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Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ 2  = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ 2  = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI., (© 2024. The Author(s).)

Objectives: To identify data-driven cognitive profiles in older adults with remitted major depressive disorder (rMDD) with or without mild cognitive impairment (MCI) and examine how the profiles differ regarding demographic, clinical, and neuroimaging measures., Design: Secondary cross-sectional analysis using latent profile analysis., Setting: Multisite clinical trial in Toronto, Canada., Participants: One hundred seventy-eight participants who met DSM-5 criteria for rMDD without MCI (rMDD-MCI; n = 60) or with MCI (rMDD + MCI; n = 118)., Measurements: Demographic, clinical, neuroimaging measures, and domain scores from a neuropsychological battery assessing verbal memory, visuospatial memory, processing speed, working memory, language, and executive function., Results: We identified three latent profiles: Profile 1 (poor cognition; n = 75, 42.1%), Profile 2 (intermediate cognition; n = 75, 42.1%), and Profile 3 (normal cognition; n = 28, 15.7%). Compared to participants with Profile 3, those with Profile 1 or 2 were older, had lower education, experienced a greater burden of medical comorbidities, and were more likely to have MCI. The profiles did not differ on the severity of residual symptoms, age of onset of rMDD, number of depressive episodes, psychotropic medication, cerebrovascular risk, ApoE4 carrier status, or family history of depression, dementia, or Alzheimer's disease. The profiles differed in cortical thickness of 15 regions, with the most prominent effects for left precentral and pars opercularis, and right inferior parietal and supramarginal., Conclusion: Older patients with rMDD can be grouped cross-sectionally based on data-driven cognitive profiles that differ from the absence or presence of a diagnosis of MCI. Future research should determine the differential risk for dementia of these data-driven subgroups., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen's d of the difference in global cognition between the high and low TGC groups to Cohen's d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen's d values using the whole sample. As hypothesized, Cohen's d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen's d's of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline., (© 2024. The Author(s).)

Objective: The authors evaluated whether treatment of late-life depression (LLD) with antidepressants leads to changes in cognitive function., Methods: A systematic review and meta-analysis of prospective studies of antidepressant pharmacotherapy for adults age 50 or older (or mean age of 65 or older) with LLD was conducted. MEDLINE, EMBASE, and PsycInfo were searched through December 31, 2022. The primary outcome was a change on cognitive test scores from baseline to after treatment. Secondary outcomes included the effects of specific medications and the associations between changes in depressive symptoms and cognitive test scores. Participants with bipolar disorder, psychotic depression, dementia, or neurological disease were excluded. Findings from all eligible studies were synthesized at a descriptive level, and a random-effects model was used to pool the results for meta-analysis., Results: Twenty-two studies were included. Thirteen of 19 studies showed an improvement on at least one cognitive test after antidepressant pharmacotherapy, with the most robust evidence for the memory and learning (nine of 16 studies) and processing speed (seven of 10 studies) domains and for sertraline (all five studies). Improvements in depressive symptoms were associated with improvement in cognitive test scores in six of seven relevant studies. The meta-analysis (eight studies; N=493) revealed a statistically significant overall improvement in memory and learning (five studies: effect size=0.254, 95% CI=0.103-0.404, SE=0.077); no statistically significant changes were seen in other cognitive domains. The evaluated risk of publication bias was low., Conclusion: Antidepressant pharmacotherapy of LLD appears to improve certain domains of cognitive function, particularly memory and learning. This effect may be mediated by an improvement in depressive symptoms. Studies comparing individuals receiving pharmacotherapy with untreated control participants are needed., Competing Interests: Dr. Blumberger has received research support from Brain Canada, CIHR, NIH, and the Temerty Family Foundation through the CAMH Foundation and the Campbell Family Research Institute; he has received research support and in-kind equipment support and was the site principal investigator for investigator-initiated and sponsor-initiated studies for BrainsWay; he has received in-kind equipment support from MagVenture for investigator-initiated studies; he has received medication supplies for an investigator-initiated trial from Indivior; and he has served on advisory boards for Janssen and Welcony. Dr. McAndrews has received grant support from CIHR, the Ontario Brain Institute, and the Weston Brain Institute. Dr. Pollock has received research support from the Alzheimer’s Drug Discovery Foundation, the Alzheimer’s Society of Canada, Brain Canada, BrightFocus Foundation, the CAMH Foundation and Discovery Fund, the Canadian Consortium on Neurodegeneration in Aging, the Centre for Aging and Brain Health Innovation, CIHR, the Garfield Weston Foundation, Genome Canada, National Institute of Aging, the Ontario Brain Institute, the Peter and Shelagh Godsoe Endowed Chair in Late-Life Mental Health, and the Weston Brain Institute; he has received honoraria from the American Geriatrics Society for book authorship and editorial services; and he holds provisional patents in the United States (16/490,680 and 17/396,030) and Canada (3,054,093) for a cell-based assay and kits for assessing serum anticholinergic activity. Dr. Rajji has received research support from the Brain and Behavior Research Foundation, Brain Canada, BrightFocus Foundation, the Canada Foundation for Innovation, Canada Research Chair, the Centre for Aging and Brain Health Innovation, CIHR, NIH, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute; he has received in-kind equipment support for an investigator-initiated study from Newronika and in-kind research online accounts from Scientific Brain Training Pro; he has participated in advisory activities for Biogen Canada; and he is listed as an inventor on a U.S. provisional patent (17/396,030) for cell-based assays and kits to assess serum cholinergic receptor activity. Dr. Mulsant has received support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; he has received research support from Brain Canada, the CAMH Foundation, Capital Solution Design, CIHR, HAPPYneuron, NIH, and the Patient-Centered Outcomes Research Institute; and he has served as a consultant for Myriad Neuroscience. The other authors report no financial relationships with commercial interests.

