Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

OBJECTIVE: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria. DESIGN: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. SETTING: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto. PARTICIPANTS: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both. MEASUREMENTS: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses. RESULTS: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele. CONCLUSION: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.

Disruption of Neural Homeostasis as a Model of Relapse and Recurrence in Late-Life Depression.

The significant public health burden associated with late-life depression (LLD) is magnified by the high rates of recurrence. In this manuscript, we review what is known about recurrence risk factors, conceptualize recurrence within a model of homeostatic disequilibrium, and discuss the potential significance and challenges of new research into LLD recurrence. The proposed model is anchored in the allostatic load theory of stress. We review the allostatic response characterized by neural changes in network function and connectivity and physiologic changes in the hypothalamic-pituitary-adrenal axis, autonomic nervous system, immune system, and circadian rhythm. We discuss the role of neural networks' instability following treatment response as a source of downstream disequilibrium, triggering and/or amplifying abnormal stress response, cognitive dysfunction and behavioral changes, ultimately precipitating a full-blown recurrent episode of depression. We propose strategies to identify and capture early change points that signal recurrence risk through mobile technology to collect ecologically measured symptoms, accompanied by automated algorithms that monitor for state shifts (persistent worsening) and variance shifts (increased variability) relative to a patient's baseline. Identifying such change points in relevant sensor data could potentially provide an automated tool that could alert clinicians to at-risk individuals or relevant symptom changes even in a large practice.

Treatment Considerations for Depression Research in Older Married Couples: A Dyadic Case Study.

OBJECTIVE: Critical gaps remain in understanding optimal approaches to intervening with older couples. The focus of this report is to describe the pros and cons of incorporating spousal dyads into depression-prevention research. METHODS: In an intervention development study, the authors administered problem-solving therapy (PST) dyadically to participants with mild cognitive impairment (MCI) and their caregivers. Dyads worked with the same interventionist in the same therapy session. The dyadic PST (highlighted in a case example of a husband with MCI and his wife/support person) and the potential feasibility of the program are described. RESULTS: The authors found that the wife of the individual with MCI could be trained as a PST coach to help her husband learn and use problem-solving skills. A decrease in depressive symptom severity was observed for the individual with MCI, which was sustained over 12 months of follow-up. Neither the husband nor wife experienced an incident episode of major depression over the course of the study. CONCLUSION: Dyadic interventions need to be further developed in geriatric psychiatry; proven methods such as PST can be modified to include patients' support persons. Recommendations are offered for developing randomized controlled trials that aim to recruit dyads and prevent depression in at-risk older married couples.

Design and Implementation of an Intervention Development Study: Retaining Cognition While Avoiding Late-Life Depression (ReCALL).

OBJECTIVE: To discuss the design, rationale, and implementation of an intervention development study addressing indicated and selective prevention of depression and anxiety in individuals 60 years and older with mild cognitive impairment (MCI) and in their caregivers. METHODS: In Phase I, now completed, we developed and standardized problem-solving therapy (PST) and the combined PST + moderate-intensity physical exercise (PE) intervention to be administered to participants with MCI and their caregivers together, dyadically, with both participants working with the same interventionist in the same therapy sessions. In Phase II we have been testing the interventions against enhanced usual care (EUC) and have addressed challenges to recruitment. Randomization was to one of three cells: PST + PE, PST, or EUC. RESULTS: Although we set out to intervene dyadically, many individuals with MCI lived alone or did not have a support person who could participate in the study with them. Consequently, we modified the study to include MCI participants with and without support persons. Ninety-four participants were enrolled: 20 with MCI together with their support persons (N = 20 dyads) and 54 MCI participants without accompanying support persons. Most participants have been satisfied with the usefulness of the interventions in managing stress and cognitive problems. CONCLUSION: PST and moderate-intensity PE are acceptable interventions for depression and anxiety prevention in older adults with MCI and their available caregivers.

Challenges and Solutions for Depression Prevention Research: Methodology for a Depression Prevention Trial for Older Adults with Knee Arthritis and Emotional Distress.

