Mindfulness-Enhanced Computerized Cognitive Training for Depression: An Integrative Review and Proposed Model Targeting the Cognitive Control and Default-Mode Networks.

Depression is often associated with co-occurring neurocognitive deficits in executive function (EF), processing speed (PS) and emotion regulation (ER), which impact treatment response. Cognitive training targeting these capacities results in improved cognitive function and mood, demonstrating the relationship between cognition and affect, and shedding light on novel targets for cognitive-focused interventions. Computerized cognitive training (CCT) is one such new intervention, with evidence suggesting it may be effective as an adjunct treatment for depression. Parallel research suggests that mindfulness training improves depression via enhanced ER and augmentation of self-referential processes. CCT and mindfulness training both act on anti-correlated neural networks involved in EF and ER that are often dysregulated in depression-the cognitive control network (CCN) and default-mode network (DMN). After practicing CCT or mindfulness, downregulation of DMN activity and upregulation of CCN activity have been observed, associated with improvements in depression and cognition. As CCT is posited to improve depression via enhanced cognitive function and mindfulness via enhanced ER ability, the combination of both forms of training into mindfulness-enhanced CCT (MCCT) may act to improve depression more rapidly. MCCT is a biologically plausible adjunct intervention and theoretical model with the potential to further elucidate and target the causal mechanisms implicated in depressive symptomatology. As the combination of CCT and mindfulness has not yet been fully explored, this is an intriguing new frontier. The aims of this integrative review article are four-fold: (1) to briefly review the current evidence supporting the efficacy of CCT and mindfulness in improving depression; (2) to discuss the interrelated neural networks involved in depression, CCT and mindfulness; (3) to present a theoretical model demonstrating how MCCT may act to target these neural mechanisms; (4) to propose and discuss future directions for MCCT research for depression.

Computerized Games versus Crosswords Training in Mild Cognitive Impairment.

BACKGROUND: Mild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in patients with MCI is unclear. METHODS: In a two-site, single-blinded, 78-week trial, participants with MCI - stratified by age, severity (early/late MCI), and site - were randomly assigned to 12 weeks of intensive, home-based, computerized training with Web-based cognitive games or Web-based crossword puzzles, followed by six booster sessions. In mixed-model analyses, the primary outcome was change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score, a 70 point scale in which higher scores indicate greater cognitive impairment at 78 weeks, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score, University of California San Diego Performance-Based Skills Assessment (functional outcome) score, and Functional Activities Questionnaire (functional outcome) score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed. RESULTS: Among 107 participants (n=51 [games]; n=56 [crosswords]), ADAS-Cog score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, -1.44; 95% confidence interval [CI], -2.83 to -0.06; P=0.04). From baseline to week 78, mean ADAS-Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, -2.45; SE, 0.89; 95% CI, -4.21 to -0.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, -1.08; 95% CI, -1.97 to -0.18). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI, 0.51 to 67.63 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04 [cortical thickness]). CONCLUSIONS: Home-based computerized training with crosswords demonstrated superior efficacy to games for the primary outcome of baseline-adjusted change in ADAS-Cog score over 78 weeks. (Supported by the National Institutes of Health, National Institute on Aging; ClinicalTrials.gov number, NCT03205709.).

Cortical thickness predicts remission of depression with antidepressants in patients with late-life depression and cognitive impairment.