Background: Almost half of older patients with major depressive disorder (MDD) present with cognitive impairment, and one-third meet diagnostic criteria for mild cognitive impairment (MCI). However, mechanisms linking MDD and MCI remain unclear. We investigated multivariate associations between brain structural alterations and cognition in 3 groups of older patients at risk for dementia, remitted MDD (rMDD), MCI, and rMDD+MCI, as well as cognitively healthy nondepressed control participants., Methods: We analyzed magnetic resonance imaging data and cognitive domain scores in participants from the PACt-MD (Prevention of Alzheimer's Disease With Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression) study. Following quality control, we measured cortical thickness and subcortical volumes of selected regions from 283 T1-weighted scans and fractional anisotropy of white matter tracts from 226 diffusion-weighted scans. We assessed brain-cognition associations using partial least squares regressions in the whole sample and in each subgroup., Results: In the entire sample, atrophy in the medial temporal lobe and subregions of the motor and prefrontal cortex was associated with deficits in verbal and visuospatial memory, language skills, and, to a lesser extent, processing speed (p < .0001; multivariate r = 0.30, 0.34, 0.26, and 0.18, respectively). Widespread reduced white matter integrity was associated with deficits in executive functioning, working memory, and processing speed (p = .008; multivariate r = 0.21, 0.26, 0.35, respectively). Overall, associations remained significant in the MCI and rMDD+MCI groups, but not the rMDD or healthy control groups., Conclusions: We confirm findings of brain-cognition associations previously reported in MCI and extend them to rMDD+MCI, but similar associations in rMDD are not supported. Early-onset and treated MDD might not contribute to structural alterations associated with cognitive impairment., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD)., Design: Cross-sectional analysis., Setting: Five academic health centers in Toronto., Participants: Older adults with MCI with/without rMDD., Measurements: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography., Results: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22)., Conclusion: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is associated with an increased risk of developing dementia. The present study aimed to better understand this risk by comparing resting state functional connectivity (rsFC) in the executive control network (ECN) and the default mode network (DMN) in older adults with MDD or mild cognitive impairment (MCI). Additionally, we examined the association between rsFC in the ECN or DMN and cognitive impairment transdiagnostically. We assessed rsFC alterations in ECN and DMN in 383 participants from five groups at-risk for dementia-remitted MDD with normal cognition (MDD-NC), non-amnestic mild cognitive impairment (naMCI), remitted MDD + naMCI, amnestic MCI (aMCI), and remitted MDD + aMCI-and from healthy controls (HC) or individuals with Alzheimer's dementia (AD). Subject-specific whole-brain functional connectivity maps were generated for each network and group differences in rsFC were calculated. We hypothesized that alteration of rsFC in the ECN and DMN would be progressively larger among our seven groups, ranked from low to high according to their risk for dementia as HC, MDD-NC, naMCI, MDD + naMCI, aMCI, MDD + aMCI, and AD. We also regressed scores of six cognitive domains (executive functioning, processing speed, language, visuospatial memory, verbal memory, and working memory) on the ECN and DMN connectivity maps. We found a significant alteration in the rsFC of the ECN, with post hoc testing showing differences between the AD group and the HC, MDD-NC, or naMCI groups, but no significant alterations in rsFC of the DMN. Alterations in rsFC of the ECN and DMN were significantly associated with several cognitive domain scores transdiagnostically. Our findings suggest that a diagnosis of remitted MDD may not confer functional brain risk for dementia. However, given the association of rs-FC with cognitive performance (i.e., transdiagnostically), rs-FC may help in stratifying this risk among people with MDD and varying degrees of cognitive impairment., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Major depressive disorder (MDD) is a risk factor for Alzheimer's disease (AD). Cerebrovascular disease (CVD) is implicated in MDD and AD. Our study compared participants with AD positive and negative cerebrospinal fluid (CSF) biomarkers on neuropsychological performance, remitted MDD status, and CVD burden. Next, we compared AD-CSF biomarkers and white matter hyperintensities (WMH) burden among three groups: mild cognitive impairment (MCI) (n = 12), MCI with remitted MDD (MDD+MCI) (n = 12), and remitted MDD alone (MDD) (n = 7). Few participants (18%) with MCI+MDD exhibited AD(+) biomarkers. Nearly all participants had moderate-severe WMH. WMH may contribute to cognitive impairment or depression in MCI patients with AD(-) biomarkers.

Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study., Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed., Setting: Community-based multi-centered study based in Toronto across 5 academic sites., Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls., Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores., Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD., Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (Copyright © 2021. Published by Elsevier Inc.)

Background: Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS)., Objective: To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261)., Methods: Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size., Results: In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males., Conclusion: Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

Objectives: Anticholinergic burden has been associated with deleterious effects on cognition particularly in those with an underlying brain disorder. We developed a new assay based on cultured cells to measure serum anticholinergic activity (cSAA). We report on its relationships with established anticholinergic burden rating scales and cognitive assessments in older patients with mild cognitive impairment (MCI) or major depressive disorder (MDD) in remission or both., Design: The study was cross sectional in nature., Setting: This was a five-centre study conducted in Toronto, Canada., Participants: Serum samples were collected and cSAA levels were measured in 311 participants aged 60 years or older (154 with MCI, 57 with MDD, and 100 with MCI + MDD)., Measurements: The cSAA assay uses radio-ligand binding to cultured cells stably expressing the muscarinic M1 receptors, with an added procedure to remove potential confounds associated with serum proteins. Lists of medications were used to calculate Anticholinergic Burden and Anticholinergic Drug Scale total scores. Participants also completed a comprehensive cognitive battery., Results: Higher cSAA levels were associated with higher anticholinergic burden and anticholinergic drug scale scores, and also with lower performance on executive function tests, after adjusting for age, gender, education, and diagnosis., Conclusions: These results support the use of the cSAA assay as a laboratory measure of anticholinergic burden., Competing Interests: CONFLICTS OF INTEREST AND SOURCES OF FUNDING W.W., and N.H. have nothing to disclose. T.K.R. has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. T.K.R. also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. R.R., B.G.P. and J.N.N. have a patent No.62/466,651 US provisional patent for a cell-based assay and kits for assessing serum anticholinergic activity, status pending. S.K. reports grants from BrightFocus Foundation, grants from Center for Aging and Brain Health Innovation, grants from Brain Canada, grants from University of Toronto, grants from Brain and Behavior Foundation, grants from National Institute of Aging, grants from Canadian Institute of Health research, non-financial support from Soterix Medical, outside the submitted work. N. A. and S.C. report grants from Health Canada and the Chagnon Family, grants from Canada Brain Research Fund, grants from CAMH Foundation during the conduct of the study. L.M. reports non-financial support from Brainsway Ltd, outside the submitted work. K.L. reports grants from Abbvie, personal fees from Abide, personal fees from BioXcel, personal fees from Cerevel, personal fees from ICG Pharma, personal fees from Kondor Pharma, other from Highmark Interactive, personal fees from Otsuka, personal fees from Exciva, outside the submitted work. C.E.F. reports grants from Vielight Inc, grants from Hoffman LaRoche, outside the submitted work. B.H.M. holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He reports grants from Brain Canada, grants from Canadian Institutes of Health Research, grants from Centre for Addiction and Mental Health (CAMH) Foundation, grants from Patient-Centred Outcomes Research Institute, grants from US National Institutes of Health, non-financial support from Eli Lilly, non-financial support from Pfizer, non-financial support from Capital Solutions Design LLC, from HAPPYneuron, c, outside the submitted work. A.J.F. reports grants from Brain Canada, during the conduct of the study; grants from National Institutes of Health, grants from Patient-Centered Outcomes Research Institute, grants from Canadian Institutes of Health Research, grants from Brain Canada, grants from Alzheimer's Association, grants from AGE-WELL, outside the submitted work. B.G.P. reports research support from the Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health, CAMH Foundation and Discovery Fund, National Institute of Aging, Brain Canada, the Canadian Institutes of Health Research, the Alzheimer's Drug Discovery Foundation, the Ontario Brain Institute, the Centre for Aging and Brain Health Innovation, the Bright Focus Foundation, the Alzheimer's Society of Canada, the W. Garfield Weston Foundation, the Weston Brain Institute, the Canadian Consortium on Neurodegeneration in Aging and Genome Canada. Honoraria from the American Geriatrics Society. This work has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family; and by CAMH Foundation. The sponsor had no role in the design of the study, collection or analysis of the data, or in writing the manuscript., (Copyright © 2021 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Hierarchical, quantitative models of psychopathology focus primarily on higher-order constructs, whereas less is known about the structure and content comprising lower-order dimensions of psychopathology. Here, we address this gap in the literature by using targeted factor analysis to integrate the 25 maladaptive facet-level traits of the Personality Inventory for Diagnostic and Statistical Manual of Mental Disorder-Fifth edition and the 10 aspect-level traits of the normal personality hierarchy within a sample of 198 psychiatric outpatients. A 10-factor solution replicated previous work, with each of the 10 aspects primarily characterizing only one factor. In addition, the 10 factors differentially predicted a range of diagnoses, including alcohol use disorder, major depression, panic disorder, social anxiety, and borderline and avoidant personality disorders. Our results suggest that research on the development, causes, and structure of lower-order traits within the normal personality hierarchy may serve as an important guide to research on the causes and structure of maladaptive personality.

