Cited by 317Treatment of Major DepressionNeural and Behavioral Psychology StudiesAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

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Executive Dysfunction and the Course of Geriatric Depression

Alexopoulos, George S., Kiosses, Dimitris N., Heo, Moonseong, Murphy, Christopher F., Shanmugham, Bindu, Gunning-Dixon, Faith·2005·Biological Psychiatry

DOI 10.1016/j.biopsych.2005.04.024

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Abstract

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

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Treatment Course With Antidepressant Therapy in Late-Life Depression
Sheline, Y. I., Disabato, B. M., Hranilovich, J., Morris, C., D’Angelo, G., Pieper, C., Toffanin, T., Taylor, W. D., MacFall, J. R., Wilkins, C., et al. (2012) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2012.12010122 · Cited by 86
“hyperintensities (7, 8, 21, 34) and neuropsychological deficits (21, 35) contribute to depression outcome in latelife depression adds to our understanding of the pathophysiology of the disorder.”
Problem solving therapy for the depression‐executive dysfunction syndrome of late life
Alexopoulos, G. S., Raue, P. J., Kanellopoulos, D., Mackin, S. R., & Areán, P. A. (2008) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.1988 · Cited by 87
“Specifically, impairment in some executive functions predict poor or slow response to antidepressant treatment (Leuchter et al., 1994; Hickie et al., 1995; Simpson et al., 1998; Kalayam and Alexopoulos, 1999; Potter et al., 2004; Alexopoulos et al., 2005) as well as early relapse and recurrence of geriatric depression…”
Background
Depressive symptoms and cognitive decline: A longitudinal analysis of potentially modifiable risk factors in community dwelling older adults
Gallagher, D., Kiss, A., Lanctôt, K. L., & Herrmann, N. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.09.046 · Cited by 88
“Executive dysfunction and functional decline have been associated with persistent depression and reduced response to treatment thereby perpetuating the toxic and self-reinforcing interplay between depression and cognitive decline (Alexopoulos et al., 2005; Gallagher et al., 2013).”
Background
Neuropsychological characteristics as predictors of SSRI treatment response in depressed subjects
Gorlyn, M., Keilp, J. G., Grunebaum, M. F., Taylor, B. P., Oquendo, M. A., Bruder, G. E., Stewart, J. W., Zalsman, G., & Mann, J. J. (2008) · Journal of Neural Transmission · doi:10.1007/s00702-008-0084-x · Cited by 84
“…equivocal (Dunkin et al. 2000; Taylor et al. 2006) and group differences were not detected in the current sample, but nonresponder deficits in other tests typically considered measures of executive functions have been reported (Alexopoulos et al. 2005; Kampf-Sherf et al. 2004; Marcos et al. 2005).”
BackgroundInfluential
Clinical Presentation and Outcome of Geriatric Depression in Subcortical Ischemic Vascular Disease
Bella, R., Pennisi, G., Cantone, M., Palermo, F., Pennisi, M., Lanza, G., Zappia, M., & Paolucci, S. (2010) · Gerontology · doi:10.1159/000272003 · Cited by 78
Late-Life Depression, Cognitive Impairment, and Relationship with Alzheimer’s Disease
Invernizzi, S., Loureiro, I. S., Arachchige, K. K., & Lefèbvre, L. (2021) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000519453 · Cited by 89
Moderators of Outcome in Late-Life Depression: A Patient-Level Meta-Analysis
Nelson, J. C., Delucchi, K. L., & Schneider, L. S. (2013) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2012.12070927 · Cited by 80
Explicit and Implicit Memory in Late-Life Depression
Elderkin‐Thompson, V., Moody, T. D., Knowlton, B. J., Hellemann, G., & Kumar, A. A. (2010) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181e89a5b · Cited by 82
Problem-Solving Therapy
Beaudreau, S. A., Gould, C. E., Sakai, E. Y., & Huh, J. W. T. (2017) · Springer eBooks · doi:10.1007/978-981-287-082-7_90 · Cited by 80
Impact of Delirium on Cognition, Distress, and Health-Related Quality of Life After Hematopoietic Stem-Cell Transplantation
Fann, J. R., Alfano, C. M., Roth‐Roemer, S., Katon, W. J., & Syrjala, K. L. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.07.9079 · Cited by 76
Cognitive Deficits in Geriatric Depression
Morimoto, S. S., & Alexopoulos, G. S. (2013) · Psychiatric Clinics of North America · doi:10.1016/j.psc.2013.08.002 · Cited by 85
“These studies indicate that abnormal performance on some tests of executive function predicts both poor and unstable antidepressant response (12, 16, 19, 20), as well as current and future disability (21, 22) although some disagreement exists (23).”
Background
Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder
Herrera-Guzmán, I., Gudayol-Ferré, E., Lira-Mandujano, J., Herrera-Abarca, J., Herrera-Guzmán, D., Montoya-Pérez, K., & Guardia-Olmos, J. (2008) · Psychiatry Research · doi:10.1016/j.psychres.2007.04.012 · Cited by 78
“Other authors found that abnormal scores in the initiation/perseveration subscale of the Mattis Dementia Rating Scale and low performance in the Stroop test predicted a poor response of geriatric depression to citalopram (Alexopoulos et al., 2005).”
Background
Antidepressant Medication and Executive Dysfunction: A Deleterious Interaction in Late-Life Depression
Sneed, J. R., Culang‐Reinlieb, M. E., Keilp, J. G., Rutherford, B. R., Devanand, D. P., & Roose, S. P. (2010) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181c796d2 · Cited by 75
“without deficits in Stroop performance.(2) Sneed et al.”
fMRI Activation During Executive Function Predicts Response to Cognitive Behavioral Therapy in Older, Depressed Adults
