Slowed Processing Speed Disrupts Patient Expectancy in Late Life Depression.

OBJECTIVE: Slowed processing speed and executive dysfunction are associated with poor outcomes in Late Life Depression (LLD), though it is unclear why. We investigated whether these variables interfere with the development of positive treatment expectancies in an antidepressant trial. METHODS: Depressed older subjects were randomized to Open (intended to increase patient expectancy) or Placebo-controlled (termed 'Hidden,' intended to decrease expectancy) administration of antidepressant medication for 8 weeks. Analysis of covariance analyzed the between-group difference on expectancy (Credibility and Expectancy Scale [CES]) and depression (Hamilton Rating Scale for Depression [HRSD], Clinical Global Impressions [CGI] Severity). Moderator analyses examined whether these Open versus Hidden differences varied based on higher versus lower processing speed and executive function. RESULTS: Among the 108 participants, a significant between-group difference was observed on expectancy (effect size [ES, Cohen's d] = 0.51 on CES Item 2; ES = 0.64 on Item 4), indicating the manipulation was effective. Processing speed as measured by the Stroop Color-Word Test (number color-words named in congruent condition) was a significant moderator of the Open versus Hidden effect on expectancy. Depressive symptom improvement was greater on average for Open versus Hidden participants who received active drug (CGI-severity ES = 1.25, HRSD ES = 0.41), but no neurocognitive moderators of the between-group difference reached statistical significance. CONCLUSIONS: Slowed processing speed impairs the development of expectancies in antidepressant trials for LLD, which may help explain lower antidepressant response among older adults. Future studies may address whether interventions to optimize treatment expectancies are capable of improving treatment outcomes.

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.

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

OBJECTIVE: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). RESULTS: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. CONCLUSION: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

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.

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.

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.

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.

The nuances of cognition and depression in older adults: the need for a comprehensive assessment.

OBJECTIVES: This study aimed to examine the confluence of depression, cognitive impairment, and vascular risk factors in older individuals. METHODS: The study uses baseline data from the National Alzheimer's Coordinating Center. Data were collected across Alzheimer's Disease Centers in the USA. The sample included 12,634 individuals (cognitive intact = 8022; amnestic mild cognitive impairment [aMCI] = 3652; nonamnestic MCI [nonaMCI] = 960). The Geriatric Depression Scale assessed depression; the Trail Making Test assessed executive function. RESULTS: The proportion of participants with depression was higher in the aMCI (18%) and nonaMCI group (21%) as compared with that in the cognitively intact group (8%); there was no difference in rates of depression between aMCI and nonaMCI groups. The proportion of participants with executive dysfunction differed between nondepressed and depressed individuals for the cognitively intact (8% vs. 12%) and aMCI groups (28% vs. 35%), but not for the nonaMCI group (37% vs. 41%). Nine percent of the cognitively intact group had executive dysfunction compared with 31% of the aMCI group and 40% of the nonaMCI group. The proportion of participants with hypertension was greater in individuals with executive dysfunction compared with those with no executive deficits; the presence of hypertension was not associated with depression severity. CONCLUSIONS: The confluence of vascular risk factors, episodic memory impairment, and depression and executive dysfunction highlights the need for comprehensive assessment of depressed older adults that can aid clinicians in the formulation of treatment planning and inform clinicians and researchers about long-term prognosis.

Vascular depression: overrepresented among African Americans?

OBJECTIVE: Our primary aim was to compare the rate of vascular depression among a clinical sample of African American and Caucasian depressed older adults. Secondary aims included characterizing the clinical and neuropsychological profile of vascular depression and comparing antidepressant response rates between patients with vascular and nonvascular depression. METHODS: This was a two-site, multi-ethnic, open 8-week trial of antidepressant medication in older adults with depression. Men and women 50 years or older meeting DSM-IV criteria for nonpsychotic unipolar depression participated in this trial. Each participant underwent a comprehensive psychiatric and neuropsychological evaluation and a brain MRI, which were performed at baseline. RESULTS: Forty-six patients met inclusion and exclusion criteria. Forty-two of those patients received an MRI at baseline. Sixteen patients met criteria for vascular depression. Patients with vascular depression were significantly more likely to be African American and have a higher likelihood of being female, a higher rate of hypertension and psychomotor retardation, a lower rate of family history of affective illness, and frontal systems dysfunction on neuropsychological testing. The difference in response rates between patients with vascular and nonvascular depression did not reach statistical significance. CONCLUSIONS: This is the first study to document high rates of vascular depression in a clinical sample of African Americans and Caucasians. Our findings suggest that vascular depression may be overrepresented among African Americans, which is consistent with the high rates of cardiovascular disease, hypertension, and stroke in this population.