Background: Cardiovascular risk factors (CVRFs) have been linked to both depression and cognitive decline but their role in neuropsychiatric symptoms (NPS) has yet to be clarified., Objective: Understanding the role of CVRFs in the etiology of NPS for prospective treatments and preventive strategies to minimize these symptoms., Methods: We examined the distribution of NPS using the Neuropsychiatric Inventory (NPI) scores in three cohorts from the Prevention of Alzheimer's Dementia with Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) study: older patients with a lifetime history of major depressive disorder (MDD) in remission, patients with mild cognitive impairment (MCI), and patients with combined MCI and MDD. We also examined the link between individual NPS and CVRFs, Framingham risk score, and Hachinski ischemic score in a combined sample., Results: Analyses were based on a sample of 140 subjects, 70 with MCI, 38 with MCI plus MDD, and 32 with MDD. There was no effect of age, gender, education, cognition, or CVRFs on the presence (NPI >1) or absence (NPI = 0) of NPS. Depression was the most prevalent affective NPS domain followed by night-time behaviors and appetite changes across all three diagnostic groups. Agitation and aggression correlated negatively while anxiety, disinhibition, night-time behaviors, and irritability correlated positively with CVRFs (all p-values <0.05). Other NPS domains showed no significant association with CVRFs., Conclusion: CVRFs are significantly associated with individual NPI sub-scores but not with total NPI scores, suggesting that different pathologies may contribute to different NPS domains.

Objective: Early and preferential targeting of limbic structures by Alzheimer disease (AD)-related pathology suggests emotion dysregulation may serve as a marker of AD risk. We studied emotional verbal memory in two groups at risk for AD, amnestic mild cognitive impairment (aMCI) and late-onset depression (LOD), to test the hypothesis that aMCI and LOD would be characterized by a negative bias in emotional memory, whereas cognitively normal (CN) adults would show the "positivity effect" associated with healthy aging., Methods: Participants completed a novel test of emotional verbal memory, the Emotional Verbal Learning Test (EVeLT), consisting of a 15-item list of words with positive, negative, or neutral valence. Recall as a function of group and valence was analyzed using mixed analysis of variance. Spearman's rho was used to examine associations between EVeLT, mood, and executive function. MCI and CN participants had no current or past history of mood or anxiety disorders. aMCI participants met neuropsychological criteria for single-domain aMCI (sd-aMCI). LOD developed their first episode of depression at ≥60 years of age., Results: CN adults recalled more positive words, whereas sd-aMCI and LOD adults recalled more negative, relative to neutral, words on the EVeLT. Positive emotional memory and negative attitudes regarding self were inversely correlated in CN adults., Conclusion: sd-aMCI and LOD groups show negative emotional memory biases, consistent with our hypothesis that emotion dysregulation is a signature of AD risk., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: We recently reported an unexpected interaction between olanzapine and sertraline in a population being treated for psychotic depression. Contrary to knowledge of cytochrome p450 interactions sertraline increased apparent clearance of olanzapine by 30%. Here we examined the pharmacokinetics of sertraline in the same population. Existing studies suggest that sertraline apparent clearance is significantly increased in male subjects and suggested an age/sex interaction., Methods: We studied subjects undergoing combination of sertraline/olanzapine treatment for psychotic depression in the Study of the Pharmacotherapy of Psychotic Depression. Nonlinear mixed effect modelling software was used to examine the sertraline pharmacokinetics, evaluating age, sex, race, and olanzapine exposure as covariates., Results: Eighty-seven subjects (median age 62 years, 28 male subjects, 11 African-Americans) provided 138 samples for sertraline concentration. Olanzapine exposure had a 14.8-fold range. A one compartment model with combined residual error described the sertraline concentration data adequately. Half-life and sex effect on sertraline apparent clearance (males averaging 50% higher (p < 0.005); 96.6 l/h vs 64.8 in female subjects) were similar to previous reports. No other covariate (age, race or olanzapine exposure) had a significant impact on apparent clearance, and no age/sex interaction emerged., Conclusion: Sertraline pharmacokinetics were similar to historical descriptions in populations not taking antipsychotics. Unlike our unexpected finding that sertraline increases olanzapine apparent clearance, olanzapine exposure had no impact on sertraline pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background and Objective: Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods., Methods: The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration., Results: Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance., Conclusions: Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

Background: It remains unclear regarding the contribution of each individual symptom in predicting the outcome in major depressive disorder (MDD). The objective of this analysis was to evaluate trajectories of individual symptoms over time to identify which specific depressive item(s) could predict subsequent clinical response., Methods: The data of 2874 outpatients with nonpsychotic MDD who received citalopram for up to 14 weeks in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were analyzed. Average trajectories of individual symptoms over time were estimated for remitters and non-remitters. Moreover, specific symptoms whose improvement at week 2 predicted remission were identified, using binary logistic regression analysis., Results: Trajectories were significantly different between remitters and non-remitters in all depressive symptoms. All depressive symptoms in the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) in the two groups, except for hypersomnia and weight change in non-remitters, substantially improved within 2 weeks and gradually continued to improve thereafter throughout the 14 weeks. Early improvements in the following five symptoms, in order of magnitude, in the QIDS-SR16 were significantly associated with remission: sad mood, negative self-view, feeling slowed down, low energy, and restlessness (P<0.001, P<0.001, P=0.001, P=0.004, P=0.021)., Limitations: The participants were limited to the nonpsychotic MDD outpatients who received citalopram. Further, symptomatology was not evaluated at the very beginning of treatment., Conclusions: While the data pertain to citalopram and replication is necessary for other antidepressants, early improvements in certain core depressive symptoms may serve as a predictor of subsequent remission., (© 2013 Elsevier B.V. All rights reserved.)