Thompson, D. G., Kesler, S. R., Sudheimer, K., Mehta, K. M., Thompson, L. W., Marquett, R. M., Holland, J. M., Reiser, R., Rasgon, N., Schatzberg, A., et al. (2015) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2014.02.001 · Cited by 74
“Several studies have implicated executive dysfunction in LLD, and several fMRI studies have demonstrated that prefrontal regions subserve executive dysfunction (19).”
Background
Executive dysfunction and treatment response in late‐life depression
Pimontel, M. A., Culang‐Reinlieb, M. E., Morimoto, S. S., & Sneed, J. R. (2011) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.2808 · Cited by 76
“REVIEW ARTICLE A number of studies have shown that executive dysfunction in late-life depression predicts poor response to antidepressant medication (Lockwood et al., 2002; Alexopoulos et al., 2005; Sneed et al., 2007).”
BackgroundMethodInfluential
Anterior cingulate dysfunction in geriatric depression
Alexopoulos, G. S., Gunning‐Dixon, F. M., Latoussakis, V., Kanellopoulos, D., & Murphy, C. F. (2007) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.1939 · Cited by 72
“The biological contributors to geriatric depression remain unclear, although several brain abnormalities have been identified (Alexopoulos, 2005; Alexopoulos et al., 2005b).”
BackgroundMethod
Mild cognitive impairment: searching for the prodrome of Alzheimer's disease
Rosenberg, P. B., & Lyketsos, C. G. (2008) · World Psychiatry · doi:10.1002/j.2051-5545.2008.tb00159.x · Cited by 75
“Other studies of late-life depression have noted a particular association with executive dysfunction (41).”
Background
Impact of Delirium on Distress, Health-Related Quality of Life, and Cognition 6 Months and 1 Year after Hematopoietic Cell Transplant
Basinski, J. R., Alfano, C. M., Katon, W. J., Syrjala, K. L., & Fann, J. R. (2010) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2010.01.003 · Cited by 70
“Our results are consistent with a growing body of evidence associating depressive and cognitive symptoms, potentially through the link between executive dysfunction [37] and decreased prefrontal lobe perfusion [38].”
Result
Personality and Suicidal Behavior in Old Age: A Systematic Literature Review
Szücs, A., Szántó, K., Aubry, J., & Dombrovski, A. Y. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00128 · Cited by 75
“This construct has already been linked to late-onset, treatment-resistant depression (129, 130) as well as to suicidal behavior (131).”
Background
Diminished performance on neuropsychological testing in late life depression is correlated with microstructural white matter abnormalities
Mettenburg, J., Benzinger, T. L. S., Shimony, J. S., Snyder, A. Z., & Sheline, Y. I. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.02.044 · Cited by 67
“In addition, given the large body of work addressing cognitive function in late life depression (Alexopoulos et al., 2005; Boone, 1995; Butters et al., 2004; Hart and Kwentus, 1987; Kramer-Ginsberg et al., 1999; Sheline et al., 2006; 2010), we hypothesized that structural abnormalities identified…”
Cognitive Impairment in Depressed Older Adults: Implications for Prognosis and Treatment
Morimoto, S. S., Kanellopoulos, T., & Alexopoulos, G. S. (2014) · Psychiatric Annals · doi:10.3928/00485713-20140306-05 · Cited by 66
Self-citation
Trajectories of major depression in middle‐aged and older adults: A population‐based study
Xiang, X., & Cheng, J. (2019) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.5161 · Cited by 65
“Cognitive dysfunction, particularly executive dysfunction, is common in geriatric depression and increases the risk for poor response to antidepressants.(48) However, findings on the association between cognitive impairment and the clinical course of depression have been divergent in both clinical‐ and population‐base…”
Result
Neurocognitive performance and repeated-dose intravenous ketamine in major depressive disorder
Zheng, W., Zhou, Y.-L., Liu, W.-J., Wang, C.-Y., Zhan, Y.-N., Li, H.-Q., Chen, L.-J., Li, M.-D., & Ning, Y.-P. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2018.12.005 · Cited by 64
Cognitive Improvement Following Treatment in Late-Life Depression: Relationship to Vascular Risk and Age of Onset
Barch, D. M., D'Angelo, G., Pieper, C., Wilkins, C. H., Welsh-Bohmer, K., Taylor, W., Garcia, K. S., Gersing, K., Doraiswamy, P. M., & Sheline, Y. I. (2012) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e318246b6cb · Cited by 64
Cognitive errors, symptom severity, and response to cognitive behavior therapy in older adults with generalized anxiety disorder
Caudle, D. D., Senior, A. C., Wetherell, J. L., Rhoades, H. M., Beck, J. G., Kunik, M. E., Snow, A. L., Wilson, N. L., & Stanley, M. A. (2007) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e31803c550d · Cited by 62
A 35-Year Longitudinal Assessment of Cognition and Midlife Depression Symptoms: The Vietnam Era Twin Study of Aging
Franz, C. E., Lyons, M. J., O'Brien, R., Panizzon, M. S., Kim, K., Bhat, R., Grant, M. D., Toomey, R., Eisen, S., Xian, H., et al. (2011) · The American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181ef79f1 · Cited by 62
“Sorting out the interrelationships among cognitive performance and depressive symptoms is particularly important given the long term implications for functional status and independence in later life (6,16-20).”
Background
Cognitive Behavioral Therapies in older adults with depression and cognitive deficits: a systematic review
Simon, S. S., Córdas, T. A., & Bottino, C. M. C. (2014) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4239 · Cited by 65
“In comparison to depressed elders without cognitive deficits, these patients tend to present more apathy and psychomotor sluggishness, but fewer feelings of guilt and insight (Alexopoulos et al., 2002; Alexopoulos et al., 2005).”
