CM E

Executive Functioning in Late-Life Depression

Kevin J. Manning, PhD; George S. Alexopoulos, MD; Amanda R. McGovern, PhD;
Sarah Shizuko Morimoto,PsyD; Genevieve Yuen, MD, PhD;
Theodora Kanellopoulos, PhD; and Faith M. Gunning, PhD

Kevin J. Manning, PhD, is a Clinical Neuro-

psychology Fellow, Weill Cornell Institute of
Geriatric Psychiatry. George S. Alexopoulos,
MD, is S.P. Tobin and A.M. Cooper Professor
of Psychiatry, Weill Cornell Medical College.
Amanda R. McGovern, PhD, is a Post-Doctoral
Fellow of Psychology in Psychiatry, Weill Cor-
nell Institute of Geriatric Psychiatry. Sarah Shi-
zuko Morimoto, PsyD, is Assistant Professor of
Psychology in Psychiatry, Weill Cornell Insti-
tute of Geriatric Psychiatry. Genevieve Yuen,
MD, PhD, is a Postdoctoral Research Fellow,
Weill Cornell Institute of Geriatric Psychiatry.
Theodora Kanellopoulos, PhD, is a Research

Psychiatry Fellow, Weill Cornell Medical Col-
lege. Faith M. Gunning, PhD, is an Associate
Professor of Psychology in Psychiatry, Weill
Cornell Institute of Geriatric Psychiatry.
Address correspondence to: Faith M. Gun-
ning, PhD, 21 Bloomingdale Road, White
Plains, NY 10605; email: fgd2002@med.
cornell.org.
Disclosure: George S. Alexopoulos, MD, has
received fees for non-CME-related services
from Astra Zeneca, Novartis, and Sunovion.
The other authors have no relevant financial
relationships to disclose.
doi: 10.3928/00485713-20140306-06
ABSTRACT
Executive functions are control mech-
ical outcome. Thus, elderly depressed pa-
tients with executive functioning impair-
ment require careful treatment planning
and close follow-up. This review aims to
provide the clinician with a practical un-
derstanding of executive dysfunction in
older adults with major depression. To
this end, it provides an introduction to
the neurobiology and clinical manifesta-
tions of executive dysfunction in late-life
depression. Special attention is given to
current assessment practices that can be
used to enhance clinical evaluation and
treatment planning.
© Shutterstock
initiate, monitor, and modify behavior to
achieve their goals. Executive dysfunction
is common in late-life depression and asso-
ciated with poor course of illness. Roughly
30% to 40% of non-demented older adults
with major depression exhibit signs of
executive dysfunction.1,2 Executive dys-
function is associated with greater levels
of disability in late-life depression.3 Fur-
thermore, executive dysfunction is a pre-
dictor of poor antidepressant response,4-6
may persist following remission,7 and is
associated with an increased relapse of de-
pression.8 These observations indicate that
depressed older adults with impairment in

anisms that regulate aspects of cognition
and emotion. Impairments in executive
functioning are prominent following
disruption to frontolimbic connections
involved in mood regulation. Executive
dysfunction is common in older adults
with major depression and is associated
with poor course of illness and worse clin-
E
xecutive functioning is a broad
term used to refer to frontally me-
diated functions encompassing
control mechanisms that modulate aspects
of cognition and emotion.1 Executive func-
tions are higher-order processes that enable
individuals to seek rewards; evaluate risks;
make decisions; and successfully plan,
executive functions require careful treat-
ment planning and close follow-up. In this
review, the relevance of executive dysfunc-
tion to the care of older adults with major
depression is discussed through describing
the neurobiology and subsequent clinical
manifestations of executive dysfunction
in late-life depression. Current assessment