Context: Cognitive impairment in late-life depression is a core feature of the illness., Objective: To test whether donepezil hydrochloride and antidepressant therapy is superior to placebo and antidepressant therapy in improving cognitive performance and instrumental activities of daily living and in reducing recurrences of depression over 2 years of maintenance treatment., Design: Randomized, double-blind, placebo-controlled maintenance trial., Setting: University clinic., Participants: One hundred thirty older adults aged 65 years and older with recently remitted major depression., Interventions: Random assignment to maintenance antidepressant pharmacotherapy and donepezil or to maintenance antidepressant pharmacotherapy and placebo., Main Outcome Measures: Global neuropsychological performance, cognitive instrumental activities of daily living, and recurrent depression., Results: Donepezil and antidepressant therapy temporarily improved global cognition (treatment × time interaction, F₂,₂₁₆ = 3.78; P = .03), but effect sizes were small (Cohen d = 0.27, group difference at 1 year). A marginal benefit to cognitive instrumental activities of daily living was also observed (treatment × time interaction, F₂,₁₃₇ = 2.94; P = .06). The donepezil group was more likely than the placebo group to experience recurrent major depression (35% [95% confidence interval {CI}, 24%-46%] vs 19% [95% CI, 9%-29%], respectively; log-rank χ² = 3.97; P = .05; hazard ratio = 2.09 [95% CI, 1.00-4.41]). Post hoc subgroup analyses showed that of 57 participants with mild cognitive impairment, 3 of 30 participants (10% [95% CI, 0%-21%]) receiving donepezil and 9 of 27 participants (33% [95% CI, 16%-51%]) receiving placebo had a conversion to dementia over 2 years (Fisher exact test, P = .05). The mild cognitive impairment subgroup had recurrence rates of major depression of 44% with donepezil vs 12% with placebo (likelihood ratio = 4.91; P = .03). The subgroup with normal cognition (n = 73) showed no benefit with donepezil and no increase in recurrence of major depression., Conclusions: Whether a cholinesterase inhibitor should be used as augmentation in the maintenance treatment of late-life depression depends on a careful weighing of risks and benefits in those with mild cognitive impairment. In cognitively intact patients, donepezil appears to have no clear benefit for preventing progression to mild cognitive impairment or dementia or for preventing recurrence of depression., Trial Registration: clinicaltrials.gov Identifier: NCT00177671.

The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, body mass index, sex, race, and clinical site were evaluated as possible covariates. In total, 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A 1-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L, respectively. CYP2C19 genotype, weight, and age had a significant effect on CL/F, and patient body mass index affected estimated V/F. Patients from Pisa, Italy, had significantly lower clearances than patients from Pittsburgh that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Postprocessed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19(*)2 or (*)3 (n = 82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous (*)2 or (*)3 ((*)17/(*)2, (*)17/(*)3, (*)1/(*)2, (*)1/(*)3, (*)2/(*)2, (*)2/(*)3, and (*)3/(*)3, n = 46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n = 45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30 to 50 years (n = 84) and older than 50 years of age (n = 43), respectively. CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. These variables may affect patient tolerance of this antidepressant and may provide important information in the effort to tailor treatments to patients' individual needs.

Depressive symptoms, poor sleep quality, and systemic markers of inflammation (e.g., interleukin (IL)-6) are frequently associated. Interferon-alpha (IFN-alpha) therapy results in Major Depressive Disorder (MDD) in some people, offering the possibility to elucidate the relationship of MDD to sleep and inflammation during treatment. In particular, delineating the temporal relations among these factors could help inform their causal relationships. To this end, a cohort of 95 non-depressed hepatitis C patients was followed prospectively for four consecutive months during IFN-alpha therapy. We found that higher pre-treatment levels of circulating IL-6 predicted incidence of MDD (X(2)(1)=7.7; p<0.05). Time-lagged mixed-effect analyses supported uni-directional associations in which IL-6 predicted next month's PSQI scores (F(47,11.6)=78.4; p<0.0005), and PSQI scores predicted next month's depressive Beck Depression Inventory-II (BDI) scores (F(16,22.6)=3.4; p<0.005). In addition, on any given month of treatment, IL-6 levels predicted BDI symptoms the following month (F(16,97.5)=7.3; p<0.0005), and conversely BDI predicted next month's IL-6 (F(14,7.4)=5.2; p<0.05) - providing evidence for a positive feedback relationship between depressive symptoms and systemic inflammation. These data provide further evidence that high levels of inflammation and poor sleep quality may be risk factors for IFN-alpha induced depression. Furthermore, these findings highlight the complex temporal relationships that exist among sleep, depression, and inflammation, and support the need for further prospective investigations to elucidate the dynamics that underlie depression during IFN-alpha treatment.

Background: Major depressive disorder (MDD) occurs in a subset of patients receiving interferon-alpha treatment, although many are resilient to this side effect. Genetic differences in the serotonin reuptake transporter promoter (5-HTTLPR) may interact with the inflammatory system and influence depression risk., Methods: A cohort of 71 nondepressed hepatitis C patients about to receive interferon-alpha was prospectively followed, employing a diagnostic structured clinical interview (Structured Clinical Interview for DSM-IV Axis I Disorders [SCID-I]) and self-report questionnaires. Patients were genotyped for the 5-HTTLPR (L(G), L(A), and S) and the variable number of tandem repeats (VNTR) polymorphism in the second intron. Kaplan-Meier analyses were used to compare major depression incidence. Genotype effects on sleep quality (Pittsburgh Sleep Quality Index) and Beck Depression Inventory (BDI) were assessed using mixed-effect repeated-measure analyses., Results: The L(A) allele was associated with a decreased rate of developing MDD (Mantel-Cox log rank test p < .05) with the L(A)/L(A) genotype being the most resilient. This genotype was also associated with better sleep quality [F(61.2,2) = 3.3, p < .05]. The ability of baseline sleep quality to predict depression incidence disappeared when also including genotype in the model. Conversely, the relationship of neuroticism with depression incidence (B = .07, SE = .02, p < .005) was not mitigated when including genotype., Conclusions: Using a prospective design, 5-HTTLPR is associated with MDD incidence during interferon-alpha treatment. Preliminary evidence that this effect could be mediated by effects on sleep quality was observed. These findings provide support for a possible interaction between inflammatory cytokine (interferon-alpha) exposure and 5-HTTLPR variability in MDD.

Objective: To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression., Method: This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks., Results: Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks., Conclusions: In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk., Trial Registration: clinicaltrials.gov Identifier: NCT00177671., (Copyright 2009 Physicians Postgraduate Press, Inc.)