Background
Effects of Transcranial Magnetic Stimulation on the Cognitive Control of Emotion
Lantrip, C., Gunning, F. M., Flashman, L. A., Roth, R. M., & Holtzheimer, P. E. (2017) · Journal of Ect · doi:10.1097/yct.0000000000000386 · Cited by 67
“For example, poor cognitive inhibition contributes to poor emotion regulation and may sustain TRD and persistence of depressive episodes.(22,29,39,40) Emotion dysregulation has been implicated in the maintenance of depression,(41) and improving cognitive control over the generation and persistence of emotional respons…”
Background
Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression
Kaneriya, S. H., Robbins-Welty, G. A., Smagula, S. F., Karp, J. F., Butters, M. A., Lenze, E. J., Mulsant, B. H., Blumberger, D. M., Anderson, S., Dew, M. A., et al. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2015.3447 · Cited by 61
Crosstalk between Existential Phenomenological Psychotherapy and Neurological Sciences in Mood and Anxiety Disorders
Balogh, L., Tanaka, M., Török, N., Vécsei, L., & Taguchi, S. (2021) · Biomedicines · doi:10.3390/biomedicines9040340 · Cited by 57
“Elevated connectivity was found between the insula and DMN in patients with LLD [96].”
BackgroundInfluential
Depression among Centenarians and the Oldest Old: Contributions of Cognition and Personality
Margrett, J., Martin, P., Woodard, J. L., Miller, L. S., MacDonald, M., Baenziger, J., Siegler, I. C., Davey, A., & Poon, L. (2010) · Gerontology · doi:10.1159/000272018 · Cited by 57
Executive Function and Short-Term Remission of Geriatric Depression: The Role of Semantic Strategy
Morimoto, S. S., Gunning, F. M., Murphy, C. F., Kanellopoulos, D., Kelly, R. E., & Alexopoulos, G. S. (2010) · American Journal of Geriatric Psychiatry · doi:10.1097/jgp.0b013e3181e751c4 · Cited by 57
What predicts persistent depression in older adults across Europe? Utility of clinical and neuropsychological predictors from the SHARE study
Gallagher, D., Savva, G. M., Kenny, R. A., & LAWLOR, B. A. (2012) · Journal of Affective Disorders · doi:10.1016/j.jad.2012.10.037 · Cited by 57
“Previous studies have reported an independent association between alternate tests of executive function, processing speed and persistence of depression (Alexopoulos et al., 2005; Sanders et al., 2011).”
Background
Disruption of Neural Homeostasis as a Model of Relapse and Recurrence in Late-Life Depression
Andreescu, C., Ajilore, O., Aizenstein, H. J., Albert, K. M., Butters, M. A., Landman, B. A., Karim, H. T., Krafty, R. T., & Taylor, W. D. (2019) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2019.07.016 · Cited by 57
Impaired Cerebral Haemodynamics in Vascular Depression: Insights From Transcranial Doppler Ultrasonography
Puglisi, V., Bramanti, A., Lanza, G., Cantone, M., Vinciguerra, L., Pennisi, M., Bonanno, L., Pennisi, G., & Bella, R. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00316 · Cited by 56
“As known, elderly with geriatric depression are at higher risk of dementia (5, 46) and WMLs and executive dysfunction are both linked to poor response to treatment and the occurrence of chronic depression (47, 48).”
Background
Distinct functional networks associated with improvement of affective symptoms and cognitive function during citalopram treatment in geriatric depression
Diaconescu, A. O., Kramer, E., Hermann, C., Ma, Y., Dhawan, V., Chaly, T., Eidelberg, D., McIntosh, A. R., & Smith, G. S. (2011) · Human Brain Mapping · doi:10.1002/hbm.21135 · Cited by 54
“In some studies, deficits on such tests persist after remission of depression symptoms [Alexopoulos et al., 2005; Bhalla et al., 2006; Lockwood et al., 2000; Nebes et al., 2000].”
Background
Depressive Symptoms, Cognition, and Everyday Function Among Community-Residing Older Adults
Brewster, G. S., Peterson, L. J., Roker, R., Ellis, M. L., & Edwards, J. D. (2016) · Journal of Aging and Health · doi:10.1177/0898264316635587 · Cited by 56
“It is important to understand more about the EF and SOP domains in the context of depressive symptoms, and to try to disentangle which impairment is most prominent because if the impairment is one of EF, it may influence how well a patient responds to a particular treatment (Alexopoulos et al., 2005).”
Background
Predictors of serious suicidal behavior in late-life depression
Szántó, K., Galfalvy, H., Kenneally, L. B., Almasi, R. C., & Dombrovski, A. Y. (2020) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2020.06.005 · Cited by 56
“Executive dysfunction may increase the frequency of suicidal ideation and interfere with treatment progress, as it is associated with greater levels of disability (Alexopoulos et al., 2004) and poorer illness outcomes in late-life depression (Alexopoulos et al., 2005, 2004, 2000).”
Background
Intrinsic inter-network brain dysfunction correlates with symptom dimensions in late-life depression
Li, W., Wang, Y., Ward, B. D., Antuono, P., Li, S., & Goveas, J. S. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.12.011 · Cited by 58
“…that poor treatment outcomes in the depressed elderly are associated with greater symptom severity and cognitive impairment, specifically persistent executive function and episodic memory impairments (Alexopoulos et al., 2005; Andreescu et al., 2007; Gildengers et al., 2005; Sheline et al., 2010a).”
Background
Targeting Cognitive Control Deficits With Neuroplasticity-Based Computerized Cognitive Remediation in Patients With Geriatric Major Depression: A Randomized, Double-Blind, Controlled Trial
Morimoto, S. S., Altizer, R., Gunning, F. M., Hu, W., Liu, J., Cote, S. E., Nitis, J., & Alexopoulos, G. S. (2020) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2020.05.023 · Cited by 51