Speed of processing and depression affect function in older adults with mild cognitive impairment.

OBJECTIVES: To evaluate the effect of depression and cognition on function in older adults with amnestic and nonamnestic mild cognitive impairment (aMCI and nonaMCI). DESIGN: The study uses baseline data from the National Alzheimer's Coordinating Center. SETTING: Data were collected at multiple Alzheimer's Disease Centers in the United States. PARTICIPANTS: The sample included a total of 3,117 individuals with MCI, mean age = 74.37 years, SD: 9.37 (aMCI, n = 2,488; non-aMCI, n = 629). MEASUREMENTS: The 10-item Pfeffer Functional Activities Questionnaire assessed function. RESULTS: Depressive symptoms (Geriatric Depression Scale), memory impairment (Logical Memory II), and processing speed decrements (Digit Symbol Substitution Test) were significantly associated with functional impairment (p <0.001). Processing speed partially mediated the effect of depression on function and fully mediated the effect of executive dysfunction on function (p <0.001) in the total MCI and aMCI subsample, while in the non-aMCI subsample, processing speed mediated the effect of executive function but not the effect of depression (p = 0.20) on function. CONCLUSIONS: The findings show that processing speed is central to the effect that depression and executive dysfunction have on functional impairment in cognitively impaired older adults. Future studies are needed to better understand the physiologic underpinnings in age-related and disease-specific decrements in processing speed, and to address the problems in the assessment of processing speed in clinical samples.

The external validity of MRI-defined vascular depression.

OBJECTIVE: Multiple diagnostic criteria have been used to define vascular depression (VD). As a result, there are discrepancies in the clinical characteristics that have been established for the illness. The aim of this study was twofold. First, we used empirically established diagnostic criteria to determine the clinical characteristics of magnetic resonance imaging (MRI)-defined VD. Second, we assessed the agreement between a quantitative and qualitative method for identifying the illness. METHOD: We examined the baseline clinical and neuropsychological profile of 38 patients from a larger, double-blind, randomized, 12-week clinical trial comparing nortriptyline with sertraline in depressed older adults. Ten patients met quantitative criteria for MRI-defined VD based on the highest quartile of deep white matter hyperintensity (DWMH) volume. Fourteen patients met qualitative criteria for MRI-defined VD based on a DWMH score of 2 or higher on the Fazekas' modified Coffey rating scale. RESULTS: Age, gender, cumulative illness rating scale-geriatric (CIRS-G) score, two measures of psychomotor retardation [the psychomotor retardation item of the Hamilton Rating Scale for Depression (HRSD) as well as performance on the Purdue Pegboard], and performance on the Stroop Color/Word test (a measure of the response inhibition component of executive functioning) were significantly different between those with VD and non-VD. CONCLUSIONS: Patients with VD have a distinct clinical and neuropsychological profile that is mostly consistent across different methods for identifying the illness. These findings support the notion that MRI-defined VD represents a unique and valid subtype of late-life depression.

Novel Diagnostic and Therapeutic Approaches to Temporomandibular Dysfunction: A Narrative Review.

Temporomandibular dysfunction (TMD) is a burgeoning area of study within the dental field. TMD is caused by abnormalities in the temporomandibular joint or muscles of mastication and can lead to pain, loss of function, and other complications. As this area of patient care receives increased focus, the ability to accurately diagnose TMD becomes paramount. The aim of this review is to summarize novel diagnostic and therapeutic techniques that have been proposed within the last approximately 3 years in order to inform readers of the cutting-edge advances in the field of TMD diagnosis and management, while also analyzing the clinical relevance of each study. A PubMed search was completed on 1 March 2023, using MeSH terms related to TMD diagnosis and treatment. The search yielded seven articles that pertained to the aim of this review article. The main findings from each study are summarized in this review article. These novel methods of diagnosing and treating TMD may improve our ability to assess and treat patients suffering from TMD.