The objective of this study was to compare population pharmacokinetic models of escitalopram developed from dosage times recorded by a medication event monitoring system (MEMS) versus the reported times from patients with diagnosed depression. Seventy-three patients were prescribed doses of 10, 15, or 20 mg escitalopram daily. Sparse blood samples were collected at weeks 4, 12, 24, and 36 with 185 blood samples obtained from the 73 patients. NONMEM was used to develop a population pharmacokinetic model based on dosing records obtained from MEMS prior to each blood sample time. A separate population pharmacokinetic analysis using NONMEM was performed for the same population using the patient-reported last dosing time and assuming a steady-state condition as the model input. Objective function values and goodness-of-fit plots were used as model selection criteria. The absolute mean difference in the last dosing time between MEMS and patient-reported times was 4.48 +/- 10.12 hours. A 1-compartment model with first-order absorption and elimination was sufficient for describing the data. Estimated oral clearance (CL/F) to escitalopram was statistically insensitive to reported dosing methods (MEMS vs patient reported: 25.5 [7.0%] vs 26.9 [6.6%] L/h). However, different dosing report methods resulted in significantly different estimates on the volume of distribution (V/F; MEMS vs patient reported: 1000 [17.3%] vs 767 [17.5%] L) and the absorption rate constant K(a) (MEMS vs patient reported: 0.74 [45.7%] vs 0.51 [35.4%] h(-1)) for escitalopram. Furthermore, the parameters estimated from the MEMS method were similar to literature reported values for V/F ( approximately 1100 L) and K(a) ( approximately 0.8-0.9 h(-1)) arising from traditional pharmacokinetic approaches.

A randomized, placebo-controlled study was performed to evaluate whether the onset of the glucose metabolic effects of a selective serotonin reuptake inhibitor (paroxetine) would be accelerated by total sleep deprivation (TSD). Patients were randomly assigned to one of three groups: TSD and paroxetine treatment, TSD and 2 weeks of placebo followed by paroxetine treatment, or 2 weeks of paroxetine treatment. Sixteen elderly depressed patients who met DSM-IV criteria for major depressive disorder and nine age-matched comparison subjects underwent positron emission tomography (PET) studies of cerebral glucose metabolism at baseline, post-TSD (or a normal night's sleep for the paroxetine- only group), post-recovery sleep and 2 weeks post-paroxetine or placebo treatment (patients only). TSD was not consistently associated with a decrease in depressive symptoms between groups nor with decreases in cerebral metabolism in cortical regions that have been associated with rapid and sustained clinical improvement (e.g. anterior cingulate gyrus). The observation of a synergistic antidepressant effect of combined TSD and paroxetine treatment that was observed in a previous "open label" pilot study was not observed in the present randomized study, consistent with lack of a cerebral metabolic effect in brains regions previously shown to be associated with improvement of depressive symptoms.

Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine. Desvenlafaxine succinate is now undergoing active evaluation for its therapeutic efficacy in a variety of disorders, including major depressive disorder, vasomotor symptoms associated with menopause, fibromyalgia and diabetic neuropathy. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with similar activity to its parent compound venlafaxine, and little affinity for other brain targets, including muscarinic, cholinergic, histamine H(1) and alpha-adrenergic receptors. Desvenlafaxine has linear pharmacokinetics, low protein binding, a half-life of approximately 10 hours and is metabolized primarily via glucuronidation, and to a minor extent through CYP3A4. The desvenlafaxine succinate formulation appears to have good oral bioavailability. Clearance rates are reduced in the elderly, those with severe renal dysfunction and those with moderate to severe hepatic dysfunction, which may require dosage adjustments. Three published clinical trials have shown supportive but mixed results for the efficacy of desvenlafaxine in the treatment of major depressive disorder with daily doses ranging from 100 mg to 400 mg. One published clinical trial has shown mixed results for the efficacy of desvenlafaxine in the treatment of vasomotor symptoms associated with menopause with daily doses ranging from 50 mg to 200 mg. In these four clinical trials, desvenlafaxine was associated with several mild adverse effects, with the most common effect being nausea. Less common, but more serious, adverse effects reported in these trials included hypertension, QTc interval prolongation, exacerbation of ischemic cardiac disease, elevated lipids and elevated liver enzymes. The exact nature of these serious adverse effects, including the prevalence, clinical significance and potential risk factors, still needs to be fully elucidated. Desvenlafaxine has a low propensity for pharmacokinetic-based drug interactions, although it has the same potential for pharmacodynamic interactions as other serotonin-norepinephrine reuptake inhibitors. Desvenlafaxine is currently another treatment option for major depressive disorder. The only identified potential advantage of desvenlafaxine over venlafaxine or other antidepressant agents at this time is the apparently reduced risk for pharmacokinetic drug interactions., (Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.)

Objective: Several predictors of treatment response in late-life depression have been reported in the literature. The aim of this analysis was to develop a clinically useful algorithm that would allow clinicians to predict which patients will likely respond to treatment and thereby guide clinical decision making., Method: A total of 461 patients with late-life depression were treated under structured conditions for up to 12 weeks and assessed weekly with the 17-item Hamilton Rating Scale for Depression (HAM-D-17). The authors developed a hierarchy of predictors of treatment response using signal-detection theory. The authors developed two models, one minimizing false predictions of future response and one minimizing false predictions of future nonresponse, to offer clinicians two clinically useful treatment algorithms., Results: In the first model, early symptom improvement (defined by the relative change in HAM-D-17 total score from baseline to week 4), lower baseline anxiety, and an older age of onset predict response at 12 weeks. In the second model, early symptom improvement represents the principal guide in tailoring treatment, followed by baseline anxiety level, baseline sleep disturbance, and--for a minority of patients--the adequacy of previous antidepressant treatment., Conclusions: Our two models, developed to help clinicians in different clinical circumstances, illustrate the possibility of tailoring the treatment of late-life depression based on clinical characteristics and confirm the importance of early observed changes in clinical status.

Objective: To investigate whether variable antidepressant response may be influenced by an interaction between the serotonin transporter promoter polymorphism (5-HTTLPR) and antidepressant concentration., Methods: Elderly subjects with depression treated with paroxetine (n = 110) were genotyped and assessed with the Hamilton Rating Scale for Depression (HAMD). A mixed-effect analysis of repeated measures was used., Results: There was an interaction between early paroxetine concentration and 5-HTTLPR genotype on symptomatic improvement over 12 weeks (F(18,59.5) = 1.8, p < 0.05), as well as main effects of both paroxetine concentration (F(68,55.3) = 2.4, p < 0.005) and genotype (F(2,74.2) = 5.7, p < 0.005). Paroxetine concentrations were correlated with change in HAMD scores after 2 weeks of treatment in subjects with the short (s) allele (r = 0.31, p < 0.05) but not in subjects homozygous for the long (l) allele., Conclusion: The results demonstrate a concentration-response relation for paroxetine in late-life depression and support the hypothesis for both a direct main effect and a moderating influence of 5-HTTLPR alleles on this concentration-response relation.