BACKGROUND: Depression (DEP) and cognitive impairment (CI) share etiological risk factors, anatomical underpinnings, and interact to produce deleterious treatment outcomes. Both DEP and CI exhibit altered patterns of cortical thickness which may impact the course of antidepressant treatment, though inconsistencies in directionality and affected brain regions have been reported. In this study, we examined the relationship between cortical thickness and treatment outcome in older adults with comorbid DEP-CI. METHODS: 55 patients with DEP-CI received baseline MRI scans as part of a larger clinical trial at NYSPI/Columbia University Medical Center and Duke University Medical Center. Mood was assessed using the Hamilton Depression Rating Scale. Patients received open antidepressant treatment for 8 weeks followed by another 8 weeks of the same medication or switch to another antidepressant for a total of 16 weeks. Cortical thickness was extracted using an automated brain segmentation program (FreeSurfer). Vertex-wise analyses evaluated the relationship between cortical thickness and treatment outcome. RESULTS: Remitters exhibited diffuse clusters of greater cortical thickness and reduced cortical thickness compared to non-remitters. Thicker baseline middle frontal gyrus most consistently predicted greater likelihood and faster rate of remission. White matter hyperintensities and hippocampal volume were not associated with antidepressant treatment outcome. LIMITATIONS: MRI was conducted at baseline only and sample size was small. DISCUSSION: Cortical thickness predicts treatment remission and magnitude of early improvement. Results indicate that individuals with DEP-CI exhibit unique patterns of structural abnormalities compared to their depressed peers without CI that have consequences for their recovery with antidepressant treatment.

Cortical Thickness and Hippocampal Volume in Vascular and Non-vascular Depressed Patients.

Background: Reduced cortical thickness and hippocampal volume are prevalent markers of late life depression as well as mild cognitive impairment (MCI) but are conspicuously absent in the vascular depression (VD) literature. The present study aimed to determine differences in cortical thickness and hippocampal volume between VD and non-VD patients. Methods: Participants were enrolled in an 8-week open treatment antidepressant trial. Forty-one depressed individuals aged 50 and older underwent brain magnetic resonance imaging at baseline and were classified as VD or non-VD. Cortical thickness values for the left and right entorhinal, parahippocampal, and precuneal cortices, as well as left and right hippocampal volume, were linearly regressed on VD status to determine mean differences between VD and non-VD. Covariates included site, age, sex, and mean thickness or intracranial volume. Results: No statistical differences were found between VD and non-VD patients in cortical thickness of the bilateral precuneal, entorhinal, or parahippocampal cortices, or hippocampal volume (p > 0.001). Conclusions: The absence of statistical differences in gray matter between VD and non-VD patients raises several diagnostic, etiological, and developmental possibilities, namely that VD may not be connected with other late-life psychiatric illnesses such as MCI or dementia and that vascular disease may not be a common etiological risk factor for depression and dementia. Larger datasets, prospective longitudinal studies, and cognitively intact controls are needed to further address these types of questions.

Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression.

OBJECTIVE: While patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes. DESIGN: Neuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated. RESULTS: Fractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response. CONCLUSION: In late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.

Testing the Mechanism of Action of Computerized Cognitive Training in Young Adults with Depression: Protocol for a Blinded, Randomized, Controlled Treatment Trial.

BACKGROUND: Depression is associated with a broad range of cognitive deficits, including processing speed (PS) and executive functioning (EF). Cognitive symptoms commonly persist with the resolution of affective symptoms and increase risk of relapse and recurrence. The cognitive control network is comprised of brain areas implicated in EF and mood regulatory functions. Prior research has demonstrated the effectiveness of computerized cognitive training (CCT) focused on PS and EF in mitigating both cognitive and affective symptoms of depression. METHODS: Ninety participants aged 18-29 with a current diagnosis of major depressive disorder or persistent depressive disorder, or a Hamilton Depression Rating Scale score ≥12, will be randomized to either PS/EF CCT, verbal CCT, or waitlist control. Participants in the active groups will complete 15 min of training 5 days/week for 8 weeks. Clinical and neuropsychological assessments will be completed at baseline, week 4, week 8, and 3-month follow-up. Structural and functional magnetic resonance imaging (fMRI) will be completed at baseline and week 8. We will compare changes in mood, cognition, daily functioning, and fMRI data. We will explore cognitive control network functioning using resting-state and task-based fMRI. RESULTS: Recruitment began in October 2019; we expect to finish recruitment by April 2022 and subsequently begin data analysis. CONCLUSIONS: This study is innovative in that it will include both active and waitlist control conditions and will explore changes in neural activation. Identifying the neural networks associated with improvements following CCT will allow for the development of more precise and effective interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03869463; https://clinicaltrials.gov/ct2/show/NCT03869463.