Authors: Alexopoulos, G. S., Kiosses, D. N., Heo, M., Murphy, C. F., Shanmugham, B., & Gunning-Dixon, F.
Affiliations: Cornell University (US)
Corresponding author: Alexopoulos, George S.
ORCID: Alexopoulos, George S.
Kiosses, Dimitris N.
Heo, Moonseong
Murphy, Christopher F.
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2005-08
Volume: 58
Issue: 3
Pages: 204-210
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2005.04.024
OpenAlex: W2030120831
Cited by: 317
References: 57
Citations by year: 2026: 9 · 2025: 9 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 12 · 2020: 15 · 2019: 10 · 2018: 21 · 2017: 18 · 2016: 13 · 2015: 21 · 2014: 15 · 2013: 24 · 2012: 25
FWCI: 9.20
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (P30MH068638, R01-MH51842, R01MH042819, R01MH065653)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords: executive dysfunction, geriatric depression, citalopram, treatment response prediction, Stroop task, Mattis Dementia Rating Scale, medical burden, selective serotonin reuptake inhibitors, cognitive impairment
MeSH terms: Aged, Aged, 80 and over, Antidepressive Agents, Demography, Depression, Female, Humans, Learning Disabilities, Male, Neuropsychological Tests, Predictive Value of Tests, Problem Solving, Psychiatric Status Rating Scales, Time Factors, Citalopram, Geriatric Assessment, Multivariate Analysis

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Executive Dysfunction and the Course of Geriatric Depression

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