Objective: Interferon-alpha2 (IFN-alpha) injections may be capable of triggering depression in some individuals. The first objective was to further characterize this depression and, secondly, to examine whether pre-treatment temperament was correlated with subsequent vulnerability to IFN-alpha., Methods: Twenty-three initially euthymic adults undergoing year-long PEG-IFN-alpha treatment for hepatitis C were evaluated at baseline and then prospectively monitored using both the Structured Clinical Interview for DSM-IV (SCID) and self-report questionnaires., Results: A major depressive episode developed within 3 months in 39%. Principal component analysis of the change in self-report scores after 1 month of treatment demonstrated three orthogonal factors: (i) a specific increase in depression as manifested in the Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS), (ii) an increase in hostility and anxiety, (iii) and a generalized combination of worse symptoms including somatic symptoms on the Symptom Check List (SCL-90). BDI at 1 month was predicted by baseline BDI (r=0.76, P=.004). Hostility at 1 month was predicted by low baseline agreeableness (r=0.75, P=.01). Controlling for baseline BDI scores, categorical major depression was predicted by combined high baseline neuroticism and low agreeableness (combined r=0.66, P=.03)., Conclusion: These initial results (i) support the depressogenic nature of IFN-alpha treatment in a subset of vulnerable individuals, (ii) indicate that some individuals are also independently vulnerable to worsened hostility, and (iii) suggest that it may be possible to clinically predict these vulnerabilities in initially euthymic subjects.

Objective: Few data are available concerning the utility of augmentation in late-life depression treatment. The authors examined likelihood, speed, and predictors of recovery in older adults receiving augmentation pharmacotherapy after inadequate response to standardized treatment with paroxetine plus interpersonal psychotherapy., Method: Depression levels were monitored during open treatment in 195 adults age 70 or older. Patients were grouped by whether they required augmentation (bupropion, nortriptyline, or lithium) and compared on likelihood, time, and predictors of recovery., Results: Augmentation was required for 105 patients (53.8%) because of inadequate treatment response (N=77) or response followed by relapse (N=28). Of these patients, 69 received augmentation and 36 did not (primarily because of consent withdrawal or comorbid medical conditions). Patients receiving augmentation showed lower recovery rates than patients never requiring augmentation: recovery occurred in 50.0% of patients receiving it because of inadequate response, 66.7% of those receiving it after early relapse, and 86.7% of patients never requiring augmentation. Patients receiving augmentation because of inadequate response recovered more slowly, with modestly more side effects than other patients. Greater medical burden and anxiety predicted slower recovery., Conclusions: Despite a lower likelihood of recovery in elderly people receiving augmentation, the recovery by over one-half of such patients suggests the value of augmentation for those able to tolerate it. Need for augmentation presages slower recovery in patients showing initial inadequate response; those requiring it after early relapse recovered more quickly. Strategies to further improve the likelihood and speed of recovery after initial treatment failure are needed.

Background: Comorbid anxiety is common in depressive disorders in both middle and late life, and it affects response to antidepressant treatment., Aims: To examine whether anxiety symptoms predict acute and maintenance (2 years) treatment response in late-life depression., Method: Data were drawn from a randomised double-blind study of pharmacotherapy and interpersonal psychotherapy for patients age 70 years and over with major depression. Anxiety symptoms were measured using the Brief Symptom Inventory. Survival analysis tested the effect of pre-treatment anxiety on response and recurrence., Results: Patients with greater pretreatment anxiety took longer to respond to treatment and had higher rates of recurrence. Actuarial recurrence rates were 29% (pharmacotherapy, lower anxiety), 58% (pharmacotherapy, higher anxiety), 54% (placebo, lower anxiety) and 81% (placebo, higher anxiety)., Conclusions: Improved identification and management of anxiety in late-life depression are needed to achieve response and stabilise recovery.

Background: Potential cardiovascular side effects from venlafaxine-XR must be considered when prescribing this medication, especially in geriatric patients, who often present with comorbid medical conditions., Methods: Participants age 60 and older with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of a major depressive episode without psychotic features were treated openly with venlafaxine-XR for 12 weeks during which venlafaxine-XR was titrated based on tolerability and response according to predefined guidelines. Sitting and standing blood pressures and heart rates were measured. A 12-lead electrocardiogram was obtained at baseline and at week 12., Results: Sixty-two participants started treatment; 59 completed at least two weeks of the 12-week study. The mean final dose of venlafaxine-XR was 195.5 mg/day (standard deviation: 72.2). Twenty-four percent (95% confidence interval [CI]: 7.3%-40.7%) of initially normotensive participants and 54% (95% CI: 34.3%-74%) of those with preexisting hypertension experienced an increase in blood pressure. Twenty-nine percent (95% CI: 14.6%-43.4%) of participants developed orthostatic hypotension. Two participants experienced a clinically significant increase in QTc interval. One participant reported new-onset mild dizziness, whereas four participants reported new-onset tachycardia or palpitation. Overall, 17 unique participants (28.8%; 95% CI: 17.3%-40.4%) experienced a new-onset cardiovascular problem, potentially related to the study medication., Conclusion: Overall, venlafaxine-XR was well tolerated. However, similar to previous reports, venlafaxine-XR was associated with some undesirable cardiovascular effects in some of the participants. Systematic monitoring of cardiovascular parameters during treatment with venlafaxine-XR should be strongly recommended, especially in the elderly.

Introduction: The elderly are at increased risk for medication-related adverse events. Recent reports indicate that venlafaxine may put the elderly at increased risk of cardio- and cerebrovascular adverse events. We investigated the relationship between the CYP2D6 polymorphism and steady-state plasma concentration of venlafaxine (VEN) and its primary metabolite o-desmethylvenlafaxine (ODV) in elderly participants receiving venlafaxine-XR for major depression in order to explore the contribution of pharmacogenetics to medication tolerability., Methods: Forty-six elderly participants received venlafaxine-XR for the treatment of major depression. CYP2D6 genotype and steady-state plasma levels of VEN and ODV were determined., Results: Sixty-five percent of participants were homozygous of the wild type (WT) allele, whereas 35% carried one or more variant alleles associated with intermediate and poor 2D6 metabolizer status. VEN concentration per unit dose was significantly higher and ODV concentration per unit dose was significantly lower in participants who carried one or more variant alleles compared to participants who were homozygous for the WT allele. The VEN and ODV concentrations per unit dose were also correlated with creatinine clearance. CYP2D6 genotype was not associated with medication associated side-effects., Conclusions: Plasma dose-corrected concentrations of VEN and ODV correlated with genetically determined CYP2D6 enzymatic activity in depressed elders treated with venlafaxine-XR. This relationship was not masked by the effects of age-related illness or polypharmacy. Future clinical application of pharmacogenetics to examine 2D6-dependent medications may help reduce the incidence of medication adverse events particularly in those elders at higher risk for medication adverse events due to impaired renal or cardiac function.