PSYCHIATRIC ANNALS 44:3 | MARCH 2014 Healio.com/Psychiatry | 143


practices and recommendations for clini-
cians who observe executive dysfunction
in their patients are also discussed.
FUNCTIONAL NEUROANATOMY OF
EXECUTIVE FUNCTIONS
Executive functions are instantiated in
regions of the frontal lobe, namely the dor-
solateral prefrontal cortex, anterior cingu-
late cortex, dorsomedial, and orbitofrontal
cortices and their connections with striatal,
limbic, and posterior association cortices.
Notably, major depressive disorder in the
elderly is characterized by structural and
functional abnormalities in these same re-
gions and their connections with limbic and
striatal systems. Below, a succinct review
of the functional neuroanatomy of fronto-
limbic regions related to the expression of
executive dysfunction in major depression
is provided. Disruption to brain regions
other than the frontal lobes, striatum, and
limbic system, such as the thalamus and
cerebellum, may also result in executive
dysfunction. However, detailed descrip-
tions of these fronto-striatal-thalamic and
fronto-cerebellar networks are beyond the
scope of this paper, and the interested read-
er may consult Koziol and Budding.9
Major depression is characterized by
hypometabolism of the anterior cingulate
cortex, dorsolateral prefrontal cortex, and
orbitofrontal cortex.1 The primary cogni-
tive functions of the dorsolateral prefrontal
cortex (Brodmann areas 9,10) include the
regulation of effortful attention and work-
ing memory (ie, the ability to maintain and
manipulate information for brief periods of
time). With input from the superior parietal
cortex (Brodmann area 7), the dorsolateral
cortex maintains the attentional demands
of tasks, while the dorsal anterior cingulate
(Brodmann areas 24 and 32) monitors on-
going performance.10 Together, the dorso-
lateral prefrontal cortex and dorsal regions
of the anterior cingulate and posterior as-
sociation cortices constitute the “cognitive
control network,” which is responsible for
the efficient pursuit of goal-directed behav-
ior. Clinically, disruption of the cognitive
144 | Healio.com/Psychiatry PSYCHIATRIC ANNALS 44:3 | MARCH 2014
CM E
control network results in a tendency to
attend to irrelevant information, impaired
concentration, disorganization, difficulty
shifting attention, and perseveration, or the
inability to disengage from prior behav-
ioral response.1
Ventromedial prefrontal regions, in-
cluding the orbitofrontal cortex (Brod-
mann areas 10, 11, 47), ventral-rostral
anterior cingulate (Brodmann areas 25,
24, 32, 33), and their connections with the
amygdala, mediate divergent functions
such as processing of emotional informa-
tion, utilization of cues in the environment
to predict rewarding or aversive events,
and the regulation of behavioral responses,
particularly in the context of changing re-
inforcement contingencies.11 The ventral-
rostral anterior cingulate and the dorsal an-
terior cingulate are the distribution centers
of emotional and cognitive information, re-
spectively. Another prominent function of
the ventromedial region is reward-related
decision-making, a complex task involv-
ing option generation, evaluation of risks
and consequences, and choice of a course
of action. Lesions to ventromedial regions
result in poor decision-making as well as
signs of emotional dyscontrol, such as
mood lability, irritability, and even mania.11
Disruption to the cognitive control
network is prominent in late-life depres-
sion and associated with poor course of
illness. Increasing evidence indicates that
cognitive control dysfunction underlies re-
sistance to standard antidepressant drugs.
Failure to achieve remission following
treatment with escitalopram in late-life
depression is associated with decreased
grey matter volume in the dorsal and ros-
tral anterior cingulate,12 with white matter
integrity likely contributing to the discon-
nection between these brain regions and
poor treatment response.13 Late-life de-
pression is characterized by low functional
connectivity between the anterior cingulate
cortex and the dorsolateral prefrontal cor-
tex, an abnormality found to be associated
with poor remission rate during treatment
with escitalopram.14 Notably, the cognitive
control network plays a central role in in-
hibition of irrelevant responses and imple-
mentation of effective strategies aimed to
organize behavior, which in turn has been
linked to poor treatment response to antide-
pressants in depressed elders.4,5
COGNITIVE CONTROL DYSFUNCTION
IN LATE-LIFE DEPRESSION
Investigations of executive dysfunction
in late-life depression have mostly focused
on dorsolateral and anterior cingulate cor-
tex functioning.1 The “depression-execu-
tive dysfunction syndrome” of late-life is
characterized by reduced verbal fluency,
diminished interest in activities, psycho-
motor slowing, and pronounced disabil-
ity.15 Clinically, many of these patients lack
motivation and initiative. A subsequent
investigation showed that disruption to
medial connections, notably the anterior
cingulate and nucleus accumbens, is asso-
ciated with the clinical expression of apa-
thy in late-life depression.16 Evaluations of
neuropsychological functions in late-life
depression have consistently revealed im-
pairment in working memory, verbal fluen-
cy, sustained attention, cognitive flexibility,
planning-organization, and cognitive inhi-
bition. Depressed older adults often per-
form poorly on tests of verbal fluency, the
Wisconsin Card Sorting Test (a measure of
problem solving and cognitive flexibility),
and the Stroop Color Word Interference
Test (a measure of cognitive inhibition).17
VENTROMEDIAL DYSFUNCTION IN
LATE-LIFE DEPRESSION
Classic neuropsychological tests pri-
marily assess the cognitive control net-
work and offer little information on the
ventromedial prefrontal regions. Several
case reports describe patients who, follow-
ing disruption to the orbitofrontal cortex,
exhibit disturbances in social and occupa-
tional functioning but perform adequately
in tests of verbal fluency or the Wiscon-
sin Card Sorting Test.18 The need to as-
sess ventromedial functioning led to the
development of reward-related decision-
 CM E