Impact of Computerized Cognitive Training on Default Mode Network Connectivity in Subjects at Risk for Alzheimer's Disease: A 78-week Randomized Controlled Trial.

BACKGROUND: Mild cognitive impairment (MCI) represents a high risk group for Alzheimer's disease (AD). Computerized Cognitive Games Training (CCT) is an investigational strategy to improve targeted functions in MCI through the modulation of cognitive networks. OBJECTIVE: The goal of this study was to examine the effect of CCT versus a non-targeted active brain exercise on functional cognitive networks. METHODS: 107 patients with MCI were randomized to CCT or web-based crossword puzzles. Resting-state functional MRI (fMRI) was obtained at baseline and 18 months to evaluate differences in fMRI measured within- and between-network functional connectivity (FC) of the default mode network (DMN) and other large-scale brain networks: the executive control, salience, and sensorimotor networks. RESULTS: There were no differences between crosswords and games in the primary outcome, within-network DMN FC across all subjects. However, secondary analyses suggest differential effects on between-network connectivity involving the DMN and SLN, and within-network connectivity of the DMN in subjects with late MCI. Paradoxically, in both cases, there was a decrease in FC for games and an increase for the crosswords control (p < 0.05), accompanied by lesser cognitive decline in the crosswords group. CONCLUSION: Results do not support a differential impact on within-network DMN FC between games and crossword puzzle interventions. However, crossword puzzles might result in cognitively beneficial remodeling between the DMN and other networks in more severely impaired MCI subjects, parallel to the observed clinical benefits.

Change in cognitive functioning in depressed older adults following treatment with sertraline or nortriptyline.

OBJECTIVE: The aim of this study was to compare the impact of nortriptyline to sertraline on change in cognitive functioning in depressed older adults. METHODS: We used pre-post neuropsychological data collected as part of a 12-week medication trial comparing sertraline to nortriptyline in the treatment of older adults with non-psychotic, unipolar major depression to examine change in cognitive functioning. Neuropsychological assessments included mental status (Mini-Mental Status Exam), psychomotor speed (Purdue Pegboard), attention (Continuous Performance Test, Trail Making Test A), executive functioning (Stroop Color/word Test, Trail Making Test B), and memory (Buschke Selective Reminding Test). RESULTS: Within treatment groups, patients treated with sertraline improved only on verbal learning. This change did not depend on responder status. Between treatment groups, patients treated with sertraline improved more in verbal learning compared with patients treated with nortriptyline. Looking at change in cognition as a function of medication condition and responder status revealed that sertraline responders improved more in verbal learning compared with nortriptyline responders but not more than sertraline non-responders or nortriptyline non-responders. Nortriptyline responders were the only treatment by responder status group to show no improvement in verbal learning from baseline to endpoint. CONCLUSIONS: Unexpectedly, nortriptyline responders showed no improvement in verbal learning as compared with patients treated with sertraline or nortriptyline non-responders. However, given the small sample sizes and number of statistical tests (potential for type 1 error), replication is warranted.

Executive dysfunction and treatment response in late-life depression.

OBJECTIVES: Executive dysfunction in geriatric depression has been shown to predict poor response to antidepressant medication. The purpose of this review is to clarify which aspects of executive functioning predict poor antidepressant treatment response. METHODS: Literature review. RESULTS: From our review, the aspects of executive functioning that appear to be associated with antidepressant response rates are verbal fluency and response inhibition. There is some indication that the semantic strategy component may account for the effects of verbal fluency, although evidence comes from one study and needs replication. Processing speed has been proposed as a substrate that may underlie the effects of executive dysfunction on treatment response. Although processing speed does not appear to account for the relationship between response inhibition and treatment outcome, this issue has yet to be assessed with respect to verbal fluency. CONCLUSIONS: Verbal fluency and response inhibition are specific aspects of executive dysfunction that appear to impact antidepressant response rates. Disruption of the frontostriatal limbic circuit (particularly the anterior cingulate and dorsolateral prefrontal cortex) may explain the relation between these two mechanisms.