OBJECTIVE: To describe the methodology, challenges, and baseline characteristics of a prevention development trial entitled "Reducing Pain, Preventing Depression." METHODS: A sequential multiple assignment randomized trial (SMART) compared sequences of cognitive behavioral therapy (CBT) and physical therapy for knee pain and prevention of depression and anxiety. Participants were randomized to CBT, physical therapy, or enhanced usual care and followed for 12 months for new-episode depression or anxiety. Participants were age ≥ 60 with knee osteoarthritis and subsyndromal depression, defined as 9-item Patient Health Questionnaire (PHQ-9) score ≥1 (which included the endorsement of one of the cardinal symptoms of depression [low mood or anhedonia]) and no diagnosis of major depressive disorder per the Structured Clinical Interview for DSM-IV. Depression and anxiety severity and characterization of new episodes were assessed with the PHQ-9, Generalized Anxiety Disorder-7, and the PRIME-MD. Knee pain was characterized with the Western Ontario McMaster Arthritis Index. Response was defined as at least "Very Much Better" on a Patient Global Impression of Change. RESULTS: At baseline there were 99 patients with an average age of 71; 61.62% were women and 81.8% white. The average PHQ-9 was 5.6 and average Generalized Anxiety Disorder-7, was 3.2. Most were satisfied with the interventions and study procedures. The challenges and solutions described here will also be used in a confirmatory clinical trial of efficacy. CONCLUSION: A SMART design for depression and anxiety prevention, using both CBT and physical therapy, appears to be feasible and acceptable to participants. The methodologic innovations of this project may advance the field of late-life depression and anxiety prevention.

Plasma and cerebrospinal fluid amyloid-ß levels in late-life depression: A systematic review and meta-analysis.

This study aimed to evaluate differences in plasma and cerebrospinal fluid (CSF) levels of Aß peptides in older adults with late-life depression compared to non-depressed older controls. We conducted a systematic review and meta-analysis of the literature using PubMed, Web of science and Scopus databases with no search limits for publication dates or languages. Two independent reviewers extracted data and assessed quality. Six hundred references were retrieved, and we included 12 studies in the meta-analysis after eligibility screening. Older adults with late-life depression (LLD) had a higher plasma Aß40:Aß42 ratio compared to non-depressed participants (SMD = 1.10, CI95% [0.28; 1.96], p = 0.01), and marginally significant reduction of CSF Aß42 levels (SMD = -1.12, CI95% [-2.47; 0.22], p = 0.1). The present results evidence that older adults with depression have significant differences in Aß metabolism, in the same direction observed in individuals with AD. These differences in the Aß metabolism may help identify a subgroup of subjects with LLD at higher risk of developing AD.

The effect of gender, age, and symptom severity in late-life depression on the risk of all-cause mortality: the Bambuí Cohort Study of Aging.

BACKGROUND: Increased mortality risk and its moderators is an important, but still under recognized, negative outcome of late-life depression (LLD). Therefore, we aimed to evaluate whether LLD is a risk factor for all-cause mortality in a population-based study with over 10 years of follow-up, and addressed the moderating effect of gender and symptom severity on mortality risk. METHODS: This analysis used data from the Bambuí Cohort Study of Aging. The study population comprised 1.508 (86.5%) of all eligible 1.742 elderly residents. Depressive symptoms were annually evaluated by the GHQ-12, with scores of five or higher indicating clinically significant depression. From 1997 to 2007, 441 participants died during 10,648 person-years of follow-up. We estimated the hazard ratio for mortality risk by Cox regression analyses. RESULTS: Depressive symptoms were a risk factor for all-cause mortality after adjusting for confounding lifestyle and clinical factors (adjusted HR = 1.24 CI95% [1.00-1.55], P = .05). Mortality risk was significantly elevated in men (adjusted HR = 1.45 CI95% [1.01-2.07], P = 0.04), but not in women (adjusted HR = 1.13 CI95% [0.84-1.48], P = 0.15). We observed a significant interaction between gender and depressive symptoms on mortality risk ((HR = 1.72 CI95% [1.18-2.49], P = 0.004). CONCLUSION: The present study provides evidence that LLD is a risk factor for all-cause mortality in the elderly, especially in men. The prevention and adequate treatment of LLD may help to reduce premature disability and death among elders with depressive symptoms.

Impaired Executive Function in Contemplated and Attempted Suicide in Late Life.