making paradigms, such as the Iowa Gam-

TABLE 1.
bling Task.19 When performing the Iowa,
individuals select cards, one at a time, Common Neuropsychological Tests of Executive Functions
from one of four decks. Half of the decks
are disadvantageous (ie, higher immediate Primary
Neuroanatomic
rewards but long-term negative outcomes) Test Name Test Tasks Functions Assessed Substrates
and the other half is advantageous (ie, low-
Iowa Gambling Test Select cards from decks Reward-related VMPFC;
er immediate rewards but long-term posi- classified according to decision-making. BA 10, 11, 4725
tive outcomes). reward probability.
Overall, older adults with major de- Stroop Color Word Name the ink color of Cognitive inhibition; DLPFC; ACC
pression do not differ from age-matched Test words printed in a different conflict monitoring. BA: 6, 8, 9, 3226
controls on the Iowa or other gambling color ink.
paradigms.20,21 However, older adults with Tower Test Replicate spatial puzzles Spatial planning; rule- DLPFC; ACC
major depression and clinical evidence of using as few moves as monitoring; cognitive BA 9, 10, 46, 24,
poor decision-making (as evidenced by possible. inhibition. 3227
a history of attempted suicide) perform Trail-Making Test Alternate between con- Attention-switching; DLPFC;
worse on a gambling task when compared Part B necting numbers and let- working memory; BA 6, 46, 7, 39
to older depressed adults with no history of ters in sequential order. processing speed. (28)
suicide.21 In contrast, apathetic, depressed Verbal Fluency Generation of words begin- Verbal initiation; DLPFC; ACC
elderly patients demonstrate an advanta- ning with a specific letter response monitoring; BA 9, 44, 45, 46,
geous strategy on the Iowa Gambling Task or belonging to a certain organization. 4729
(selecting cards from the conservative category.
decks) when compared to non-apathetic, Wisconsin Card- Sort stimuli into different Cognitive flexibility; DLPFC;
depressed older adults.20 Better perfor- Sorting Test categories and adapt when attention-switching; BA 9, 46, 47, 1230
the sorting rules change. problem-solving.
mance on the Iowa Gambling Task appears
counterintuitive upon first glance; however, ACC = anterior cingulate cortex; BA = Brodmann area; DLPFC = dorsolateral prefrontal cortex; VMPFC = ventromedial prefrontal cortex.
consistent with the conceptualization of
apathy as a disorder of motivation, these
patients are not influenced by immediate their psychometric properties as individual havior Scale (FrSBe),25 patients or in-
reinforcers, such as the high rewards of the screening tests have not been investigated. formants rate the presence of behavioral
disadvantageous decks. Although further The IP is a composite measure of verbal syndromes of apathy and disinhibition as
research into this behavioral phenomenon fluency, motor control, and susceptibility well as difficulties in working memory,
is necessary, our group observed that ab- to perseveration. We observed that abnor- planning, sequencing, organizing, and ab-
normal resting functional connectivity in mal IP performance is associated with stracting. Preliminary evidence suggests
networks related to decision-making (ie, disability,3 poor response to antidepres- that behavioral abnormalities identified
ventromedial circuitry) occurs in apathetic, sants,4,5 and early relapse and recurrence by the FrSBe are associated with slower
depressed elderly patients.16 of late life depression.8 The executive in- response of late-life depression to escita-
terview (EXIT) is a composite measure lopram.26 In addition to offering informa-
NEUROPSYCHOLOGICAL of tests of working memory, verbal and tion on behavioral dimensions of frontal
ASSESSMENT OF EXECUTIVE design fluency, cognitive inhibition, motor systems dysfunction, questionnaires like
FUNCTIONS IN LATE-LIFE DEPRESSION perseveration, frontal-release signs, and the FrSBe have the advantage of ease of
Screening tests of executive functions questions specifically designed to elicit administration and interpretation over tra-
can help the clinician identify whether a poor social skills.23 The EXIT is clinically ditional neuropsychological measures. For
patient has executive dysfunction and what useful in that it can be administered at bed- example, executive functioning behavioral
executive functions need further testing. side but it does not discriminate between questionnaires could be administered to
The Dementia Rating Scale22 is a global patients with late-life depression and age- elderly, depressed patients in psychiatry
test of cognitive impairment. Two of the matched healthy controls.24 waiting rooms. This information could
DRS subscales, conceptualization and ini- Questionnaires can also be used to then be used to alert clinicians in real-time
tiation/perseveration (IP), are often used to screen for behavior related to executive to the presence of behavioral abnormalities
assess for executive dysfunction, although dysfunction. On the Frontal Systems Be- related to the executive networks.