Background: Elderly patients with major depression, including those having a first episode, are at high risk for recurrence of depression, disability, and death., Methods: We tested the efficacy of maintenance paroxetine and monthly interpersonal psychotherapy in patients 70 years of age or older who had depression (55 percent of whom were having a first episode) in a 2-by-2, randomized, double-blind, placebo-controlled trial. Among patients with a response to treatment with paroxetine and psychotherapy, 116 were randomly assigned to one of four maintenance-treatment programs (either paroxetine or placebo combined with either monthly psychotherapy or clinical-management sessions) for two years or until the recurrence of major depression. Clinical-management sessions, conducted by the same nurses, social workers, and psychologists who provided psychotherapy, involved discussion of symptoms., Results: Major depression recurred within two years in 35 percent of the patients receiving paroxetine and psychotherapy, 37 percent of those receiving paroxetine and clinical-management sessions, 68 percent of those receiving placebo and psychotherapy, and 58 percent of those receiving placebo and clinical-management sessions (P=0.02). After adjustment for the effect of psychotherapy, the relative risk of recurrence among those receiving placebo was 2.4 times (95 percent confidence interval, 1.4 to 4.2) that among those receiving paroxetine. The number of patients needed to be treated with paroxetine to prevent one recurrence was 4 (95 percent confidence interval, 2.3 to 10.9). Patients with fewer and less severe coexisting medical conditions (such as hypertension or cardiac disease) received greater benefit from paroxetine (P=0.03 for the interaction between treatment with paroxetine and baseline severity of medical illness)., Conclusions: Patients 70 years of age or older with major depression who had a response to initial treatment with paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine. Monthly maintenance psychotherapy did not prevent recurrent depression. (ClinicalTrials.gov number, NCT00178100.)., (Copyright 2006 Massachusetts Medical Society.)

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

The authors examined the effect of psychosocial and clinical variables on treatment response trajectory in elderly patients with major depressive disorder. Three studies provided data on treatment response in 360 elderly depressed subjects who participated in protocols using either nortriptyline or paroxetine as monotherapy or, in 2 studies, combined with interpersonal psychotherapy. Treatment response was assessed with the Hamilton Rating Scale for Depression-17 Item (HRSD-17) score over 12 weeks of acute treatment in each study. The mixture-modeling method of trajectory analysis was used to identify different subpopulations of response, and to determine whether baseline HRSD-17 score, depressive illness course (single or recurrent), current episode duration, Interpersonal Self Evaluation List-Self-esteem factor, age at study entry, and medical burden were risk factor covariates associated with response trajectory. As a contrast, logistic regression was used to assess the association between the same covariates and the probability of response (defined as HRSD-17 < or =10 and 50% reduction from baseline). In each study, there were 2 response trajectories with similar course, but with different speed. We classified the trajectories as "rapid response" and "slower response." Baseline HRSD-17 score was a significant predictor of response trajectory, with higher initial score related to slower response trajectory. Higher self-esteem was associated with more rapid response trajectory. In the logistic regression analysis, in two of the studies, higher baseline HRSD-17 score was a significant risk factor for nonresponse. In the study without psychotherapy, higher self-esteem was associated with responding to treatment. Thus, trajectory analysis can identify different trajectories of responders and determine psychosocial and clinical variables associated with response trajectory in the acute treatment of geriatric depression. Further study focusing on risk factors associated with slower response may help optimize treatment in elderly patients who do not respond quickly to first-line therapies.

Objective: To explore clinical and treatment-response variability in late-onset vs early-onset non-bipolar, non-psychotic major depression., Methods: We grouped patients from a late-life depression treatment study according to illness-course characteristics: those with early-onset, recurrent depression (n = 59), late-onset, recurrent depression (n = 27), and late-onset, single-episode depression (n = 95). Early-onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late-onset was defined as having a first episode of major depression at age 60 or later. We characterized the three groups of patients with respect to baseline demographic, neuropsychological, and clinical characteristics, use of augmentation pharmacotherapy to achieve response, and treatment outcomes., Results: Rates of response, remission, relapse, and termination were similar in all three groups; however, patients with late-onset, recurrent major depression took longer to respond to treatment than those with late-onset, single-episode depression (12 weeks vs 8 weeks) and had more cognitive and functional impairment. Additionally, patients with recurrent depression (whether early or late) were more likely to require pharmacotherapy augmentation to achieve response than patients with a single lifetime episode., Conclusion: Late-onset, recurrent depression takes longer to respond to treatment than late-onset single-episode depression and is more strongly associated with cognitive and functional impairment. Further study of biological, neuropsychologic, and psychosocial correlates of late-onset, recurrent depression is needed., (Copyright 2005 John Wiley & Sons, Ltd.)

Objective: Authors tested the hypothesis that one night of total sleep deprivation (TSD) would accelerate antidepressant response to paroxetine, as compared with TSD+placebo (PBO) and paroxetine-alone, in late-life major depression., Methods: Eighty elderly outpatients with current episodes of non-psychotic, non-bipolar major depression were randomly assigned to one of three treatment conditions: TSD+paroxetine (N = 27), TSD + PBO (N = 27), and paroxetine-only (N = 26). Primary outcome was percentage of subjects in each condition who demonstrated early response (Hamilton Rating Scale for Depression scores [Ham-D: 17-item] of < or = 10) or remission (score of < or = 7) on Day 14., Results: Response rates after 14 days were 22% in subjects randomly assigned to the TSD + paroxetine condition, 41% in TSD + PBO, and 46% in paroxetine alone. Remission rates after 14 days were 11% in TSD+paroxetine, 22% in TSD + PBO, and 38% in paroxetine. After adjusting for baseline depression severity, there were no statistically significant differences in response or remission rates., Conclusion: Contrary to the study hypothesis, one night of total sleep deprivation did not accelerate onset of antidepressant response to paroxetine pharmacotherapy of late-life depression. The data suggest, rather, that the two interventions might have counteracted each other.

Objective: The authors examined the serotonin transporter gene-linked polymorphic region (5-HTTLPR) as a predictor of major depressive disorder and depressive symptoms after hip fracture, a common stressful medical event., Methods: This was a prospective, observational study of 23 elderly rehabilitation-hospital patients during their inpatient stay. Depressive symptoms were assessed by Hamilton Rating Scale for Depression (Ham-D) and PRIME-MD. Subjects were also genotyped for 5-HTTLPR., Results: Survival analysis showed that genotype significantly predicted time-to-major depressive episode. Subjects with an s allele (genotype s/l or s/s) had significantly higher Ham-D scores over 14 weeks of follow-up than those with the l/l genotype., Conclusion: Depressive symptoms and major depressive disorder in elderly persons after a stressful medical event may be associated with 5-HTTLPR genotype. This finding requires confirmation in a larger sample.

The selection of a method for estimating treatment effects in an intent-to-treat analysis from clinical trial data with missing values often depends on the field of practice. The last observation carried forward (LOCF) analysis assumes that the responses do not change after dropout. Such an assumption is often unrealistic. Analysis with completers only requires that missing values occur completely at random (MCAR). Ignorable maximum likelihood (IML) and multiple imputation (MI) methods require that data are missing at random (MAR). We applied these four methods to a randomized clinical trial comparing anti-depressant effects in an elderly depressed group of patients using a mixed model to describe the course of the treatment effects. Results from an explanatory approach showed a significant difference between the treatments using LOCF and IML methods. Statistical tests indicate violation of the MCAR assumption favoring the flexible IML and MI methods. IML and MI methods were repeated under the pragmatic approach, using data collected after termination of protocol treatment and compared with previously reported results using piecewise splines and rescue (treatment adjustment) pragmatic analysis. No significant treatment differences were found. We conclude that attention to the missing-data mechanism should be an integral part in analysis of clinical trial data.