Vascular depression for radiology: A review of the construct, methodology, and diagnosis.

Vascular depression (VD) as defined by magnetic resonance imaging (MRI) has been proposed as a unique subtype of late-life depression. The VD hypothesis posits that cerebrovascular disease, as characterized by the presence of MRI-defined white matter hyperintensities, contributes to and increases the risk for depression in older adults. VD is also accompanied by cognitive impairment and poor antidepressant treatment response. The VD diagnosis relies on MRI findings and yet this clinical entity is largely unfamiliar to neuroradiologists and is rarely, if ever, discussed in radiology journals. The primary purpose of this review is to introduce the MRI-defined VD construct to the neuroradiology community. Case reports are highlighted in order to illustrate the profile of VD in terms of radiological, clinical, and neuropsychological findings. A secondary purpose is to elucidate and elaborate on the measurement of cerebrovascular disease through visual rating scales and semi- and fully-automated volumetric methods. These methods are crucial for determining whether lesion burden or lesion severity is the dominant pathological contributor to VD. Additionally, these rating methods have implications for the growing field of computer assisted diagnosis. Since VD has been found to have a profile that is distinct from other types of late-life depression, neuroradiologists, in conjunction with psychiatrists and psychologists, should consider VD in diagnosis and treatment planning.

Cognitive training and neuroplasticity in mild cognitive impairment (COG-IT): protocol for a two-site, blinded, randomised, controlled treatment trial.

INTRODUCTION: Mild cognitive impairment (MCI) is common in older adults and represents a high-risk group for progression to Alzheimer's disease (AD). Medication trials in MCI have generally failed, but new discoveries with brain plasticity in ageing have led to the study of cognitive training as a potential treatment to improve cognitive abilities. Computerised cognitive training (CCT) involves computerised cognitive exercises that target specific cognitive abilities and neural networks to potentially improve cognitive functioning through neuroplasticity. METHODS AND ANALYSIS: In a two-site study (New York State Psychiatric Institute/Columbia University Medical Center and Duke University Medical Center), we will randomise 100 patients with MCI (Wechsler Memory Scale-III Logical Memory II score 0-11; Folstein Mini Mental State Examination ≥23) to home-based CCT (suite of exercises: memory, matching, spatial recognition, processing speed) or a home-based active control condition (computerised crossword puzzle training (CPT)) with 12 weeks of intensive training followed by regular booster sessions up to 78 weeks. All patients will receive standard neuropsychological and functional assessments in clinic as well as structural/functional brain MRI scans at study entry and endpoint. We will test if CCT, versus CPT, leads to improved cognitive functioning, transfers to functional ability and tasks of everyday life and impacts hippocampal volume changes and changes in the default mode network of the brain measured by resting-state functional MRI. ETHICS AND DISSEMINATION: The study will be conducted following ethics approval and written informed consent will be obtained from all subjects. Study results will be disseminated via publication, clinicaltrials.gov, media and conference presentations. This will be the first controlled long-term trial to evaluate the effects of home-based CCT versus computerised CPT on cognitive abilities and functional measures and neural outcomes as determined by MRI indices in patients with MCI. Positive results from trial may support further development of home-based CCT. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier (NCT03205709).

Computerized cognitive training in young adults with depressive symptoms: Effects on mood, cognition, and everyday functioning.