OBJECTIVE: Executive deficits may play an important role in late-life suicide. Yet, current evidence in this area is inconclusive and does not indicate whether these deficits are broadly associated with suicidal ideation or are specific to suicidal behavior. This study examined global cognition and specifically executive function impairments as correlates of suicidal ideation and suicidal behavior in depressed older adults, with the goal of extending an earlier preliminary study. DESIGN: Case-control study. SETTING: University-affiliated psychiatric hospital. PARTICIPANTS: All participants were age 60+: 83 depressed suicide attempters, 43 depressed individuals having suicidal ideation with a specific plan, 54 nonsuicidal depressed participants, and 48 older adults with no history of psychiatric disorders. MEASUREMENTS: Global cognitive function was assessed with Dementia Rating Scale (DRS) and executive function with Executive Interview (EXIT). RESULTS: Both suicide attempters and suicide ideators performed worse than the two comparison groups on the EXIT, with no difference between suicide attempters and suicide ideators. On the DRS total score, as well as on Memory and Attention subscales, suicide attempters and ideators and nonsuicidal depressed subjects performed similarly and were impaired relative to nonpsychiatric control subjects. Controlling for education, substance use disorders, and medication exposure did not affect group differences in performance on either the EXIT or the DRS. CONCLUSIONS: Executive deficits, captured with a brief instrument, are associated broadly with suicidal ideation in older depressed adults but do not appear to directly facilitate suicidal behavior. Our data are consistent with the idea that different vulnerabilities may operate at different stages in the suicidal process.

Dynamic prediction of treatment response in late-life depression.

OBJECTIVE: To identify actionable predictors of remission to antidepressant pharmacotherapy in depressed older adults and to use signal detection theory to develop decision trees to guide clinical decision making. METHOD: We treated 277 participants with current major depression using open-label venlafaxine XR (up to 300 mg/day) for 12 weeks, in an NIMH-sponsored randomized, placebo-controlled augmentation trial of adjunctive aripiprazole. Multiple logistic regression and signal detection approaches identified predictors of remission in both completer and intent-to-treat samples. RESULTS: Higher baseline depressive symptom severity (odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.80-0.93; p <0.001), smaller symptom improvement during the first two weeks of treatment (OR: 0.96, 95% CI: 0.94-0.97; p <0.001), male sex (OR: 0.41 95% CI: 0.18-0.93; p = 0.03), duration of current episode ≥2 years (OR: 0.26, 95% CI: 0.12-0.57; p <0.001) and adequate past depression treatment (ATHF ≥3) (OR: 0.34, 95% CI: 0.16-0.74; p = 0.006) predicted lower probability of remission in the completer sample. Subjects with Montgomery Asberg (MADRS) decreasing by greater than 27% in the first 2 weeks and with baseline MADRS scores of less than 27 (percentile rank = 51) had the best chance of remission (89%). Subjects with small symptom decrease in the first 2 weeks with adequate prior treatment and younger than 75 years old had the lowest chance of remission (16%). CONCLUSION: Our results suggest the clinical utility of measuring pre-treatment illness severity and change during the first 2 weeks of treatment in predicting remission of late-life major depression.

Reliability and validity of the Executive Interview (EXIT) and Quick EXIT among community dwelling older adults.

OBJECTIVES: To investigate the psychometric properties of the Executive Interview (EXIT) and Quick EXIT in community dwelling older adults. DESIGN: Secondary analysis of data obtained as part of a longitudinal study of cognitive function in late-life depression. SETTING: A university hospital. PARTICIPANTS: Community-dwelling adults (N = 422), aged 59 years and older, with current or recent history of non-psychotic unipolar major depression, and never-depressed comparison subjects. MEASUREMENTS: The EXIT and other measures of executive control functions (ECF), non-executive cognitive domains, and global cognitive function. We calculated Quick EXIT scores from the EXIT. RESULTS: The EXIT demonstrated high inter-rater reliability (Intraclass correlation coefficient = 0.978, F(7, 21) = 174.85, p <0.001), and both the EXIT and Quick EXIT demonstrated moderate internal consistency (α = 0.66 and α = 0.68, respectively). Both tests also demonstrated acceptable convergent validity against several standard tests of ECF (rs -0.399 to 0.322, except for the Trail Making Test B, where rs was 0.057 to 0.063) as well as against measures of multifactorial cognitive function (rs -0.432 to 0.491). Both tests, however, demonstrated inconsistent discriminant validity against a variety of standard non-ECF tests (rs -0.013 to 0.376). CONCLUSIONS: Both the EXIT and the Quick EXIT have adequate reliability and appear to require ECF in this population. However, both the EXIT and the Quick EXIT also reflect non-ECF domains. The EXIT and Quick EXIT should be considered to be measures of global cognitive function rather than pure ECF measures. Given similar reliability and validity, the Quick EXIT is recommended clinically as it is briefer and less burdensome than the full EXIT.