cornell scale is a 19‐item clinician‐administered scale of depression that uses information from interviews with both patients and their caregivers. The Cornell scale has been validated in demented patients. In this study, the Cornell scale was psychometically tested in nondemented geriatric subjects by administering it to 15 depressed patients, 15 patients with other psychiatric diagnoses, and 15 normal control subjects. The Cornell scale had high interrater reliability (Cohens κ = 0.74), internal consistency (Kuder‐Richardsons coefficient = 0.98), and sensitivity, and correlated significantly (Spearmans r = 0.81) with Research Diagnostic Criteria psychiatric diagnoses associated with various intensity of depression. To our knowledge, the Cornell scale is the only depression‐rating instrument that has been validated in both demented and nondemented geriatric subjects.