BACKGROUND: Computerized cognitive training (CCT) has previously improved cognition and mood in people with depression. Existing research has not determined if the benefits following CCT are specific to the content of CCT or are a function of participation in an engaging activity. In this double-blind randomized controlled trial, we tested whether executive functioning and processing speed (EF/PS)-focused CCT could outperform verbal ability-focused CCT. METHODS: 46 young adults with at least mild depressive symptoms (HDRS ≥ 10) were recruited from the community and randomized to either EF/PS CCT or verbal ability CCT. Participants trained on their mobile device 5 days per week for 8 weeks. Depressive severity, everyday functioning, and cognition were evaluating pre and post-training. RESULTS: The EF/PS group had greater gains in executive functioning and processing speed than the verbal group. There were no differences between groups in mood or everyday functioning improvement, though the EF/PS obtained equivalent improvement with half the training time. Both groups saw significant improvements in self and clinician-rated depressive severity, everyday functioning, and cognition. LIMITATIONS: There was no waitlist control condition and the sample consisted of individuals with mild depressive symptoms and not diagnosed major depressive disorder. CONCLUSIONS: CCT is associated with improved mood, cognition, and everyday functioning, though the type of CCT content does not differentially impact depressive symptom change. EF/PS focused CCT has greater impact on processing speed and executive functioning and leads to equivalent mood/everyday functioning gains as verbal-focused CCT more efficiently. Common factors remain plausible drivers of CCT's therapeutic effects.

Clinical and radiological characteristics of early versus late mild cognitive impairment in patients with comorbid depressive disorder.

OBJECTIVE: The classification of mild cognitive impairment (MCI) continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. Our aim was to examine baseline characteristics of DEP-CI patients in the DOTCODE trial, a randomized controlled trial of open antidepressant treatment for 16 weeks followed by add-on donepezil or placebo for 62 weeks. METHODS/DESIGN: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HAM-D) score >14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. RESULTS: Seventy-nine DEP-CI patients were recruited of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9, and mean HAM-D was 23.0. Late mild cognitive impairment patients had significantly worse ADAS-Cog (P < .001), MMSE (P = .004), Block Design (P = .024), Visual Rep II (P = .006), CFL Animal (P = .006), UPSIT (P = .051), as well as smaller right hippocampal volume (P = .037) compared to EMCI patients. MRI indices of cerebrovascular disease did not differ between EMCI and LMCI patients. CONCLUSIONS: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer's disease.

Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study.

OBJECTIVES: To evaluate the impact of obstructive sleep apnea (OSA) on neurocognitive function and brain morphology in older adults with depression and cognitive impairment. METHODS: We prospectively screened OSA with the STOP-Bang questionnaire in the last 25 patients enrolled into the Donepezil Treatment of Cognitive Impairment and Depression (DOTCODE) trial. High and low probability of OSA were defined as a STOP-Bang score of ≥5 (h-OSA) and of <5 (l-OSA), respectively. Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial. RESULTS: After 16 weeks of antidepressant treatment, the h-OSA group performed significantly worse on the Selective Reminding Test delayed recall task than the l-OSA group, controlling for baseline performance (F = 19.1, df = 1,22, p < 0.001). In 19 of 25 participants who underwent brain MRI, the h-OSA group had significantly greater volumes of MRI hyperintensities in deep white matter, periventricular white matter, and subcortical gray matter compared with the l-OSA group. There was no significant association between OSA and hippocampal or entorhinal cortex volumes in our sample, even after controlling for intracranial volume. CONCLUSIONS: OSA is associated with impaired verbal episodic memory and microvascular damage in older adults with depression and cognitive impairment. One possibility is that by contributing to cerebral microvascular damage, OSA may exacerbate progressive memory decline.

Biological Aging and the Future of Geriatric Psychiatry.

Advances in understanding the biological bases of aging have intellectually revitalized the field of geriatric psychiatry and broadened its scope to include promoting successful aging and studying resilience factors in older adults. To describe the process by which this paradigm shift has occurred and illustrate its implications for treatment and research of late-life brain disorders, late-life depression is discussed as a prototype case. Prior phases of geriatric psychiatry research were focused on achieving depressive symptom relief, outlining pharmacokinetic and pharmacodynamic differences between older and younger adults, and identifying moderators of treatment response. Building on this work, current geriatric psychiatry researchers have begun to disentangle the etiologic complexity in late-life depression by focusing on the causative aging-related processes involved, identifying both neurobiological and behavioral intermediates, and finally delineating depression subtypes that are distinguishable by their underlying biology and the treatment approach required. In this review, we discuss several age-related processes that are critical to the development of late-life mood disorders, outline implications of these processes for the clinical evaluation and management of later-life psychiatric disorders, and finally put forth suggestions for better integrating aging and developmental processes into the National Institute of Mental Health's Research Domain Criteria.