PSYCHIATRIC ANNALS 44:3 | MARCH 2014 Healio.com/Psychiatry | 145


Concern regarding cognitive dysfunc-
tion warrants a neuropsychological consul-
tation. Screening tests and questionnaires
can be useful to detect select aspects of ex-
ecutive dysfunction. However, the useful-
ness of screening measures and question-
naires is limited in the following situations:
1. The executive deficits are subtle and/
or the patient is of above average in-
telligence.
2. There is concern about a comorbid
dementia.
3. The patient and/or family member is
not a reliable informant in the case of
questionnaires.
4. More ventral frontal networks me-
diate the executive deficits. In such
cases, clinicians concerned about ex-
ecutive dysfunction in their patients
should consult with a neuropsycholo-
gist for a detailed assessment of cog-
nitive abilities.
Neuropsychological evaluation in-
cludes the comprehensive assessment of
brain behavior relationships using stan-
dardized instruments (Table 1) and may
clarify the presence, pattern, and severity
of executive dysfunction in late-life depres-
sion and distinguish it from other cognitive
dysfunctions.
CONCLUSION
Executive functioning assessment is
important in late-life depression. Execu-
tive dysfunction and its underlying neuro-
biological changes occur in 30% to 40% of
older adults with major depression. Clini-
cal manifestations of executive dysfunction
include a tendency to attend to irrelevant
stimuli, impaired concentration, disorgani-
zation, difficulty shifting attention, perse-
veration, and poor decision-making. Exec-
utive dysfunction often persists following
remission, predicts failure to remit with
standard antidepressant treatment, increas-
es the risk of depression relapse, and is as-
sociated with greater disability. Therefore,
older depressed adults with impairment in
executive functions require careful treat-
ment planning and close follow-up.
146 | Healio.com/Psychiatry PSYCHIATRIC ANNALS 44:3 | MARCH 2014
CM E
REFERENCES
1. Alexopoulos GS, Gunning-Dixon FM, Latous-
sakis V, Kanellopoulos D, Murphy CF. Anterior
cingulate dysfunction in geriatric depression. Int
J Geriatr Psychiatry. 2008;23(4):347-355.
2. Lockwood KA, Alexopoulos GS, van Gorp
WG. Executive dysfunction in geriatric depres-
sion. Am J Psychiatry. 2002;159(7):1119-1126.
3. Kiosses DN, Alexopoulos GS. IADL functions,
cognitive deficits, and severity of depression:
a preliminary study. Am J Geriatr Psychiatry.
2005;13(3):244-249.
4. Alexopoulos GS, Kiosses DN, Murphy C, Heo
M. Executive dysfunction, heart disease burden,
and remission of geriatric depression. Neuropsy-
chopharmacology. 2004;29(12):2278-2284.
5. Morimoto SS, Gunning FM, Murphy CF,
et al. Executive function and short-term re-
mission of geriatric depression: the role of
semantic strategy. Am J Geriatr Psychiatry.
2011;19(2):115-122.
6. Alexopoulos GS, Kiosses DN, Heo M, et
al. Executive dysfunction and the course
of geriatric depression. Biol Psychiatry.
2005;58(3):204-210.
7. Murphy CF, Alexopoulos GS. Longitudinal as-
sociation of initiation/perseveration and severity
of geriatric depression. Am J Geriatr Psychiatry.
2004;12(1):50-56.
8. Alexopoulos GS, Meyers BS, Young RC, et al.
Executive dysfunction and long-term outcomes
of geriatric depression. Arch Gen Psychiatry.
2000;57(3):285-290.
9. Koziol LF, Budding DE. Subcortical Struc-
tures and Cognition: Implications for Neu-
ropsychological Assessment. New York, NY:
Springer; 2009.
10. MacDonald AW 3rd, Cohen JD, Stenger
VA, Carter CS. Dissociating the role of the
dorsolateral prefrontal and anterior cingu-
late cortex in cognitive control. Science.
2000;288(5472):1835-1838.
11. Zald DH, Andreotti C. Neuropsychologi-