Late life major depression (LLMD) is frequently associated with cognitive impairment, and increases the risk for subsequent dementia. Cerebrovascular disease, Alzheimer's disease (AD), and dementia with Lewy bodies (DLB) have all been hypothesized to contribute to this increased risk, though prospective studies have yet to examine these hypotheses with autopsy confirmation of the clinical diagnoses. The aim of this study is to examine the rates of cerebrovascular, AD, and DLB pathology among the first 10 participants in an LLMD brain tissue donation program. Subjects' psychiatric diagnoses and cognitive status were prospectively determined during their participation in clinical research protocols of the Intervention Research Center for Late Life Mood Disorders. After death, final clinical diagnoses were made using all clinical information, while blind to neuropathologic diagnoses. Neuropathologic assessments were conducted blind to final clinical diagnoses. Rates of neuropathology were compared with those in a cohort of subjects with dementia, without a history of LLMD, participating in an Alzheimer Disease Research Center. Seven (70%) subjects had evidence of onset of a dementia prior to death. LLMD with dementia was significantly associated with a neuropathologic diagnosis of AD. Cerebrovascular disease and DLB pathology were also frequent in the LLMD subjects with dementia, and were found in an LLMD subject without dementia. Rates of AD, DLB, and cerebrovascular disease were similar to those in the comparison subjects. These preliminary findings suggest that AD is the predominant neuropathologic condition in LLMD subjects with dementia. Further assessment of the role of comorbid cerebrovascular disease and comorbid DLB is needed.

Objective: The authors tested the hypothesis that impaired executive functioning leads to high rates of relapse and recurrence in late-life depression., Methods: They analyzed data from subjects participating in two independent intervention trials. Study I included 53 elderly depressed patients who participated in an open trial comparing the efficacy of paroxetine and nortriptyline and recurrence prevention over 18 months. Study II focused on 146 elderly depressed patients who received open treatment with paroxetine in a relapse-prevention study over 4 months of continuation treatment. They examined the effect of cognitive functioning, in general, and executive functioning, in particular, on time-to-relapse/recurrence, using baseline and post-treatment measures of neuropsychological functioning., Results: The associations between cognitive measures and both probability of, and time-to-relapse/recurrence were small and statistically nonsignificant., Conclusion: Data failed to support the hypothesis that cognitive impairment, in general, or executive dysfunction, in particular, predicts relapse or recurrence of major depression in late life. Authors recommend future testing of the hypothesis with detailed, comprehensive measures over longer periods of observation during maintenance trials.

Context: Cognitive impairment in late-life depression (LLD) is highly prevalent, disabling, poorly understood, and likely related to long-term outcome., Objectives: To determine the characteristics and determinants of neuropsychological functioning LLD., Design: Cross-sectional study of groups of LLD patients and control subjects., Setting: Outpatient, university-based depression research clinic., Participants: One hundred patients without dementia 60 years and older who met DSM-IV criteria for current episode of unipolar major depression (nonpsychotic) and 40 nondepressed, age- and education-equated control subjects., Main Outcome Measures: A comprehensive neuropsychological battery., Results: Relative to control subjects, LLD patients performed poorer in all cognitive domains. More than half exhibited significant impairment (performance below the 10th percentile of the control group). Information processing speed and visuospatial and executive abilities were the most broadly and frequently impaired. The neuropsychological impairments were mediated almost entirely by slowed information processing (beta =.45-.80). Education (beta =.32) and ventricular atrophy (beta =.28) made additional modest contributions to variance in measures of language ability. Medical and vascular disease burden, apolipoprotein E genotype, and serum anticholinergicity did not contribute to variance in any cognitive domain., Conclusions: Late-life depression is characterized by slowed information processing, which affects all realms of cognition. This supports the concept that frontostriatal dysfunction plays a key role in LLD. The putative role of some risk factors was validated (eg, advanced age, low education, depression severity), whereas others were not (eg, medical burden, age at onset of first depressive episode). Further studies of neuropsychological functioning in remitted LLD patients are needed to parse episode-related and persistent factors and to relate them to underlying neural dysfunction.

Serum alphal-acid glycoprotein (AAG) concentrations were examined in relationship to age, medical burden, depression, and mental status in elderly control (n = 19, mean age = 72.1 +/- 6.8 years) and depressed (n = 58, mean age = 71.9 +/- 7.1 years) subjects. DNA was analyzed for allelic variants of the AGP1 (ORM1) gene in both groups. Depressed subjects' AAG serum levels were measured at baseline and after 6 weeks of antidepressant treatment. Before treatment, depressed subjects had significantly higher serum AAG concentrations than nondepressed controls (t49.2 = -3.48, P = .0011). Pretreatment AAG levels also correlated with degree of medical burden, measured by the Cumulative Illness Rating Scale-Geriatrics (r = 0.28, P = .0303), but not with age, depression severity, or cognitive scores. There was no significant difference between responders and nonresponders on changes in AAG levels from baseline to week 6. Frequency differences in ORM1 allelic variants apparently did not influence increased AAG concentrations in depressed patients.

This study investigated the development of hyponatremia and its underlying mechanism in elderly patients prescribed paroxetine. Patients were 15 men and women (mean age, 75.7 +/- 5.3 years) who were participants in a treatment study of late-life depression and who were without medical illness or other medications known to cause hyponatremia or alter antidiuretic hormone (ADH) secretion. Blood samples for measurement of plasma sodium, ADH, blood urea nitrogen (BUN), creatinine, glucose, and osmolality were determined prior to initiation of paroxetine (week 0) and at 2, 4, 6, and 12 weeks of treatment with paroxetine. Hyponatremia (serum sodium < 135 mEq/L) was identified in 6 of 15 patients after 2 weeks of treatment with paroxetine. Despite low plasma osmolality, ADH levels were not suppressed appropriately. Data suggest hyponatremia is a common adverse event in elderly patients prescribed paroxetine and implicates inappropriate secretion of ADH as the potential mechanism.

Apathy and executive cognitive dysfunction (ECD) are important though conceptually different aspects of late-life depression. The primary objective of this study was to evaluate the relationship of apathy to ECD. The authors also evaluated the relationship of apathy and ECD to global cognitive impairment and word generation. Fifty-two elderly subjects with major depression and MMSE scores of 15 or greater were evaluated with apathy-related items from the Hamilton rating scale for depression (ApHRSD), the Executive Interview (EXIT), the Dementia Rating Scale (DRS), and the Controlled Oral Word Association test (COWA). ApHRSD scores were not significantly correlated with any of these variables. EXIT scores were correlated significantly with DRS and COWA. The results suggest that apathy and ECD may be independent of each other in some samples of elderly with late-life depression. Correlations may have been reduced by low variance for the variables of interest and by psychometric limitations of the ApHRSD.