Computerized cognitive training and functional recovery in major depressive disorder: A meta-analysis.

OBJECTIVE: Depression is common, frequently resistant to antidepressant treatment, and associated with impairments in cognition and everyday functioning. Computerized cognitive training (CCT) paradigms offer potential to improve cognition, mood and everyday functioning, but their effectiveness is not well established. The goal of this article was to conduct a systematic review and meta-analysis to determine the efficacy of CCT in depressive disorders. METHOD: A search was conducted to identify high quality randomized controlled CCT trials per PRISMA guidelines using PsycINFO and MEDLINE with the keywords "Cognitive training" or "Cognitive remediation" or "Cognitive rehabilitation" and "Depression". 9 randomized trials for depressed adults met inclusion criteria. Effect sizes (Hedge's g) were calculated for key outcome measures of mood symptom severity, daily functioning, and cognition. A 3-level Bayesian hierarchical linear model was used to estimate effect sizes for each domain and study. Publication bias was assessed using Classic Fail Safe N's and homogeneity was evaluated using Q and I(2) indexes. RESULTS: Significant small-moderate effects for Symptom Severity (0.43) and Daily Functioning (0.72), and moderate-large effects for Attention (0.67), Working Memory (0.72), and Global Functioning (1.05) were found. No significant effects were found for Executive Functioning or Verbal Memory. Moderator variable analysis revealed decreased effect of CCT with age. Gender and concurrent medication treatment did not affect the results. LIMITATIONS: Small sample size, short duration, pseudo-specificity, and high heterogeneity for Verbal Memory measures. CONCLUSIONS: CCT is associated with improvement in depressive symptoms and everyday functioning, though produces inconsistent effects on cognition.

A Meta-Analysis of Executive Dysfunction and Antidepressant Treatment Response in Late-Life Depression.

OBJECTIVE: Depressed older adults with executive dysfunction (ED) may respond poorly to antidepressant treatment. ED is a multifaceted construct and different studies have measured different aspects of ED, making it unclear which aspects predict poor response. Meta-analytic methods were used to determine whether ED predicts poor antidepressant treatment response in late-life depression and to determine which domains of executive functioning are responsible for this relationship. METHODS: A Medline search was conducted to identify regimented treatment trials contrasting executive functioning between elderly responders and nonresponders; only regimented treatment trials for depressed outpatients aged 50 and older were included. Following the most recent PRISMA guidelines, 25 measures of executive functioning were extracted from eight studies. Six domains were identified: cognitive flexibility, planning and organization, response inhibition, selective attention, verbal fluency, and the Dementia Rating Scale Initiation/Perseveration composite score (DRS I/P). Hedge's g was calculated for each measure of executive functioning. A three-level Bayesian hierarchical linear model (HLM) was used to estimate effect sizes for each domain of executive functioning. RESULTS: The effect of planning and organization was significantly different from zero (Bayesian HLM estimate of domain effect size: 0.91; 95% CI: 0.32-1.58), whereas cognitive flexibility, response inhibition, selective attention, verbal fluency, and the DRS I/P composite score were not. CONCLUSION: The domain of planning and organization is meaningfully associated with poor antidepressant treatment response in late-life depression. These findings suggest that therapies that focus on planning and organization may provide effective augmentation strategies for antidepressant nonresponders with late-life depression.

Antidepressant treatment of melancholia in older adults.