cal assessment of the orbital and ventrome-
dial prefrontal cortex. Neuropsychologia.
2010;48(12):3377-3391.
12. Gunning-Dixon FM, Cheng J, Murphy CF, et
al. Anterior cingulate cortical volumes and treat-
ment remission of geriatric depression. Int J
Geriatr Psychiatry. 2009;24(8):829-836.
13. Alexopoulos GS, Murphy CF, Gunning-Dixon
FM, et al. Microstructural white matter abnor-
malities and remission of geriatric depression.
Am J Psychiatry. 2008;165(2):238-244.
14. Alexopoulos GS, Hoptman MJ, Kanellopoulos
D, et al. Functional connectivity in the cogni-
tive control network and the default mode net-
work in late-life depression. J Affect Disord.
2012;139(1):56-65.
15. Alexopoulos GS, Kiosses DN, Klimstra S,
Kalayam B, Bruce ML. Clinical presentation
of the “depression-executive dysfunction syn-
drome” of late life. Am J Geriatr Psychiatry.
2002;10(1):98-106.
16. Alexopoulos GS, Hoptman MJ, Yuen G, et al.
Functional connectivity in apathy of late-life
depression: a preliminary study. J Affect Disord.
2013;149(1-3):398-405.
17. Lim J, Oh IK, Han C, et al. Sensitivity of
cognitive tests in four cognitive domains in
discriminating MDD patients from healthy
controls: a meta-analysis. Int Psychogeriatr.
2013;25(9):1543-1557.
18. Rahman S, Sahakian BJ, Hodges JR, Rogers
RD, Robbins TW. Specific cognitive deficits in
mild frontal variant frontotemporal dementia.
Brain. 1999;122(Pt 8):1469-1493.
19. Bechara A, Damasio AR, Damasio H, Anderson
SW. Insensitivity to future consequences follow-
ing damage to human prefrontal cortex. Cogni-
tion. 1994;50(1-3):7-15.
20. McGovern A, Alexopoulos GS, Yuen G, Morim-
oto SS, Gunning-Dixon FM. Reward-related
decision making in older adults: Relationship to
clinical presentation of depression. Int J Geriatr
Psychiatry. 2014;(under review).
21. Clark L, Dombrovski AY, Siegle GJ, et al. Im-
pairment in risk-sensitive decision-making in
older suicide attempters with depression. Psy-
chol Aging. 2011;26(2):321-330.
22. Jurica PJ, Leitten CL, Mattis S. Dementia Rat-
ing Scale — 2 Professional Manual. Lutz, FL:
Psychological Assessment Resources; 2001.
23. Royall DR, Mahurin RK, Gray KF. Bedside
assessment of executive cognitive impairment:
the executive interview. J Am Geriatr Soc.
1992;40(12):1221-1226.
24. Butters MA, Whyte EM, Nebes RD, et al. The
nature and determinants of neuropsychological
functioning in late-life depression. Arch Gen
Psychiatry. 2004;61(6):587-595.
25. Grace J, Malloy P. Frontal Systems Behavior
Scale (FrSBe): Professional Manual. Lutz, FL:
Psychological Assessment Resources; 2001.
26. Manning KJ, Alexopoulos GS, Banerjee
S, et al. Executive functioning complaints
and escitalopram treatment response in
late-life depression. Am J Geriatr Psychia-
try. 2014;pii:S1064-7481(13)00416-8; doi:
10.1016/j.jagp.2013.11.005. [Epub ahead of
print].
27. Elliott R, Baker SC, Rogers RD, et al. Prefron-
tal dysfunction in depressed patients perform-
ing a complex planning task: a study using
positron emission tomography. Psychol Med.
1997;(27):931-942.
28. Moll J, de Oliveira-Souza R, Moll FT, Bramati
IE, Andreiuolo PA. The cerebral correlates of
set-shifting: an fMRI study of the trail making
test. Arq Neuropsiquiatr. 2002;(60):900-905.
29. Gourovitch ML, Kirkby BS, Goldberg TE, et
al. A comparison of rCBF patterns during let-
ter and semantic fluency. Neuropsychology.
2000;14(3):353-360.
30. Monchi O, Petrides M, Petre V, Worsley K,
Dagher A. Wisconsin Card Sorting revisited:
distinct neural circuits participating in differ-
ent stages of the task identified by event-related
functional magnetic resonance imaging. J Neu-
rosci. 2001;21(19):7733-7741.
Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.