OBJECTIVE: This is the first prospective trial in an outpatient sample comparing the effect of nortriptyline with sertraline in the treatment of depression with and without melancholia. We hypothesized that patients with melancholia would respond better to nortriptyline than sertraline, whereas among patients without melancholia, nortriptyline and sertraline would have equal efficacy. METHODS: We conducted a randomized 12-week trial comparing sertraline with nortriptyline in the treatment of patients with nonpsychotic, unipolar major depression stratified by the presence of melancholia. One hundred ten unipolar depressed patients with and without melancholia comprised our intent-to-treat sample. Seventy-two were nonmelancholic depressed and randomly assigned to treatment with sertraline (N = 40) or nortriptyline (N = 32). Thirty-eight were melancholic depressed and randomly assigned to treatment with sertraline (N = 18) or nortriptyline (N = 20). RESULTS: The test of the interaction of medication group and melancholia status on response was not statistically significant. Among patients with melancholia, response rates were 47% to sertraline and 75% to nortriptyline, whereas among patients without melancholia, response rates were 51% to sertraline and 42% to nortriptyline. The odds of response for patients with melancholia treated with nortriptyline compared with sertraline was 3.46. The odds of response for patients without melancholia treated with sertraline compared with nortriptyline was 0.69. Similar findings were obtained in the remission and continuous outcome analyses. CONCLUSION: This study did not find a significant difference between sertraline and nortriptyline in the treatment of depressed older adults with melancholia.

Clinic visits in late-life depression trials: effects on signal detection and therapeutic outcome.

OBJECTIVE: This meta-analysis investigated how the supportive care provided in antidepressant clinical trials for late-life depression influences response and drop-out rates. METHODS: Medline, PsycINFO, and PubMed were searched to identify trials contrasting antidepressants with placebo or active comparator in outpatients aged at least 60 years with major depressive disorder. Hierarchical linear modeling was used to determine whether treatment assignment (medication versus placebo), study type (placebo-controlled or comparator), study duration, and the number of study visits affected response and attrition rates. RESULTS: In the response rate analysis, a significant interaction was found between study visits and treatment assignment (odds ratio [OR]: 0.89, t = -2.186, df = 36, p = 0.035), such that each additional visit over the grand mean for the sample increased average placebo response by 2.5% while not significantly affecting medication response. Controlling for other variables, the effect of this interaction was to dramatically decrease average medication versus placebo differences in trials having greater numbers of study visits. Neither the number of study visits (OR: 0.96, t = -0.468, df = 14, p = 0.646) nor the treatment × visits interaction (OR: 1.03, t = 0.463, df = 35, p = 0.645) influenced drop-out rates. CONCLUSION: Increased supportive care in the form of clinic visits leads to greater placebo but not antidepressant medication response in clinical trials for late-life depression. Less frequent visit schedules may increase average medication-placebo differences in randomized controlled trials without appreciably increasing drop-out rates.

Frailty and depression in older adults: a high-risk clinical population.

OBJECTIVE: To identify salient characteristics of frailty that increase risk of death in depressed elders. METHODS: Data were from the Nordic Research on Ageing Study from research sites in Denmark, Sweden, and Finland. Participants were 1,027 adults aged 75 years (436 men and 591 women). Time of death was obtained, providing a maximum survival time of 11.08 years (initial evaluation took place between 1988 and 1991). RESULTS: Depressed elders showed greater baseline impairments in each frailty characteristic (gait speed, grip strength, physical activity levels, and fatigue). Simultaneous models including all four frailty characteristics showed slow gait speed (hazard ratio: 1.84; 95% confidence interval: 1.05-3.21) and fatigue (hazard ratio: 1.94; 95% confidence interval: 1.11-3.40) associated with faster progression to death in depressed women; none of the frailty characteristics in the simultaneous model was associated with death in depressed men. In women, the effect of impaired gait speed on mortality rates nearly doubled when depression was present (nondepressed women: no gait impairment = 26%; slow gait = 40%; depressed women: no gait impairment = 32%; slow gait = 58%). A similar pattern was observed for fatigue. CONCLUSION: The confluence of specific characteristics of frailty (fatigue and slow gait speed) and depressive illness is associated with an increased risk of death in older adults; this association is particularly strong in older depressed women. Future research should investigate whether multimodal interventions targeting depressive illness, mobility deficits, and fatigue can decrease mortality and improve quality of life in older depressed individuals with characteristics of the syndrome of frailty.